Therapeutic Study Research Articles

Abstract LB281: A preclinical therapeutic study of minibody 177Lu-DOTAGA-IAB56 targeting αVβ6 for the treatment of pancreatic cancer

Abstract Pancreatic cancer represents 3% of all cancers and 7% of all cancer deaths in the USA, with a majority of cases diagnosed late and with limited treatment efficacy. Radiopharmaceutical Therapy (RPT) using antibodies (Abs) is emerging as a new approach for the treatment of solid cancers. Due to the long circulation time in blood, full-length antibodies bear concerns for hematological exposure to radioactivity. Antibody fragments with lower molecular weight like minibodies (Mb, 80 kDa) show rapid blood clearance, thus reducing off-target exposure, while maintaining the high target affinity typical of immunoglobulins. Mbs consist of two scFv antigen-binding domains fused to the CH3 domain of human IgG. Integrin αVβ6 is mainly absent in healthy adult tissues but upregulated in a variety of carcinomas, including pancreatic cancer. In this preclinical proof of concept study, we evaluated a Mb targeting human αVβ6 (IAB56) as an RPT agent for the treatment of pancreatic cancer. To this end we first evaluated the β-emitter Mb 177Lu-DOTAGA-IAB56 in a dosimetry study in mice and extrapolated the organ exposures to humans. Then we tested its therapeutic efficacy in female Nu/J mice bearing the subcutaneous ductal adenocarcinoma xenograft CFPAC-1. The IAB56 Mb was conjugated with DOTAGA and radiolabeled with 177Lu. Doses of 1.48 MBq/animal were administered intravenously (iv) in non-tumor bearing mice and biodistributions collected at 0.5, 3, 6, 24, 48, 120 and 192 hours postinjection (p.i.) to quantify time course uptake at major organs. Dosimetry data extrapolated from these biodistributions showed that exposure in humans at clearance organs (kidneys and liver), had an average dose of 3.1 and 5.0 Gy which is 8 times and 6 times below the published dosimetry thresholds of 23 Gy and 32 Gy respectively. Bone marrow and the lungs, two additional radiation sensitive sites, show doses of 0.04 and 0.4 Gy, 50.0 times and 67.5 times below the tox thresholds (2 Gy for bone marrow and 27 Gy for the lungs). The spleen had an average dose of 2.2 Gy, which is 18.2 times below the threshold of 40 Gy. Preclinical RPT studies were conducted in CFPAC-1 xenografts. A pancreatic carcinoma cell-line reported to have intermediate-to-low expression level of human αVβ6 (4-fold lower than BxPC3 pancreatic adenocarcinoma). When the tumor size reached 100-150 mm3 mice were randomized into three groups: vehicle, single dose of 18.5 MBq, or two doses 11.1 MBq and 8.1 MBq 7 days apart of 177Lu radiolabeled DOTAGA-IAB56. A rapid tumor growth inhibition response for up to 36 days was observed in both RPT groups which evoked a significant improvement in survival compared to control. Overall, our data indicate the anti-αvβ6 Mb, IAB56 is efficacious for the treatment of pancreatic cancer supporting the use of this agent as a RPT approach for solid tumors. Citation Format: Leticia M. De Souza Cordeiro, Kelley C. Atkinson, Fang Jia, Argin Aivazian, Gareth E. Smith, Ian Wilson, Alessandro Mascioni. A preclinical therapeutic study of minibody 177Lu-DOTAGA-IAB56 targeting αVβ6 for the treatment of pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB281.

Use of paralytic agents during the operative treatment of type III supracondylar humerus fractures in children: A single-center investigation and survey of Pediatric Orthopaedic Society of North America members

BackgroundParalytic agents are occasionally used during the surgical treatment of type III (OTA 13A2) supracondylar humerus fractures (SCHFx) in children depending on surgeon preference. Paralytic agents create a neuromuscular blockade and therefore may potentially help with ease of fracture reduction. Controversy regarding the use of a paralytic agent as an adjunct to anesthesia exists due to potential associated adverse drug reactions, including prolonged paralysis, cardiovascular effects, or electrolyte abnormalities.The purpose of this study was to investigate intraoperative paralytic use in pediatric type III SCHFx and to report survey responses of members of the Pediatric Orthopaedic Society of North America (POSNA) on paralytic use in SCHFx management. MethodsA retrospective chart review identified 319 type III SCHFx treated at our institution (January 2016-May 2019). Patients were assigned to three groups: Group 1, surgical treatment without a paralytic agent (n=240); Group 2, treatment with rocuronium (n=43); Group 3, treatment with succinylcholine (n=36). POSNA members were surveyed regarding paralytic use intraoperatively for type III SCHFx (November–December 2021) on paralytic use frequency, request for paralytics, reversal agent use, average time to surgery after injury and/or presentation, effect of time to surgery after injury and/or presentation on when to use a paralytic, annual number of SCHFx surgeries performed, awareness of paralytic complications, and years of surgeon experience. Statistical analysis was performed. ResultsAverage patient age was 5.2±2.2 years. Group 2 had significant increases in anesthesia duration, surgical duration, fluoroscopic time, and radiation exposure compared to Group 1. Group 2 had a higher conversion rate to open reduction than other groups. No statistically significant difference was found among groups in terms of sex, body mass index (BMI), laterality, radiographic measurements, or rates of open procedures or complications. Survey results indicated 32% (24/76) routinely use paralytics during closed reduction maneuvers; 71% (17/24) request administering paralytics at the beginning/before the case; and 33% (8/24) use paralytics in all type III SCHFx. ConclusionsSurgeons at our center reported paralytic use for closed reduction in 25% of patients; similarly, one-third of POSNA survey respondents reported paralytic use during operative management. Although paralytic agents are used during the treatment of supracondylar humerus fractures in children this study was unable to demonstrate an association of advantageous outcomes, such as shorter surgical times. Routine paralytic use to facilitate closed reduction of supracondylar humerus fractures in children warrants further study. Level of EvidenceLevel III, Retrospective chart review; Therapeutic study

Therapeutic effects of tetrandrine in inflammatory diseases: a comprehensive review.

