90-day Time Points Research Articles

A phase Ib study of immunotherapy with ex-vivo pre-activated and expanded CBNK cells in combination with cetuximab, in patients with colorectal cancer (CRC) with minimal residual disease (MRD): Final report.

176 Background: Colorectal cancer (CRC) is the second most common type of cancer. Even following successful curative treatment, patients often relapse, likely because of undetected micro-metastatic foci. Tumor-informed ctDNA testing has helped to identify those patients before they developed radiographic evidence of disease, introducing the concept of minimal residual disease (MRD) in solid tumors. No standard-of-care treatment options are available for MRD patients. Therefore, we have designed a phase IB trial of the combination of in vitro pre-activated and pre-expanded cord blood natural killer (pre-A+E CBNK) cells with cetuximab. We hypothesized that we could achieve CAR-like efficacy without genetic engineering, by pre-activating NK cells with inflammatory cytokines and by using antibodies to redirect NK cell specificity and antibody-dependent cellular cytotoxicity. The highly immunosuppressive CRC tumor microenvironment is understudied, and novel NK-cell therapy could be highly effective in MRD clearance. Methods: 15 patients with CRC-MRD were enrolled in this trial and completed treatment. All the patients received immunodepleting treatment prior to an infusion of pre-A+E CBNK cells, up to a dose of 1x10^8/kg. Patients were monitored inpatient for 24 hours after treatment for infusion-related reaction, and were then seen for toxicity follow-up in the outpatient clinic twice/week for 4 weeks (DLT window). Samples for correlative analysis were collected at different times. Results: 8/15 patients enrolled were female and 7 were male, age range 26-69. They all had no measurable radiographic evidence of disease and a positive ctDNA Signatera test at baseline. 11/15 were previously treated for metastatic disease; 13 patients had a history of metastases (including 7 liver, 2 lymph nodal, 2 peritoneal). All of them received 5-FU-based chemotherapy. 7/15 were RAS/RAF WT, 4/10 were KRAS mut, 1/10 had BRAF mutation, 1/10 had HER2 amplification. They were all pMMR. No DLT was observed, only 1 patient had G2 CRS requiring tocilizumab. 9/15 patients treated so far had ctDNA clearance at some point. One patient had negative ctDNA at 3 and 6 months, 4/15 were negative at d28 and 7/15 at d14. 4/15 patients have not met the 90-day time point yet. 10/12 patients analyzed up to the primary endpoint had decreased ctDNA over baseline CBNK cells in blood peaked 3 hours post-infusion and persisted at 3 days. Phenotype analysis of CBNK pre-post, donor NK and other immune cells is ongoing. Conclusions: Cetuximab in combination with pre-A+E CBNK is safe and showed promising results for the treatment of MRD-CRC. Clinical trial information: NCT050468 .

Opioid Consumption Following Isolated and Recurrent Shoulder Dislocation and Reduction.

Recurrent shoulder dislocations often lead to multiple encounters for reduction and eventual surgical stabilization, both of which involve exposure to opioids and potentially increase the risk of chronic opioid exposure. The purpose of our study was to characterize shoulder instability and compare pre- and post-reduction opioid usage in singular dislocators (SD) and recurrent dislocators (RD). This retrospective study was performed at a single academic institution using a prospective database. Patients were included if they were 1) age 18 or older and 2) sustained a shoulder dislocation evaluated within our institution. Electronic medical records were reviewed for patient demographics, emergency department management, and opioid exposure (number and mean morphine equivalent [MME] of opioid prescriptions) both pre- and post-reduction. Cohorts were compared using Wilcoxon rank sum tests for continuous variables and chi-squared or Fischer's exact tests for categorical variables with statistical significance set at p<0.05. 222 patients were included with mean follow-up 4.4 months (range: 0-70.1 months). 53 (23.8%) patients sustained recurrent dislocations. RDs were significantly younger (median age 26.7 years, IQR: 21.6-44.9) than SDs (55.3 years, IQR: 32.8-70.4; p<0.001) and more likely to have sustained a prior shoulder fracture (n=11 [21.2%] vs. n=3 [1.8%], p<0.001). There were no differences in sex, laterality, or follow-up duration. 18 (34.0%) RDs and 18 (10.7%) SDs underwent surgery including shoulder stabilization procedures, rotator cuff repairs, and fracture fixation (p<0.001). RDs used significantly more opioids at the first follow-up in both the prescribed number of opioids (mean 0.23± 0.5 prescriptions vs. 0.10 ± 0.3, p=0.038) and MME (mean 38.3 ± 96.2 MME vs. 10.7 ± 66.4 MME, p=0.013). This difference is not appreciated from the 30-day postoperative visit onwards. Emergency Room opioid MME prescription and consumption was similar between cohorts. Patients who sustain recurrent shoulder dislocations exhibit a higher likelihood of consuming significantly greater amounts of opioids following shoulder reduction and ultimately undergoing surgical intervention. The proportion of opioid tolerance and pre-reduction total MME up to 90-days prior to reduction in the recurrent dislocator cohort trended towards significance, but there were no differences observed between rates of opioid usage during ED encounters or at the 30-, 60-, and 90-day timepoints. Patients with chronic shoulder instability should be counseled regarding the increased risk of opioid prescription patterns in the immediate post-reduction period however this risk may decrease over time.