Inflammation can be triggered by any factor. The primary pathological manifestations can be summarized as the deterioration, exudation, and proliferation of local tissues, which can cause systemic damage in severe cases. Inflammatory lesions are primarily localized but may interact with body systems to cause provocative storms, parenchymal organ lesions, vascular and central nervous system necrosis, and other pathologic responses. Tetrandrine (TET) is a bisbenzylquinoline alkaloid extracted from the traditional Chinese herbal medicine Stephania tetrandra, which has been shown to have significant efficacy in inflammatory conditions such as rheumatoid arthritis, hepatitis, nephritis, etc., through NF-κB, MAPK, ERK, and STAT3 signaling pathways. TET can regulate the body's imbalanced metabolic pathways, reverse the inflammatory process, reduce other pathological damage caused by inflammation, and prevent the vicious cycle. More importantly, TET does not disrupt body's normal immune function while clearing the body's inflammatory state. Therefore, it is necessary to pay attention to its dosage and duration during treatment to avoid unexpected side effects caused by a long half-life. In summary, TET has a promising future in treating inflammatory diseases. The author reviews current therapeutic studies of TET in inflammatory conditions to provide some ideas for subsequent anti-inflammatory studies of TET.

Is a Rapid Recovery Protocol for THA and TKA Associated With Decreased 90-day Complications, Opioid Use, and Readmissions in a Health Safety-net Hospital?

Patients treated at a health safety-net hospital have increased medical complexity and social determinants of health that are associated with an increasing risk of complications after TKA and THA. Fast-track rapid recovery protocols (RRPs) are associated with reduced complications and length of stay in the general population; however, whether that is the case among patients who are socioeconomically disadvantaged in health safety-net hospitals remains poorly defined. When an RRP protocol is implemented in a health safety-net hospital after TKA and THA: (1) Was there an associated change in complications, specifically infection, symptomatic deep venous thromboembolism (DVT), symptomatic pulmonary embolism (PE), myocardial infarction (MI), and mortality? (2) Was there an associated difference in inpatient opioid consumption? (3) Was there an associated difference in length of stay and 90-day readmission rate? (4) Was there an associated difference in discharge disposition? An observational study with a historical control group was conducted in an urban, academic, tertiary-care health safety-net hospital. Between May 2022 and April 2023, an RRP consistent with current guidelines was implemented for patients undergoing TKA or THA for arthritis. We considered all patients aged 18 to 90 years presenting for primary TKA and THA as eligible. Based on these criteria, 562 patients with TKAs or THAs were eligible. Of these 33% (183) were excluded because they were lost before 90 days of follow-up and had incomplete datasets, leaving 67% (379) for evaluation. Patients in the historical control group (September 2014 to May 2022) met the same criteria, and 2897 were eligible. Of these, 31% (904) were excluded because they were lost before 90 days of follow-up and had incomplete datasets, leaving 69% (1993) for evaluation. The mean age in the historical control group was 61 ± 10 years and 63 ± 10 years in the RRP group. Both groups were 36% (725 of 1993 and 137 of 379) men. In the historical control group, 39% (770 of 1993) of patients were Black and 33% (658 of 1993) were White, compared with 38% (142 of 379) and 32% (121 of 379) in the RRP group, respectively. English was the most-spoken primary language, by 69% (1370 of 1993) and 68% (256 of 379) of the historical and RRP groups, respectively. A total of 65% (245 of 379) of patients in the RRP group had a peripheral nerve block compared with 54% (1070 of 1993) in the historical control group, and 39% (147 of 379) of them received spinal anesthesia, compared with 31% (615 of 1993) in the historical control group. The main elements of the RRP were standardization of preoperative visits, nutritional management, neuraxial anesthesia, accelerated physical therapy, and pain management. The primary outcomes were the proportions of patients with 90-day complications and opioid consumption. The secondary outcomes were length of stay, 90-day readmission, and discharge disposition. A multivariate analysis adjusting for age, BMI, gender, race, American Society of Anaesthesiologists class, and anesthesia type was performed by a staff biostatistician using R statistical programming. After controlling for the confounding variables as noted, patients in the RRP group had fewer complications after TKA than those in the historical control group (odds ratio 2.0 [95% confidence interval 1.3 to 3.3]; p = 0.005), and there was a trend toward fewer complications in THA (OR 1.8 [95% CI 1.0 to 3.5]; p = 0.06), decreased opioid consumption during admission (517 versus 676 morphine milligram equivalents; p = 0.004), decreased 90-day readmission (TKA: OR 1.9 [95% CI 1.3 to 2.9]; p = 0.002; THA: OR 2.0 [95% CI 1.6 to 3.8]; p = 0.03), and increased proportions of discharge to home (TKA: OR 2.4 [95% CI 1.6 to 3.6]; p = 0.01; THA: OR 2.5 [95% CI 1.5 to 4.6]; p = 0.002). Patients in the RRP group had no difference in the mean length of stay (TKA: 3.2 ± 2.6 days versus 3.1 ± 2.0 days; p = 0.64; THA: 3.2 ± 2.6 days versus 2.8 ± 1.9 days; p = 0.33). Surgeons should consider developing an RRP in health safety-net hospitals. Such protocols emphasize preparing patients for surgery and supporting them through the acute recovery phase. There are possible benefits of neuraxial and nonopioid perioperative anesthesia, with emphasis on early mobility, which should be further characterized in comparative studies. Continued analysis of opioid use trends after discharge would be a future area of interest. Analysis of RRPs with expanded inclusion criteria should be undertaken to better understand the role of these protocols in patients who undergo revision TKA and THA. Level III, therapeutic study.

Health Disparities in Patients With Musculoskeletal Injuries: Food Insecurity Is a Common and Clinically Challenging Problem.

Health disparities have important effects on orthopaedic patient populations. Socioeconomic factors and poor nutrition have been shown to be associated with an increased risk of complications such as infection in patients undergoing orthopaedic surgery. Currently, there are limited published data on how food insecurity is associated with medical and surgical complications. We sought to (1) determine the percentage of patients who experience food insecurity in an orthopaedic trauma clinic at a large Level 1 trauma center, (2) identify demographic and clinical factors associated with food insecurity, and (3) identify whether there are differences in the risk of complications and reoperations between patients who experience food insecurity and patients who are food-secure. This was a cross-sectional study using food insecurity screening surveys, which were obtained at an orthopaedic trauma clinic at our Level 1 trauma center. All patients 18 years and older who were seen for an initial evaluation or follow-up for fracture care between November 2022 and February 2023 were considered for inclusion in this study. For inclusion in this study, the patient had to have surgical treatment of their fracture and have completed at least one food insecurity screening survey. Ninety-eight percent (121 of 123) of patients completed the screening survey during the study period. Data for 21 patients were excluded because of nonoperative treatment of their fracture, nonfracture-related care, impending metastatic fracture care, and patients who had treatment at an outside facility and were transferring their care. This led to a study group of 100 patients with orthopaedic trauma. The mean age was 51 years, and 51% (51 of 100) were men. The mean length of follow-up available for patients in the study was 13 months from the initial clinic visit. Patient demographics, hospital admission data, and outcome data were collected from the electronic medical records. Patients were divided into two cohorts: food-secure versus food-insecure. Patients were propensity score matched for adjusted analysis. A total of 37% of the patients in this study (37 of 100) screened positive for food insecurity during the study period. Patients with food insecurity were more likely to have a higher BMI than patients with food security (32 kg/m 2 compared with 28 kg/m 2 ; p = 0.009), and they were more likely not to have healthcare insurance or to have Medicaid (62% [23 of 37] compared with 30% [19 of 63]; p = 0.003). After propensity matching for age, gender, ethnicity, current substance use, Charleston comorbidity index, employment status, open fracture, and length of stay, food insecurity was associated with a higher percentage of superficial infections (13% [4 of 31] compared with 0% [0 of 31]; p = 0.047). There were no differences between the groups in the risk of reoperation, deep infection, and nonunion. Food insecurity is common among patients who have experienced orthopaedic trauma, and patients who have it may be at increased risk of superficial infections after surgery. Future research in this area should focus on defining these health disparities further and interventions that could address them. Level III, therapeutic study.

Does Periacetabular Osteotomy Change Sagittal Spinopelvic Alignment?

There are few data on the impact of periacetabular osteotomy (PAO) on sagittal spinopelvic alignment. Prior studies have attempted to delineate the relationship by performing measurements on AP radiographs and using mathematical models to determine changes in postoperative pelvic tilt. This information is clinically significant to a surgeon when evaluating acetabular/pelvic position intraoperatively and understanding spinopelvic alignment changes postoperatively; therefore, radiographic changes from PAO should be described in more detail. In this study, we asked: (1) Does the performance of PAO result in consistent changes in spinopelvic alignment, as measured on EOS radiographs? (2) Does this differ for unilateral versus bilateral PAOs? (3) Does this differ in the setting of a mobile spine versus an immobile spine? (4) Does this differ based on preoperative pelvic tilt? Mean preoperative and at least 1-year postoperative (15 ± 8 months from surgery, minimum 11 months, maximum 65 months) EOS hip-to-ankle standing and sitting radiographs for 55 patients in a prospectively collected registry who underwent PAO with a single surgeon from January 1, 2019, to January 11, 2022, were measured for pelvic incidence, pelvic tilt, sacral slope, lumbar lordosis, lateral center-edge angle, L1 pelvic angle, and pubic symphysis to the sacroiliac index. Normality was assessed and paired sample t-tests (normally distributed data) or Wilcoxon signed rank tests (not normally distributed data) were utilized to assess if any measurements changed from preoperative to postoperative. Patients were then divided based on whether they had unilateral or bilateral dysplasia and unilateral or bilateral surgery, and these subgroups were analyzed the same way as the entire cohort. Two more subgroups were then formed based on lumbar mobility, defined as a change in sitting-to-standing lumbar lordosis less or greater than 1 SD from the population mean preoperatively, and the subgroups were analyzed the same way as the entire cohort. Finally, two additional subgroups were formed, preoperative standing pelvic tilt less than 10° and more than 20°, and analyzed the same as the entire cohort. For the entire cohort, the median (IQR) standing lateral-center edge angle increased 17°, from a median of 21° (10°) to a median of 38° (8° [95% confidence interval (CI) 16° to 20°; p < 0.001). The median sitting lateral center-edge angle increased 17°, from a median of 18° (8°) to a median of 35° (8° [95% CI 14° to 19°]; p < 0.001). Standing pelvic incidence increased from 50° ± 11° to 52° ± 12° (mean difference 2° [95% CI 1° to 3°]; p = 0.004), but there were no changes for other measured parameters. There were no changes in any of the spinopelvic parameters for patients with unilateral dysplasia receiving a unilateral PAO, but patients with bilateral dysplasia who underwent bilateral PAOs demonstrated an increase in pelvic incidence from 57° (14°) to 60° (16°) (95% CI 1° to 5°; p = 0.02) and a decrease in pubic symphysis to sacroiliac index from 84 mm (24 mm) to 77 mm (23 mm) (95% CI -7° to -2°; p = 0.007). Patients with mobile lumbar spines preoperatively did not exhibit any changes in sagittal spinopelvic alignment, but patients with immobile lumbar spines preoperatively experienced several changes after surgery. Patients with less than 10° of standing pelvic tilt demonstrated a median (IQR) 2° increase in pelvic incidence from median 43° (9°) to 45° (12° [95% CI 0.3° to 4°]; p = 0.03), but they did not experience any other changes in sagittal spinopelvic alignment parameters postoperatively. Patients with preoperative pelvic tilt more than 20° did not experience any change in sagittal spinopelvic parameters. PAO increases pelvic incidence, potentially because of anterior translation of the hip center. There were no changes in other spinopelvic parameters postoperatively except after bilateral PAO. Additionally, patients lacking spine mobility preoperatively, indicated by a minimal change in lumbar lordosis between standing and sitting positions, may experience several changes in spinopelvic alignment, including increased mobility of their spine after PAO. This may be because of decreased compensatory spine splinting after increasing acetabular coverage, but further research including patient-reported outcomes is warranted. Level III, therapeutic study.