EPCO-53. CHARACTERIZING THE FUNCTIONAL IMPACT OF GERMLINE-INHERITED RISK ALLELES IN GLIOMA EVOLUTION

Abstract Efforts to understand etiology of glioma led researchers to investigate associated genetic factors. Genome Wide Association Studies (GWAS) conducted to that end, uncovered an association of various single nucleotide polymorphisms (SNP) among hallmark oncogenes and tumor suppressors as risk variants in glioma incidence. Here, we perform in vitro modeling of four risk alleles/SNPs((rs723527 (EGFR), rs55705857 (MYC), rs7572263 (IDH1), rs78378222 (TP53)) mapped to non-coding regulatory regions of the genome, to assess their causal contribution to glioma evolution. To model the aforementioned risk alleles in an in-vitro system, we used a CRISPR-knock in strategy in human induced pluripotent stem cells (hiPSCs) and verified by Sanger sequencing. To study the effects of the risk alleles on brain cell types, we generated a cerebral organoid model from the edited and control lines and subjected them to downstream morphological and transcriptomic analyses. While we did not see morphological changes in the histological sections relative to controls at the early 14-day timepoint, we observed increased differentiation in both control and risk cohorts, along with an absence of neural rosettes, at the late 90-day timepoint. Bulk RNA-seq of the organoids at 14-days resulted in positive enrichment of oncogenic signaling pathways and negative enrichment of DNA repair pathways in the risk allele cohorts. Furthermore, single cell RNA seq of 14 and 90-day samples revealed a sharp decrease in neural stem cell clusters in both IDH and TP53 cohorts, while control organoids demonstrated robust production of immature neurons at 90 days. Overall, we observed a significant increase in differentiation into mature cell clusters in the control, relative to the risk allele organoids. Ongoing efforts are aimed at understanding this apparent differentiation block in the IDH and TP53 compartments, relative to control. Further analysis will lead to addressing key understudied areas of glioma etiology and associated mechanisms of risk incidence.

Contouring With Neuromodulators.

Botulinum toxins, originally used for facial rejuvenation, have emerged as a promising tool for sculpting and refining contours for both the face and body. The peer-reviewed literature on neuromodulator contouring treatments was analyzed, with a particular emphasis on studies and case reports involving the use of botulinum toxin type A. Modification of face, neck, shoulder, arm, and calf contour has been reported. Treatment and dosing protocols vary with the strength and depth of the target muscle. Regional effects of neuromodulator treatment begin to appear approximately 2 weeks after injection and are often most prominent at the 70- to 90-day time point. Although treatments are generally well tolerated, short-term muscle weakness and other side effects may occur. The use of neuromodulators to enhance facial and body contours has demonstrated efficacy, but further research is needed to validate their use and explore the full potential of this intervention through larger randomized controlled trials. The application of neuromodulators as a minimally invasive tool to address the rising demand for nonsurgical body sculpting represents a promising frontier in aesthetics.

Adherence and acceptability of multiple micronutrient supplementation during pregnancy: Study protocol for a cluster-randomized non-inferiority trial in Cambodia

BackgroundIron and folic acid (IFA) supplements are currently provided to Cambodian women during pregnancy. However, recent research has found benefits of a multiple micronutrient supplement (MMS) over just IFA alone on several outcomes of perinatal and infant health. The Ministry of Health in Cambodia has proposed a transition from IFA to MMS but to effectively guide this transition requires implementation research on the acceptability and adherence to MMS (over IFA).MethodsThis non-inferiority trial aims to assess the adherence and acceptability of IFA (60 mg elemental iron and 400 μg folic acid) compared to MMS (standard UNIMMAP formulation including 15 micronutrients) during antenatal care in Cambodia. A prospective cohort of 1545 pregnant women will be assigned to one of three trial arms: (1) IFA for 90 days [IFA-90]; (2) MMS for 180 days with two distributions of 90-count tablet bottles [MMS-90]; or (3) MMS for 180 days with one 180-count tablet bottle [MMS-180]. Each arm will enroll 515 women across 48 health centers (clusters) in Kampong Thom Province in Cambodia. The primary outcome is the non-inferiority of adherence rates of MMS-180 compared to IFA-90, as assessed by tablet counts. Mixed-effects logistic and linear regression models will be used to estimate the difference in the adherence rate between the two groups, with an ‘a priori’ determined non-inferiority margin of 15%. Acceptability of MMS and IFA will be measured using a quantitative survey conducted with enrolled pregnant women at 30-day, 90-day, and 180-day time-points. DiscussionFindings from this study will guide an effective and feasible MMS scale-up strategy for Cambodia. Additionally, the findings will be shared globally with other stakeholders planning to scale up MMS in other countries.Trial registrationNCT05867836 (ClinicalTrials.gov, registered May 18, 2023).

Abstract 7446: Transcriptomic and histological analysis of radiation-induced damage in the murine submandibular gland

Abstract Many head and neck cancer patients develop radiation-induced xerostomia (RIX). There are few clinical solutions for this condition and there is a critical need for novel therapeutics for this condition. To better understand the molecular alterations induced by radiation to the salivary glands, we used transcriptional profiling to assess acute and long-term alterations. Based on evidence that immunologic changes are induced by radiation, we used immune-depletion experiments to investigate the role of B-cells and macrophages in RIX. The submandibular gland (SMG) of male-C57/BL6-mice was irradiated (15Gy) mice were followed for 90 days. Saliva was collected throughout the time-course. SMGs were collected 3-, 7-, 60-, and 90-days following radiation. Tissues were analyzed by Nanostring Digital-Spatial-Profiling (DSP) utilizing the murine whole-transcriptome panel. Regions of interest corresponding to acini, ducts, and granular convoluted tubules (GCTs) were delineated and gene expression was assessed. Immunohistochemical staining was performed on SMG’s for fibrosis (masons trichrome), α-amylase, F4/80, Lgr5, Sox2, and MIST1 to evaluate glandular structure, salivary proteins, immune-microenvironment and pro-acinar salivary-stem-cell presence. Specific immune populations were depleted using anti-CD20 and clodronate-liposome prior to radiation and salivary function and histology was assessed at 3-, 7-, and 60-days following radiation. Radiation resulted in a significant decrease in salivary production (p-value = 0.03) in immune competent models. Transcriptional pathway analysis identified early alterations in signal-transduction and innate immune-response. Late timepoints identified alterations in B-cell activity and Wnt signaling pathways. Histological evaluation of the tissues showed increased disorganization of the gland, with decreases in size and distribution of the acinar compartments (mean area stained: No RT=25.81% vs 90d RT=19.98%, p-value=0.005). Acutely, there was an increase in expression of MIST1 and macrophages (mean area stained: No RT=14.8% vs 7d RT=18.76%, p-value=0.0004) within the SMG that resolved by the 60- and 90-day time-points. Results of immune depletion studies will be presented.Results implicate alterations in macrophages and B-cells in radiation-induced damage. These data along with the data from our immune-depletion experiments will provide valuable mechanistic insight guiding modulation of cell-therapies for treatment of RIX which can be further tested in preclinical models. Citation Format: Cristina Paz, Annemarie Glassey, Abigail Frick, Lauryn Melzer, Jasmine M. Robinson, Rebecca M. Baus, Randall J. Kimple. Transcriptomic and histological analysis of radiation-induced damage in the murine submandibular gland [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 7446.

Effectiveness of subcutaneous monoclonal antibody treatment in emergency department outpatients with COVID-19.

To evaluate whether subcutaneous neutralizing monoclonal antibody (mAb) treatment given in the emergency department (ED) setting was associated with reduced hospitalizations, mortality, and severity of disease when compared to nontreatment among mAb-eligible patients with coronavirus disease 2019 (COVID-19). This retrospective observational cohort study of ED patients utilized a propensity score-matched analysis to compare patients who received subcutaneous casirivimab and imdevimab mAb to nontreated COVID-19 control patients in November-December 2021. The primary outcome was all-cause hospitalization within 28 days, and secondary outcomes were 90-day hospitalization, 28- and 90-day mortality, and ED length of stay (LOS). Of 1340 patients included in the analysis, 490 received subcutaneous casirivimab and imdevimab, and 850 did not received them. There was no difference observed for 28-day hospitalization (8.4%vs. 10.6%; adjusted odds ratio [aOR] 0.79, 95% confidence intervals [CI] 0.53-1.17) or 90-day hospitalization (11.6%vs. 12.5%; aOR 0.93, 95% CI 0.65-1.31). However, mortality at both the 28-day and 90-day timepoints was substantially lower in the treated group (28-day 0.6%vs. 3.1%; aOR 0.18, 95% CI 0.08-0.41; 90-day 0.6%vs. 3.9%; aOR 0.14, 95% CI 0.06-0.36). Among hospitalized patients, treated patients had shorter hospital LOS (5.7vs. 11.4 days; adjusted rate ratio [aRR] 0.47, 95% CI 0.33-0.69), shorter intensive care unit LOS (3.8vs. 10.2 days; aRR 0.22, 95% CI 0.14-0.35), and the severity of hospitalization was lower (aOR 0.45, 95% CI 0.21-0.97) compared to untreated. Among ED patients who presented for symptomatic COVID-19 during the Delta variant phase, ED subcutaneous casirivimab/imdevimab treatment was not associated with a decrease in hospitalizations. However, treatment was associated with lower mortality at 28 and 90 days, hospital LOS, and overall severity of illness.

Staged Approach to Tibial Nail Removal Poses Increased Risk for Infection in the Setting of Total Knee Arthroplasty

BackgroundWhile previous research has addressed conversion arthroplasty scenarios, there is limited data on outcomes of staged or concurrent removal of intramedullary (IM) nails during total knee arthroplasty (TKA). Our study aimed to explore the association between the timing of IM nail removal and the incidence of periprosthetic joint infection (PJI), surgical site infection (SSI), manipulation under anesthesia (MUA), and aseptic revision at 90 days, 1 year, and 2 years after TKA when IM nail removal is performed in either a (1) staged or (2) concurrent manner. MethodsWe queried a national, all-payer database of all patients who underwent a primary TKA and hardware removal of an IM tibial nail. The group was separated into mutually exclusive cohorts with removal performed either (1) in a staged manner (n = 287) or (2) on the same day of TKA (n = 2,958). Surgical complications included the following: PJIs, SSIs, MUAs, and aseptic revisions. Surgical complications were collected at 90-day, 1 year, and 2-year time points. ResultsPatients who had staged nail removal before TKA demonstrated the highest incidence of PJI at 90 days, 1 year, and 2 years (13.9, 16.7, and 17.1%, respectively). Adjusted multivariate regression analyses demonstrated significantly higher odds of a PJI, SSI, and MUA at 90 days, 1 year, and 2 years for all patients who had staged nail removal TKA (P < .001). ConclusionsThere was an observed association between concurrent IM nail removal and a decreased risk of PJI, SSI, and MUA when compared to patients who had nail removal in a staged fashion. However, this does not discount the utility of the staged approach, as it may be necessary for patients less tolerant to longer operative times.