Bacterial fluorescence imaging as a predictor of skin graft integration in burn wounds

BackgroundSplit-thickness skin graft (STSG)11STSG: Split-thickness skin grafts integration rates are susceptible to improvement. Infection and/or biofilm should be appropriately addressed prior to grafting to improve the likelihood of graft-take. Incorporating technological aids such as fluorescence (FL)22FL: Fluorescence imaging (MolecuLight®), which accurately locates areas of bacterial loads above 104 CFU/gr, for graft site assessment and preparation could yield better outcomes. MethodsThis single-center, prospective observational study included adult burn patients with previously infected wounds that had been deemed clinically and microbiologically clean and were therefore candidates for grafting. Prior to grafting, a FL imaging assessment (blinded to the surgical team) localized areas positive for moderate-high bacterial loads (>104 CFU/gr). Intra-operatively, a standard swab sample from the recipient site was collected by the surgical team. Postoperatively, areas positive/negative for FL and areas of graft take and failure were overlapped and measured (cm2) over a 2D schematic. The performance and accuracy of FL imaging and swab sampling in relation to graft outcomes were assessed. Results38 patients were enrolled in the study. The mean total body surface area (TBSA)33TBSA: Total body surface area involvement was 14.5 ± 12.4 % [range 0.8 – 40.2 %]. 25/38 of the subjects enrolled had complete graft take while 13 had partial graft losses. There were no total losses. FL-imaging was positive in 100 % of losses versus 31 % (4/13) of the swab microbiology. FL-imaging was found to have a sensitivity of 86 %, specificity of 98 %, PPV of 72 %, NPV of 99 %, and an accuracy of 94 % for predicting any type or range of graft loss in the entire cohort. Meanwhile, the sensitivity of microbiology from swab samples was 30 %, with a specificity of 76 %. ConclusionsFL imaging is an accurate method for assessing recipient sites and predicting the outcome of a skin graft among burn patients. These findings suggest that FL imaging can inform better decision-making surrounding grafts that may lead to better outcomes. Level of evidenceLevel IIA, Therapeutic study

The Neutrophil/Lymphocyte Ratio in Helicobacter pylori Infected Patients: A Comparative Therapeutic Study to Reduce Risk of Gastric Cancer

The Neutrophil/Lymphocyte Ratio in Helicobacter pylori Infected Patients: A Comparative Therapeutic Study to Reduce Risk of Gastric Cancer

Optimizing percutaneous reduction and fixation with guidewire modification in pelvic and acetabular fractures: surgical technique and case series.

Minimally invasive percutaneous screw fixation for pelvic ring and acetabular fractures has become increasingly popular due to its numerous benefits. However, the precise placement of the screw remains a critical challenge, necessitating a modification of the current techniques. This paper introduces a refined technique employing a modified guidewire to enhance the precision and efficiency of percutaneous fixation in pelvic and acetabular fractures. This study details the surgical techniques implemented for correcting guidewire misdirection in percutaneous screw fixation and includes a retrospective analysis of patients treated with this modified approach over a three-year period. In this study, 25 patients with pelvic ring and acetabular fractures underwent percutaneous screw fixation. The cohort, predominantly male (23 out of 25), had an average age of 38years. The majority of injuries were due to traffic accidents (18 out of 25). Types of injuries included pelvic ring (6 cases), acetabular fractures (8 cases), and combined injuries (11 cases). Various screw types, including antegrade and retrograde anterior column screws, retrograde posterior column screws, and lateral compression screws, were used, tailored to each case. Over an average follow-up of 18months, there were no additional procedures or complications, such as neurovascular injury or hardware failure, indicating successful outcomes in all cases. This study introduces a simple yet effective method to address guidewire misdirection during percutaneous fixation for pelvic and acetabular fractures, offering enhanced precision and potentially better patient outcomes. Further research with a larger patient cohort is required for a more comprehensive understanding of its efficacy compared to traditional methods. IV. Therapeutic Study (Surgical technique and Cases-series).