Pathway Analysis of Transcriptional Alterations in the Salivary Gland Following Radiation Exposure

Radiation-induced xerostomia (RIX) is the subjective condition of dry mouth caused by radiation therapy to the head and neck and a result of hyposalivation and altered sialochemistry. Our long-term goal is to develop novel approaches to improve salivary function after radiation therapy. To better understand the molecular alterations induced by radiation in the salivary glands, we performed transcriptional profiling aimed at describing acute and long-term alterations in the murine salivary glands induced by radiation to better design effective regenerative therapies. The submandibular gland (SMG) of male C57Bl/6 mice received 15 Gy in a single fraction using a small animal image-guided irradiator. The mice were followed for 90 days. Saliva was collected at baseline and 7, 60 and 90 days after radiation. Salivary glands were collected for histology 3, 7, 60, and 90 days after radiation. The tissues were analyzed using a multiplex analysis platform processed with the murine whole transcriptome panel to investigate changes in gene expression over time. Using the multiplex analysis platform software, 96 regions of interest corresponding to acini, ducts, and granular convoluted tubules (GCTs) were delineated and gene expression was assessed separately in each area. To confirm the identified alterations, SMG tissue was histologically evaluated for fibrosis (masons tri-chrome), mucin (alcian blue), and amylase (α-amylase). Alterations in the immune microenvironment (CD19, CD3, and F4/80) and salivary gland stem cells (MIST1, SCA, Sox2, and c-Kit) were assessed by immunohistochemistry. Radiation resulted in a significant decrease in salivary production compared to nonirradiated controls (p-value = 0.03). The analysis of the transcriptional pathway identified early alterations in cell communication, DNA damage, and the immune response. Protein metabolism and extracellular matrix remodeling were up-regulated at later time points. Histological evaluation of tissues showed an increase in glandular structure disorganization over time, with a decrease in the size and distribution of the acinar compartments throughout the gland (mean area stained: No RT = 25.81% vs 90d RT = 19.98%, p-value = 0.005). There was an increase in periductal fibrosis within the tissue after 60 days compared to controls. Acutely, there was an increase in the expression of MIST1 and macrophages (mean area stained: No RT = 14.8% vs 7d RT = 18.76%, p-value = 0.0004) within the SMG that had resolved by the 60- and 90-day time points. The results implicate macrophage alterations in radiation-induced salivary gland damage and provide valuable mechanistic insight guiding potential approaches to intervene in RIX. We are pursuing cell therapy-based approaches to prevent and repair damage caused by radiation in order to improve the lives of our patients.

Determining the optimal time to report mortality after lobectomy for lung cancer: An analysis of the time-varying risk of death

ObjectiveSurgical mortality has traditionally been assessed at arbitrary intervals out to 1 year, without an agreed optimum time point. The aim of our study was to investigate the time-varying risk of death after lobectomy to determine the optimum period to evaluate surgical mortality rate after lobectomy for lung cancer. MethodsWe performed a retrospective study of patients undergoing lobectomy for lung cancer at our institution from 2015 to 2022. Parametric survival models were assessed and compared with a nonparametric kernel estimate. The hazard function was plotted over time according to the best-fit statistical distribution. The time points at which instantaneous hazard rate peaked and stabilized in the 1-year period after surgery were then determined. ResultsDuring the study period, 2284 patients underwent lobectomy for lung cancer. Cumulative mortality at 30, 90, and 180 days was 1.3%, 2.9%, and 4.9%, respectively. Log-logistic distribution showed the best fit compared with other statistical distribution, indicated by the lowest Akaike information criteria value. The instantaneous hazard rate was greatest during the immediate postoperative period (0.129; 95% confidence interval, 0.087-0.183) and diminishes rapidly within the first 30 days after surgery. Instantaneous hazard rate continued to decrease past 90 days and stabilized only at approximately 180 days. ConclusionsIn-hospital mortality is the optimal follow-up period that captures the early-phase hazard during the immediate postoperative period after lobectomy. Thirty-day mortality is not synonymous to “early mortality,” as instantaneous hazard rate remains elevated well past the 90-day time point and only stabilizes at approximately 180 days after lobectomy.

0463 Deep Learning Classification of Future PAP Adherence based on CMS and other Adherence Criteria

Abstract Introduction Improving positive airway pressure (PAP) adherence is crucial to sleep apnea therapy success. Although behavioral interventions may be deployed to increase PAP adherence, operationalization remains an ongoing clinical challenge. Treatment outcomes may be optimized by forecasting PAP use to identify patients at risk for non-adherence enabling early intervention. We build upon our previous work by leveraging a larger dataset, additional metadata, and new Deep Learning approaches to forecast future PAP adherence. Methods We collected a cohort of N=21,397 subjects with daily PAP usage recorded during 2015-2021. We defined the input to models as the number of minutes the PAP machine was used during each day for the first 30-days. The ground truth was defined as the PAP adherence of the patients at the 3-month, 6- month, and 1-year endpoints. Adherence was calculated based on a 30-day window as ≥4-hours of usage for ≥70% of nights. We evaluated a Deep Neural Network (DNN) model with 10-fold cross- validation to forecast future adherence by leveraging previous daily usage information. Results were compared to a naive method which assumes adherence at each time point equals adherence during the first 30-days. Results The DNN models predicted adherence with a sensitivity of 90%, 81%, 77% and a specificity of 90%, 81%, 77%, for 3-month, 6-month, and 1-year endpoints, with ROC-AUC values of 0.97, 0.89, and 0.84 respectively. The models converged to ROC-AUC performance &amp;gt;0.90 for the first 90-days within the first 7 to 14-days of PAP use. Conclusion DNN models demonstrated strong predictive performance for PAP adherence, as defined by the CMS adherence criteria, measured by sensitivity, specificity, and overall ROC-AUC results at clinically relevant 90-day, 6-month, and 1-year timepoints. AI approaches show promise as early predictors of the likelihood to meet key therapy utilization thresholds within the first 1-2 weeks of therapy, enabling early PAP intervention or transition to alternative therapies. Support (if any) AASM Foundation SRA205-SR-19

Does the SORG Machine-learning Algorithm for Extremity Metastases Generalize to a Contemporary Cohort of Patients? Temporal Validation From 2016 to 2020.

The ability to predict survival accurately in patients with osseous metastatic disease of the extremities is vital for patient counseling and guiding surgical intervention. We, the Skeletal Oncology Research Group (SORG), previously developed a machine-learning algorithm (MLA) based on data from 1999 to 2016 to predict 90-day and 1-year survival of surgically treated patients with extremity bone metastasis. As treatment regimens for oncology patients continue to evolve, this SORG MLA-driven probability calculator requires temporal reassessment of its accuracy. Does the SORG-MLA accurately predict 90-day and 1-year survival in patients who receive surgical treatment for a metastatic long-bone lesion in a more recent cohort of patients treated between 2016 and 2020? Between 2017 and 2021, we identified 674 patients 18 years and older through the ICD codes for secondary malignant neoplasm of bone and bone marrow and CPT codes for completed pathologic fractures or prophylactic treatment of an impending fracture. We excluded 40% (268 of 674) of patients, including 18% (118) who did not receive surgery; 11% (72) who had metastases in places other than the long bones of the extremities; 3% (23) who received treatment other than intramedullary nailing, endoprosthetic reconstruction, or dynamic hip screw; 3% (23) who underwent revision surgery, 3% (17) in whom there was no tumor, and 2% (15) who were lost to follow-up within 1 year. Temporal validation was performed using data on 406 patients treated surgically for bony metastatic disease of the extremities from 2016 to 2020 at the same two institutions where the MLA was developed. Variables used to predict survival in the SORG algorithm included perioperative laboratory values, tumor characteristics, and general demographics. To assess the models' discrimination, we computed the c-statistic, commonly referred to as the area under the receiver operating characteristic (AUC) curve for binary classification. This value ranged from 0.5 (representing chance-level performance) to 1.0 (indicating excellent discrimination) Generally, an AUC of 0.75 is considered high enough for use in clinical practice. To evaluate the agreement between predicted and observed outcomes, a calibration plot was used, and the calibration slope and intercept were calculated. Perfect calibration would result in a slope of 1 and intercept of 0. For overall performance, the Brier score and null-model Brier score were determined. The Brier score can range from 0 (representing perfect prediction) to 1 (indicating the poorest prediction). Proper interpretation of the Brier score necessitates a comparison with the null-model Brier score, which represents the score for an algorithm that predicts a probability equal to the population prevalence of the outcome for each patient. Finally, a decision curve analysis was conducted to compare the potential net benefit of the algorithm with other decision-support methods, such as treating all or none of the patients. Overall, 90-day and 1-year mortality were lower in the temporal validation cohort than in the development cohort (90 day: 23% versus 28%; p < 0.001, and 1 year: 51% versus 59%; p<0.001). Overall survival of the patients in the validation cohort improved from 28% mortality at the 90-day timepoint in the cohort on which the model was trained to 23%, and 59% mortality at the 1-year timepoint to 51%. The AUC was 0.78 (95% CI 0.72 to 0.82) for 90-day survival and 0.75 (95% CI 0.70 to 0.79) for 1-year survival, indicating the model could distinguish the two outcomes reasonably. For the 90-day model, the calibration slope was 0.71 (95% CI 0.53 to 0.89), and the intercept was -0.66 (95% CI -0.94 to -0.39), suggesting the predicted risks were overly extreme, and that in general, the risk of the observed outcome was overestimated. For the 1-year model, the calibration slope was 0.73 (95% CI 0.56 to 0.91) and the intercept was -0.67 (95% CI -0.90 to -0.43). With respect to overall performance, the model's Brier scores for the 90-day and 1-year models were 0.16 and 0.22. These scores were higher than the Brier scores of internal validation of the development study (0.13 and 0.14) models, indicating the models' performance has declined over time. The SORG MLA to predict survival after surgical treatment of extremity metastatic disease showed decreased performance on temporal validation. Moreover, in patients undergoing innovative immunotherapy, the possibility of mortality risk was overestimated in varying severity. Clinicians should be aware of this overestimation and discount the prediction of the SORG MLA according to their own experience with this patient population. Generally, these results show that temporal reassessment of these MLA-driven probability calculators is of paramount importance because the predictive performance may decline over time as treatment regimens evolve. The SORG-MLA is available as a freely accessible internet application at https://sorg-apps.shinyapps.io/extremitymetssurvival/ .Level of Evidence Level III, prognostic study.