Efficacy of artesunate-amodiaquine for treatment of uncomplicated Plasmodium falciparum malaria in mainland Tanzania

BackgroundDiversification of artemisinin-based combination therapy (ACT) is suggested as one of the strategies that can be used to contain artemisinin resistance. Artesunate-amodiaquine (ASAQ) is one of the artemisinin-based combinations that can be used in the diversification strategy as an alternative first-line treatment for uncomplicated malaria in mainland Tanzania. There is however limited data on the efficacy of ASAQ in mainland Tanzania. This study assessed the efficacy of ASAQ for treatment of uncomplicated Plasmodium falciparum malaria in selected sentinel sites for therapeutic efficacy studies in mainland Tanzania.MethodsBetween December 2018 and March 2020, children aged between 6 months and 10 years, attending at Nagaga, Mkuzi, and Mlimba primary health facilities, and with suspected uncomplicated malaria infection were screened for eligibility to participate in the study. Malaria infection was screened using microscopy. Children with uncomplicated P. falciparum monoinfection and who fulfilled all other inclusion criteria, and had none of the exclusion criteria, according to the World Health Organization (WHO) guidelines, were treated with ASAQ. Follow-up visits were scheduled on days 0, 1, 2, 3, 7, 14, 21, and 28 or on any day of recurrent infection for clinical and laboratory assessment. Polymerase chain reaction (PCR)-corrected cure rate on day 28 was the primary outcome.ResultsA total of 264 children, 88 in each of the three study sites (Mlimba, Mkuzi and Nagaga health facilities) were enrolled and treated with ASAQ. The ASAQ PCR-corrected cure rate was 100% at all the three study sites. None of the participants had early treatment failure or late clinical failure. Furthermore, none of the participants had a serious adverse event.ConclusionASAQ was highly efficacious for the treatment of uncomplicated P. falciparum malaria in mainland Tanzania, therefore, it can be deployed as an alternative first-line treatment for uncomplicated malaria as part of diversification strategy to contain the spread of partial artemisinin resistance in the country.

What is the Long-term Wear of a 5-Mrad Highly Crosslinked Polyethylene Liner? A 14-year RSA Study.

Lower doses of irradiation (≤ 5 Mrad) during the manufacture of highly crosslinked polyethylene acetabular liners may result in less crosslinking and an increased wear rate. Radiostereometric analysis (RSA) studies have found that wear of more highly irradiated highly crosslinked polyethylene liners (7 to 10 Mrad) decreases at longer-term follow-up compared with earlier reports of the same cohorts. Although wear of 5-Mrad irradiated liners appears to increase at midterm follow-up, it is unclear whether that remains true at longer follow-up. We asked: (1) In patients who underwent THA with a 5-Mrad highly crosslinked polyethylene liner, what is the wear rate evaluated with RSA during the first 14 years? (2) Does the wear rate decrease after 6 years in situ? This is a brief follow-up of prior RSA studies performed at 2 and 6 years. We prospectively reviewed the longer-term wear rate in 13 patients who underwent primary THAs with the same design of a 5-MRad irradiated crosslinked acetabular liner and a 28-mm cobalt-chromium articulation. Of the initial 30 patients who were enrolled, 13 (43%) were available at the 14-year timepoint; nine patients had died, 1 patient had withdrawn, 1 had an intraoperative fracture, 3 patients were too infirm to have radiographs, 2 had no baseline RSA radiographs, and 1 had poor-quality RSA images. Tantalum markers were inserted during surgery, and all patients had RSA radiographic examinations at 1 week, 6 months, and 1, 2, 6, and 14 years postoperatively. The mean ± standard deviation proximal, 2D, and 3D wear rates calculated between 1 year and 14 years were 0.019 ± 0.013 mm, 0.022 ± 0.015 mm, and 0.025 ± 0.019 mm per year, respectively. No patient had proximal 2D or 3D wear rates exceeding 0.06 mm per year. An increasing wear rate over time was measured for proximal and 2D wear rates between 6 and 14 years (0.024 and 0.030 mm per year) compared with that between 1 and 6 years (0.008 and 0.010 mm per year; p = 0.03). The proximal, 2D, and 3D wear of a highly crosslinked polyethylene liner produced using 5-Mrad radiation remains low in the longer-term. With the small numbers available in a long-term RSA study such as this, we confirmed that the wear rate did not decrease at longer-term follow-up, unlike previous RSA studies of more highly irradiated highly crosslinked polyethylene liners. Nevertheless, the wear rate remains very low and below the threshold typically associated with the development of osteolysis (0.1 mm/year of wear). This should provide assurance to orthopaedic surgeons monitoring patients with this 5-Mrad irradiated liner in situ, while providing useful information to manufacturers of future highly crosslinked polyethylene liners. Level IV therapeutic study.

Oromandibular dystonia: from onset to spread a multicenter italian study.