Identifying the origin of socioeconomic disparities in outcomes of major elective operations

BackgroundWhile the impact of socioeconomic status (SES) on surgical outcomes has been examined in limited series, it remains a significant determinant of healthcare outcomes at the national level. Therefore, the current study aims to determine SES disparities at three time-points: hospital accessibility, in-hospital outcomes, and post-discharge consequences. MethodsThe Nationwide Readmissions Database 2010–2018 was used to isolate major elective operations. SES was assigned using previously coded median income quartiles as defined by patient zip-code, with low SES defined as the lowest quartile and high SES as the highest. ResultsOf an estimated 4,816,837 patients undergoing major elective operations, 1,037,689 (21.3 %) were categorized as low SES and 1,288,618 (26.5 %) as high. On univariate analysis and compared to those of low SES, high SES patients were more frequently treated at high-volume centers (70.9 vs 55.6 %, p < 0.001), had lower rates of in-hospital complications (24.0 vs 29.0 %, p < 0.001) and mortality (0.4 vs 0.9 %, p < 0.001) as well as less frequent urgent readmissions at 30- (5.7 vs 7.1 %, p < 0.001) and 90-day timepoints (9.4 vs 10.7 %, p < 0.001). On multivariable analysis, high SES patients had higher odds of treatment at high-volume centers (Odds: 1.87, 95 % CI: 1.71–2.06), and lower odds of perioperative complications (Odds: 0.98, 95 % CI: 0.96–0.99), mortality (Odds: 0.70, 95 % CI: 0.65–0.75), and urgent readmissions at 90-days (Odds: 0.95, 95 % CI: 0.92–0.98). ConclusionThis study fills a much-needed gap in the current literature by establishing that all of the aforementioned timepoints include significant disadvantages for those of low socioeconomic status. Therefore, a multidisciplinary approach may be required for intervention to improve equity for surgical patients.

MP48-08 30-DAY, 90-DAY, AND 1-YEAR COMPLICATIONS FOLLOWING MAJOR UROLOGIC SURGERY: AN ANALYSIS OF MORBIDITY AND MORTALITY USING A LARGE MULTI-CENTER RESEARCH NETWORK

You have accessJournal of UrologyCME1 Apr 2023MP48-08 30-DAY, 90-DAY, AND 1-YEAR COMPLICATIONS FOLLOWING MAJOR UROLOGIC SURGERY: AN ANALYSIS OF MORBIDITY AND MORTALITY USING A LARGE MULTI-CENTER RESEARCH NETWORK Tyler Garman, Andrew Gabrielson, Una Choi, Gabriella Ewachiw, and Andrew Cohen Tyler GarmanTyler Garman More articles by this author , Andrew GabrielsonAndrew Gabrielson More articles by this author , Una ChoiUna Choi More articles by this author , Gabriella EwachiwGabriella Ewachiw More articles by this author , and Andrew CohenAndrew Cohen More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003294.08AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Many studies evaluating complication rates following urologic procedures focus on a narrow subset of procedures, include the experience of select, high volume surgeons, or have variable follow-up. We systematically compare national complication rates following an array of urologic surgeries by numerous providers, which can serve as an important benchmarking tool in the pursuit of quality care. METHODS: We performed a retrospective cohort study using the TriNetX research network from 2006-2022, which includes claims data for 110 million patients. Procedure type, age at index procedure, sex, race, and complications were queried using applicable CPT and ICD10 codes. Rates of all-cause (Clavien I-V), life-threatening (Clavien IV), and mortality (Clavien V) complications were evaluated using 30-day, 90-day, and 1-year timepoints from the index operation. Clavien IV complications included: sepsis, acute renal failure requiring dialysis, PE, reintubation, myocardial infarction, cardiac arrest, and re-operation. RESULTS: A total of 484,099 urologic procedures were included. Age, sex, race, and 30-day, 90-day, and 1-year complication rates stratified by procedure are listed in Table 1. All-cause complication rates ranged from 2-37%, 10-48%, and 17-60% for 30-day, 90-day, and 1-year time points, respectively. Rates of Clavien IV complications were less than or equal to 10% at all timepoints for most procedures with notable exceptions being total nephrectomy (14-23%), cystectomy (22-36%), and RPLND (14-22%). The 1-year mortality rate for most procedures was low. Exceptions include cystectomy (12%), TURBT (8%), RPLND (6%), and total nephrectomy (5%). Procedures with the lowest rates of 30-day, 90-day, and 1-year complications included those within reconstructive urology including AUS placement, sling procedures for incontinence, colporrhaphy, IPP placement and urethroplasty. 30-day, 90-day, and 1-year mortality rates following these procedures mirrored that of the general population not undergoing surgery. CONCLUSIONS: This analysis establishes benchmark complication rates up to 1-year post-op for many urologic procedures using a national database, which can aid hospital systems in identifying deficiencies in quality care. Source of Funding: NA © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e657 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Tyler Garman More articles by this author Andrew Gabrielson More articles by this author Una Choi More articles by this author Gabriella Ewachiw More articles by this author Andrew Cohen More articles by this author Expand All Advertisement PDF downloadLoading ...

Analysis of the urinary metabolic profiles in irradiated rats treated with Activated Protein C (APC), a potential mitigator of radiation toxicity

Purpose The goal of the current study was to identify longitudinal changes in urinary metabolites following IR exposure and to determine potential alleviation of radiation toxicities by administration of recombinant APC formulations. Materials and methods Female adult WAG/RijCmcr rats were irradiated with 13.0 Gy leg-out partial body X-rays; longitudinally collected urine samples were subject to LC-MS based metabolomic profiling. Sub-cohorts of rats were treated with three variants of recombinant APC namely, rat wildtype (WT) APC, rat 3K3A mutant form of APC, and human WT APC as two bolus injections at 24 and 48 hours post IR. Results Radiation induced robust changes in the urinary profiles leading to oxidative stress, severe dyslipidemia, and altered biosynthesis of PUFAs, glycerophospholipids, sphingolipids, and steroids. Alterations were observed in multiple metabolic pathways related to energy metabolism, nucleotide biosynthesis and metabolism that were indicative of disrupted mitochondrial function and DNA damage. On the other hand, sub-cohorts of rats that were treated with rat wildtype-APC showed alleviation of radiation toxicities, in part, at the 90-day time point, while rat 3K3A-APC showed partial alleviation of radiation induced metabolic alterations 14 days after irradiation. Conclusions Taken together, these results show that augmenting the Protein C pathway and activity via administration of recombinant APC may be an effective approach for mitigation of radiation induced normal tissue toxicity.

Abstract WP84: Optimizing Longitudinal Follow Up For Outcomes Research Among Patients With Intracerebral Hemorrhage

Intro: To address gaps in intracerebral hemorrhage (ICH) outcomes, acquisition of long-term data is necessary and resource intensive. We present our experience from follow-up of ICH patients across a 7-hospital certified stroke healthcare system. Methods: From 01/21 to 07/22, follow-up calls were made to adult non-traumatic ICH patients at 30, 90, 180, and 365-day timepoints (TP) post discharge. Consent was obtained at first successful contact, followed by collection of functional, cognitive, and quality of life outcomes. Trained research staff made multiple attempts (calls per patient) to complete assessment at each TP. An attempt was deemed successful if contact was made with a patient/proxy. We report overall and TP-specific rates of successful contact, consent, and completion using logistic regression. We also report the association of individual call success with attempt number and day of week. Results: Overall, 2,214 call attempts were made for 375 patients, of whom 246 (70.7%) were successfully contacted at least once. Of contacted, 173 (70.3%) consented, and 147 consented patients (85.0%) completed all assessments at one or more TPs (Fig A). Proportion of successful contact at 365-day (60.7%) was significantly higher compared to other TPs (Fig B). Consent rate was non-significantly higher for 30 and 90-day TPs (74.4%) compared to 180 and 365-day (68.1%). Conversely, patients were significantly less likely to complete assessments at the first three TPs compared to 365-day. For individual call attempts, first attempts were 1.5-2.4 times more likely to be successful than subsequent attempts, and calls made on Thursdays were 42-52% more likely to be successful. Conclusion: We demonstrate the need to consent patients early in their recovery when they are likely most motivated. As completion rates were lower at early vs. late TPs, we recommend curtailing laborious assessments at early TPs to decrease patient burden and continuing longitudinal follow-up.

One-stop stroke management platform reduces workflow times in patients receiving mechanical thrombectomy.

Clinical outcome in patients who received thrombectomy treatment is time-dependent. The purpose of this study was to evaluate the efficacy of the one-stop stroke management (OSSM) platform in reducing in-hospital workflow times in patients receiving thrombectomy compared with the traditional model. The data of patients who received thrombectomy treatment through the OSSM platform and traditional protocol transshipment pathway were retrospectively analyzed and compared. The treatment-related time interval and the clinical outcome of the two groups were also assessed and compared. The primary efficacy endpoint was the time from door to groin puncture (DPT). There were 196 patients in the OSSM group and 210 patients in the control group, in which they were treated by the traditional approach. The mean DPT was significantly shorter in the OSSM group than in the control group (76 vs. 122 min; P < 0.001). The percentages of good clinical outcomes at the 90-day time point of the two groups were comparable (P = 0.110). A total of 121 patients in the OSSM group and 124 patients in the control group arrived at the hospital within 360 min from symptom onset. The mean DPT and time from symptom onset to recanalization (ORT) were significantly shorter in the OSSM group than in the control group. Finally, a higher rate of good functional outcomes was achieved in the OSSM group than in the control group (53.71 vs. 40.32%; P = 0.036). Compared to the traditional transfer model, the OSSM transfer model significantly reduced the in-hospital delay in patients with acute stroke receiving thrombectomy treatment. This novel model significantly improved the clinical outcomes of patients presenting within the first 6 h after symptom onset.

Patterns of Progression on Immune Checkpoint Inhibitor Therapy for Relapsed Hodgkin Lymphoma: Implications for the Potential Role of Radiation Therapy