Detailed information about the epidemiological and phenomenological differences among the aetiological subtypes of oromandibular dystonia (OMD) is lacking. Moreover, the OMD tendency to spread to other body sites has never been investigated. To compare the main demographic and clinical features of OMD in different aetiological groups and assess the risk of spread. We retrospectively analysed data from patients contained in the Italian Dystonia Registry. The risk of spread was assessed by Kaplan Meyer curves and Cox regression analysis. The study included 273 patients (175 women) aged 55.7years (SD 12.7) at OMD onset. Female predominance was observed. Idiopathic dystonia was diagnosed in 241 patients, acquired dystonia in 22. In 50/273 patients, dystonia started in the oromandibular region (focal OMD onset); in 96/273 patients the onset involved the oromandibular region and a neighbouring body site (segmental/multifocal OMD onset); and in 127/273 patients OMD was a site of spread from another body region. Sensory trick (ST) and positive family history predominated in the idiopathic group. No dystonia spread was detected in the acquired group, whereas spread mostly occurred within the first five years of history in 34% of the focal OMD onset idiopathic patients. Cox regression analysis revealed ST as a significant predictor of spread (HR, 12.1; 95% CI, 2.5 - 18.8; P = 0.002). This large study provides novel information about the clinical phenomenology of idiopathic and acquired OMD. We pointed out a possible role of oestrogens in favouring dystonia development. Moreover, we described for the first time the association between ST and dystonia spread, revealing possible common pathophysiological mechanisms. Our findings may be suggested as a referral point for future pathophysiological and therapeutic studies on OMD.

The Mechanism of Action of Cancer Therapeutic Vaccines and Their Application Prospects

The complexity of cancer as a global health problem has also led to the development of various novel therapeutics, including prophylactic vaccines. Scientific breakthroughs and technological developments have changed cancer research; since cancer is a complicated disease with many factors, more and better vaccines are required. The research stresses the worldwide influence of cancer and modern therapeutic approaches, such as vaccination. With advances in molecular and cellular biology, cancer therapeutic vaccination studies have been advanced; the discovery of tumor markers and advances in immunology and cancer therapies have changed. In contrast to chemotherapy and radiation, immunotherapy revolutionized treatment. The cancer therapeutic vaccines elicit antigen-specific T cell responses, helper T cell stimulation, and innate immune cells; the research indicates that these vaccines use various means to arouse the body's defensive mechanism against cancer. Complex tools are explained by figures 1 and 2, which depict CD4+ T cells and innate immunity cells. Vaccines can be peptide/protein-based, whole-cell- or nucleic acid-based by application or clinical trial. Each category is looked at for its significant successes, triumphs, and failures: dendritic cell vaccines, the efficiency of antigen presentation, and clinical trial success. Cancer-therapeutic vaccines and immune checkpoint inhibitors are synergistic. Expanding the range of cancer vaccine antigens depends on finding added tumor-associated antigens and immunological checkpoints. However, there are flaws in cancer therapeutic vaccines, despite progress; tumor heterogeneity, immune evasion, and Safety are among concerns today. Recognizing these problems sets the stage for later chapters of optimization and new approaches.

The effect of antepartum depressive and anxiety symptoms on mother-infant interaction: The mediating role of antepartum maternal emotional stress

Anxiety disorders, depression, and emotional stress during the antepartum period are interlinked with adverse child development. The quality of the dyadic interaction seems to play a crucial role in the transmission of these effects. In this study, we explored the mediating effect of antepartum maternal emotional stress (assessed via the Prenatal Emotional Stress Index) regarding the relationship of antepartum maternal depressive (assessed via the Edinburgh Postpartum Depression Scale), anxiety symptoms (assessed via the Stat-Trait-Anxiety-Inventory), and depressive and anxiety disorders (assessed according to the DSM-IV-TR) in the antepartum period on postpartum interactive quality in a longitudinal design. The Face-to-Face-Still-Face Paradigm (FFSF) and the Infant and Caregiver Engagement Phases (ICEP-R) coding system were used to assess the postpartum interactive qualities of the mother-infant dyads. The sample consisted of 59 women, 38 in the clinical and 21 in the control group. We found significant indirect effects of antepartum depressive symptoms and maternal diagnostic status on the mother’s neutral engagement and on the latency to the first social positive interactive match during the interaction – effects that were mediated by antepartum stress. Moreover, there was an indirect effect of state anxiety on neutral engagement – mediated by antepartum stress. Therapeutic intervention studies focusing on maternal antepartum regulation of emotional stress and postpartum interactive patterns might be crucial to encounter maladaptive developmental trajectories.

Abstract 2680: Knockout on enhancer of zeste homolog 2 in triple-negative breast cancer model alters immune signaling and decreases tumor progression and lung metastasis

Abstract Triple-negative breast cancer (TNBC) is an aggressive and highly metastatic subtype of breast cancer. Lack of known targets, patient-to-patient variations of target antigens and resistance to immune checkpoint inhibitors make TNBC one of the most challenging cancers to treat. TNBC is enriched in tumor-infiltrating neutrophils (TINs). TINs are key contributors to pro-tumorigenic processes linked to “immunologically cold” tumors, in part by preventing recruitment of T-lymphocytes (TILs). Prior studies identified the Enhancer of zeste homolog 2 (EZH2) as a prominent methyltransferase expressed in primary and metastatic TNBC cells. EZH2 is an upstream regulator of the stimulator of interferon genes (STING), a critical innate sensor mediating anti-tumor responses that is inhibited in cold tumors. To date, EZH2/STING signaling in TINs is relatively unknown. Here, we hypothesized that EZH2 inhibition and subsequent STING activation could exert anti-tumor activity by modulating TINs. We derived EZH2-knockout (KO) and EZH2-overexpressed (OX) cell lines from the well-established 4T1 TNBC mouse cell line. We demonstrate a 10-fold decrease in lung metastasis and significant reduction of 4T1 EZH2 KO tumor growth compared to the parent 4T1 cell line. Concomitantly, the TIN:TIL ratio was significantly reduced in 4T1 EZH2 KO vs. control tumors. Overexpression of EZH2 in 4T1 TNBC cells did not affect the primary tumor growth or lung metastasis. A therapeutic study using the repeated injection of the STING agonist MSA-2 after tumor engraftment in vivo also demonstrated a decrease in lung metastasis and tumor growth in MSA-2 vs. vehicle injection with both 4T1 parent and EZH2 KO cell lines. Together, our findings suggest a key role for STING pathway modulation and TIN/TIL poise in primary TNBC progression and lung metastasis. Citation Format: Lenore Monterroza, Maria Parrilla, Sarah Samaranayake, Dormarie Rivera, Brian Dobosh, Periasamy Selvaraj, Rabindra M. Tirouvanziam. Knockout on enhancer of zeste homolog 2 in triple-negative breast cancer model alters immune signaling and decreases tumor progression and lung metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2680.