<h3>Purpose/Objective(s)</h3> Radiation therapy (RT) is increasingly utilized for patients with stage IV epithelial cancers experiencing oligometastases or oligoprogression, and often in combination with immune checkpoint inhibitors (ICI). ICIs are an approved treatment for relapsed Hodgkin lymphoma (HL) with a high overall response rate, yet most patients eventually progress. We examined patterns of HL progression during or following ICI therapy, using FDG-PET scans to identify patients who may benefit from comprehensive RT. <h3>Materials/Methods</h3> This retrospective study included patients with HL treated with an ICI from 2013 – 2022. We reviewed the pre-ICI FDG-PET and FDG-PET at progression with the goal of clarifying patterns of failure to define a group of patients who may have been amenable to RT. Optimal RT candidates were patients with ≤5 targetable areas on their pre-ICI FDG-PET and who progressed at only pre-relapse sites (i.e., local relapse). <h3>Results</h3> Eighty-nine patients were identified and 44 progressed during or after ICI – of these, 37 (42% of the total cohort) had adequate imaging for review and were therefore included in this study. For these 37 patients, median follow-up was 5.0 years and 32 (86%) had undergone autologous stem cell transplant prior to initiation of ICI. Nivolumab was the most commonly prescribed ICI (81%). At ICI initiation, 57% had ≤5 sites of disease on FDG-PET. All but one patient experienced local progression after ICI (97%), and 46% had new lesions outside of pre-ICI FDG-PET sites. The number of disease sites at ICI initiation did not predict for local versus distant relapse. Patients with relapse stage I/II nodal only disease at ICI initiation were significantly more likely to have ≤5 pre-ICI sites and only local progression after ICI (our parameters for patients who may potentially benefit from radiation) (HR 11.5, p=0.03). Less than 20% of patients with pre-ICI parenchymal, bone, or splenic disease fell within this parameter. Isolated local progression occurred at a median 261 days after ICI initiation (IQR 112-499), compared to 195 days (IQR 90-369) for those with progression at new sites. Patients who progressed in parenchymal sites had a lower 3-year OS at 38.5%, compared to at least 50% for all other sites (p=0.001). <h3>Conclusion</h3> Patients with relapsed HL experience a variable course on ICI therapy. Patients with relapse stage I/II nodal only disease experience high rates of progression at existing sites only, and may represent an optimal cohort for consolidation RT. Relapse typically occurs more than 90 days after initiation of ICI, indicating that the 90-day timepoint may be an appropriate time to consider integration of radiation if no new sites of disease have developed. This data serves as a potential benchmark for prospective evaluation of integrating RT with ICI to further improve outcomes in patients with relapsed HL, although validation is necessary.

Can We Utilize PROMIS Neuropathic Pain Quality for Assessment of Neuropathic Heel Pain?

Category: Hindfoot; Other Introduction/Purpose: Heel pain is one of the most common presentations encountered by foot and ankle specialists. While most etiologies of heel pain such as plantar fasciitis are mechanical stress driven nociceptive pain, a combined neuropathic mechanism may contribute to worse outcomes and challenges in pain management for a subset of these patients. Diagnosis and management of neuropathic pain in foot and ankle patients remain challenging. Since neuropathic pain may play an important part in indicating surgery or counseling heel pain patients, we investigated the plausibility of utilizing the Patient-Reported Outcomes Measurement Information System (PROMIS) Neuropathic Pain Quality (PQN) as an initial screening tool to diagnose and monitor the clinical effects of treatment. Secondary outcomes were prevalence of neuropathic pain and associated risk factors. Methods: New patients presenting to a tertiary care academic institution with heel pain were prospectively recruited. PROMIS PQN t-scores were obtained from all patients to detect and determine the severity of NP. Patients were grouped into no neuropathic pain (NP), mild neuropathic pain (NP), and severe NP based on the initial PROMIS PQN t-scores. Pain Interference (PI), Physical Function (PF), and Self-Efficacy (SE) scores were assessed at baseline, 30, and 90-day follow-up timepoints. Other factors such as age, smoking, body mass index (BMI), low back/neck pain, anxiety, depression, and medications were analyzed for association with outcomes. Linear mixed modeling was utilized to assess the main effects of time and NP on PROMIS t-scores, and meaningful clinically important difference (MCID) was compared. Results: A total of 48 patients with mean age of 52.4+-12.5 years old were recruited at the initial visit. The cohort consisted of 35 (73%) female patients, 7 (15%) diabetics, 6 (13%) current smokers, 18 (38%) with low back/neck pain, 6 (13%) with anxiety, 15 (31%) with depression, and 9 (19%) had taken neuromodulator, such as gabapentin. When using the PROMIS PQN as the assessment tool, 33 patients (69%) had NP at baseline; 23 (48%) with mild, and 10 (21%) with severe NP. BMI was the only significant independent factor associated with NP (p = 0.011). Higher baseline NP was significantly associated with higher PQN (p&lt;0.001) and PI (p=0.005), and lower SE (p=0.04) across timepoints. Patients who were detected to have NP based on the PQN t-score had lower PF at baseline with significantly less improvement in PF (3 vs 9.9, p=0.035), and did not meet MCID (Figure 1). Conclusion: Prevalence of neuropathic pain in patients presenting with heel pain was high. Neuropathic pain at baseline was significantly associated with worse pain and self-efficacy over time, and less clinically meaningful improvements in function. The PROMIS PQN may serve as a valuable tool to identify and guide clinical treatment decision pathways for patients with neuropathic heel pain.

Image-Based Evaluation of In Vivo Degradation for Shape-Memory Polymer Polyurethane Foam

Shape-memory polymer (SMP) polyurethane foams have been applied as embolic devices and implanted in multiple animal models. These materials are oxidatively degradable and it is critical to quantify and characterize the degradation for biocompatibility assessments. An image-based method using high-resolution and magnification scans of histology sections was used to estimate the mass loss of the peripheral and neurovascular embolization devices (PED, NED). Detailed analysis of foam microarchitecture (i.e., struts and membranes) was used to estimate total relative mass loss over time. PED foams implanted in porcine arteries showed a degradation rate of ~0.11% per day as evaluated at 30-, 60-, and 90-day explant timepoints. NED foams implanted in rabbit carotid elastase aneurysms showed a markedly faster rate of degradation at ~1.01% per day, with a clear difference in overall degradation between 30- and 90-day explants. Overall, membranes degraded faster than the struts. NEDs use more hydrophobic foam with a smaller pore size (~150–400 μm) compared to PED foams (~800–1200 μm). Previous in vitro studies indicated differences in the degradation of the two polymer systems, but not to the magnitude seen in vivo. Implant location, animal species, and local tissue health are among the hypothesized reasons for different degradation rates.