Abstract 919: Veterans Health Administration: Decentralized clinical trials

Abstract Purpose: The Veterans Health Administration (VA) created National TeleOncology (NTO) service in 2019 to provide telehealth cancer care to Veterans and to augment care provided at VA facilities through a hub and spoke model. More recently, VA established a Decentralized Clinical Trials (DCTs) infrastructure to support clinical trials (CTs) that rely on telehealth, where research staff are at different locations, and/or where a single IRB provides oversight even when subjects are at different locations. Brief Description: Research support and infrastructure is variable across VA facilities resulting in uneven access to cancer CTs in the VA system. Veterans often live in rural areas or have transportation challenges, which are barriers to participate in CTs. The COVID-19 pandemic resulted in increased telehealth use in clinical care and in CTs, providing the rationale for a focused effort in DCTs. DCTs have the potential to reduce barriers to CT involvement at the facility- and patient-level and may be more representative of real-world clinical scenarios. Summary of Data: Since its inception, NTO has provided hematology and oncology telehealth care to over 10,000 Veterans, of which 47.5% live in rural or highly rural areas, 76.5% are white and 13.2% are black or African American. Because the NTO program provides clinical care via telehealth modalities, patients who receive care through NTO may be more comfortable with participating in CTs that use telehealth, and thus are part of a pool of potentially eligible subjects.Since creation of the DCT program, three cancer DCTs have been conducted in the VA (1) BNT001 Digital Therapeutic Feasibility Pilot Study, (2) Cemiplimab Survivorship Epidemiology (CASE) Study, and (3) Proof-Of-ConcepT DEcentralized CliNical TrIAL (POTENTIAL) study. The BNT study enrolled 24 Veterans, 19 were male, 22 were white, 13 lived in rural areas, and the median age at enrollment was 68 years, including numerous cancer diagnoses. Veterans enrolled in the BNT study received cancer care at seven VA facilities. The CASE study has enrolled 24 male Veterans, 23 were white, 5 lived in rural areas, and the median age at enrollment was 74 years. The POTENTIAL study enrolled 4 male Veterans, 3 were white, 2 lived in rural areas, and the median age at enrollment was 72 years. Upcoming DCTs will focus on the following disease types: metastatic non-small cell lung cancer, multiple myeloma, and relapsed/refractory diffuse large B-cell lymphoma. Conclusions: The VA provides clinical cancer care to Veterans through the NTO program. The DCT program builds upon the existing clinical infrastructure to conduct CTs on a national scale. The NOP DCT team is a component of the VA’s Enhance Equity and Access to Clinical Trials (ENACT) initiative, which is part of Cancer Moonshot. The DCT program intends to expand CT opportunities to Veterans with cancer, minimize barriers to CT activation and enrollment, and improve access to cancer CTs for all Veterans. Citation Format: Ashlyn Press, Jennifer Ordman, Jacqueline Boreland, Zachary Burningham, Shelby Schoenborn, Tiffany Stewart, Bethany Oberg, Perri Pepperman, Holly Morris, Sarah Bloemers, Nawshin Kutub, Shannon Elam, Michael J. Kelley, Daphne Friedman. Veterans Health Administration: Decentralized clinical trials [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 919.

Abstract 6021: Lutetium-177 (177Lu) radiolabeled engineered antibody fragment against human prostate stem cell antigen (hPSCA) demonstrates targeting and antitumor effects in a syngeneic mouse model of pancreatic ductal adenocarcinoma (PDAC)

Abstract Introduction: hPSCA is a cell surface protein overexpressed in PDAC but minimally expressed in normal tissues, making it a promising therapeutic marker for targeted radiopharmaceutical therapy (TRT). Anti-hPSCA A2 scFv-Fc2DM antibody (A2DM) was engineered with a double mutation in the FcRn binding site for rapid blood clearance to the liver, reducing bone marrow and kidney radiotoxicity. The potential of using 177Lu radiolabeled A2DM antibody for targeted anti-hPSCA imaging and TRT was investigated in a syngeneic mouse model of PDAC. Methods: hPSCA knock-in mice were engrafted subcutaneously with KPC cells overexpressing hPSCA (KPC-hPSCA). ImmunoPET with zirconium-89 (89Zr) radiolabeled with A2DM was conducted to confirm in vivo targeting. For imaging, A2DM and an isotype control (anti-CD20) antibody were radiolabeled with 89Zr. Mice (n = 5; tumor sizes: 150 mm3 - 180 mm3) were i.v. injected with 89Zr-A2DM or 89Zr-isotype control (administered activity: 1.5 MBq/10 µg) or co-injected with excess cold antibody. ImmunoPET was acquired at 21 h post-injection. Ex vivo biodistribution was conducted and %ID/g was calculated based on decay-corrected standards. For therapy, KPC-hPSCA tumor bearing mice (n = 8 - 9, average tumor sizes: 20.1 ± 5.1 mm3) was i.v. injected with 177Lu-A2DM (administered activity: 17.8 MBq/10 µg or 9.25 MBq/10 µg) or saline. Tumor sizes and body weights measured every 2-3 days. Results: 89Zr immunoPET and biodistribution of A2DM demonstrated significantly higher tumor uptake (15.6 ± 0.6 %ID/g) than theisotype control (10.7 ± 1.0 %ID/g, p= 0.0001) or blocked control with 70-fold excess cold antibody (8.6 ± 1.3 %ID/g, p&amp;lt; 0.0001), suggesting A2DM binds to hPSCA-positive tumors in an antigen-specific manner. Therapy studies show tumor growth inhibition in a dose-dependent manner when treated with 17.8 MBq of 177Lu-A2DM (tumor size at day 25: 178 ± 119 mm3) or 9.25 MBq of 177Lu-A2DM (tumor size at day 25: 309 ± 182 mm3) (tumor size at day 25: 740 ± 317 mm3, p= 0.006, 0.04 respectively, compared to saline). Median survival was significantly improved in mice treated with high dose of 17.8 MBq 177Lu-A2DM compared to saline-treated group (48 vs. 25 days, p= 0.002). Median survival of mice treated with low dose 9.25 MBq of 177Lu-A2DM showed a trend towards improved survival but results were not significant (48 vs. 34 days, p= 0.25). Minimal weight loss observed in the 177Lu-A2DM and saline groups, suggesting the 177Lu therapy was well tolerated. Conclusions: 89Zr immunoPET studies confirmed specific targeting of A2DM to KPC-hPSCA tumors in vivo. 177Lu-A2DM therapeutic studies demonstrated significant tumor growth delay in a dose-dependent manner. Future studies will explore dose fractionation strategies, with the aim to enhance tumor growth control for PDAC. Citation Format: Bao Ying Chen, Masoud Farshbaf, Felix B. Salazar, Saad N. Ahmed, Sunidhi Jaiswal, Jennifer Chean, Anakim Sherman, Teresa Hong, Paul J. Yazaki, Tove Olafsen, Kirstin A. Zettlitz, Anna M. Wu. Lutetium-177 (177Lu) radiolabeled engineered antibody fragment against human prostate stem cell antigen (hPSCA) demonstrates targeting and antitumor effects in a syngeneic mouse model of pancreatic ductal adenocarcinoma (PDAC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6021.

Abstract 584: Synergistic action of ATF6 and EZH2 in sensing metabolic stress to boost anti-tumor immunity

Abstract Although immune checkpoint blockade (ICB) marked a breakthrough in melanoma treatment, half of patients fail to respond, underscoring the crucial need for complementary adjuvant and neo-adjuvant therapies. Due to the low overall response rate and the stark contrast in outcomes between patients that respond and those that fail to respond, identifying the defining characteristics of immune checkpoint blockade (ICB) response is essential for enhancing the efficacy of melanoma treatments. To recapitulate and investigate the ICB-responsive phenotype in vitro, melanoma cells were metabolically adapted to an environment lacking glucose which successfully drove the dependence on oxidative metabolism and restored MHC-I expression, two established characteristics of ICB responsive tumors. Further, metabolic adaptations significantly enhance the tumor sensitivity to T-cell killing. Surprisingly even in JAK1 and IFNAR1 deficient cells, metabolic adaptation restored MHC I antigen presentation, indicating an interferon-independent mechanism of MHC-I regulation. Proteomic analysis of three metabolically conditioned melanoma cells lines (human and mouse) identified downregulation of the histone methyltransferase EZH2 and the activating transcription factor ATF6 as key corollaries of MHC-I expression. Interestingly, EZH2 and ATF6 activity were found to be inversely related in metabolically adapted cells and patient tumor samples. These studies mechanistically explore the epigenomic control of antigen presentation machinery and the transcriptional targets of ATF6 controlling sensitivity T cell killing. Here, through in vitro and in vivo studies, we demonstrate that constitutive activation of ATF6, and thereby activation of the adaptive unfolded protein response (UPR), sensitizes melanoma to immune control. These data suggest that EZH2 and ATF6 act synergistically to balance immune mediated killing during metabolic stress whereby loss of EZH2 increases MHC-I antigen presentation and activation of ATF6 sensitizes tumor cells to T cell-mediated control. Ongoing therapeutic studies combining EZH2 inhibition, ATF6 activation, and ICB in pre-clinical models further suggest targeting the synergy between EZH2 and ATF6 is a putative adjuvant or neo-adjuvant target to improve the clinical response of ICB. Citation Format: Jacob L. Edmondson, Megan R. Reed, Daniel Fil, Billie Heflin, Brian Koss, Alan J. Tackett. Synergistic action of ATF6 and EZH2 in sensing metabolic stress to boost anti-tumor immunity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 584.

Intercalary Resection of the Tibia for Primary Bone Tumors: Are Vascularized Fibula Autografts With or Without Allografts a Durable Reconstruction?

Intercalary Resection of the Tibia for Primary Bone Tumors: Are Vascularized Fibula Autografts With or Without Allografts a Durable Reconstruction?

Surgical Hip Dislocation in the Era of Hip Arthroscopy Demonstrates High Survivorship and Improvements in Patient-reported Outcomes for Complex Femoroacetabular Impingement.

Surgical Hip Dislocation in the Era of Hip Arthroscopy Demonstrates High Survivorship and Improvements in Patient-reported Outcomes for Complex Femoroacetabular Impingement.