Cut-point Analysis Research Articles

Abstract B027: Combining total cell-free DNA (cfDNA) and circulating tumor (ctDNA) to enhance the clinical sensitivity of ddPCR assays to detect minimal residual disease (MRD) in stage IIIB/C/IV melanoma patients on adjuvant immunotherapy in CheckMate 238

Abstract Background: In patients (pts) with resected, stage III/IV melanoma receiving adjuvant immunotherapy, pre-treatment (pre-Tx) and on-treatment (on-Tx) ctDNA measurements are associated with relapse free survival; however, clinical adoption has been hindered by suboptimal assay sensitivity. Methods: We used analytically validated, mutation-specific ddPCR assays to measure ctDNA and cfDNA in pre- and on-Tx plasma samples from pts with resected stage IIIB/C/IV melanoma enrolled in CheckMate 238 (NCT02388906) receiving either adjuvant Nivolumab (NIVO) or Ipilimumab (IPI). Assay choice was personalized based on detection of one of the 7 melanoma hot-spot mutations in pt tumors: BRAF V600E/K, NRAS Q61R/L/K, or TERT promotor C228T or C250T. We evaluated associations between ctDNA detection, or high cfDNA based on cutpoint analysis (>6,000 copies/ml of plasma) and recurrence-free survival (RFS), pre-Tx tumor biomarkers including tumor cell PD-L1 expression, IFNg gene signature, CD8 infiltration, and tumor mutational burden. Survival analysis was performed using univariable and multivariable Kaplan-Meier and Cox regression models. Results: Assay mutations were identified in 87% of resected tumors. In the pre-Tx samples, ctDNA alone was detected in 94/753 (12%) pts. The detection rate increased to 20% when assay positivity was defined as either detectable ctDNA or high cfDNA. The sensitivity of ctDNA detection to predict recurrence ≤6 months(m) from pre-Tx samples increased from 25% (ctDNA alone) to 33% when high cfDNA was added to detectable ctDNA; specificity decreased to 84% from 91% (ctDNA alone). The patient subgroup defined by the combined metric of ctDNA+ or high cfDNA in pre- Tx samples was significantly enriched with higher stage of disease, elevated LDH, tumor cell PD-L1 expression < 5%, and tumor IFNg-RNA signature < median. Pts with detectable pre-Tx ctDNA or high cfDNA was associated with shorter RFS in both NIVO (median RFS 20.5 m [95%CI, 2.88, 59.15]) and IPI (median RFS 7.75 m [95%CI, 2.76, 24.08]) arms compared to those with undetectable ctDNA and low cfDNA (NIVO (median RFS 47.95 m [95%CI, 11.09, 59.89]) and IPI (median RFS 24.15 m [95%CI, 5.78, 58.38])). In a multivariable model that included sex, age, treatment, and IFNg gene signature, ctDNA+ or cfDNA high was an independent predictor of shorter RFS [HR 1.624 (95%CI, 1.275, 2.068), p<0.001]. When combining pre-Tx and on-Tx measurements at week 3 (w3) and w7, the assay performance generally increased compared to pre-Tx alone. For example, pre-Tx assay positivity had a 38% positive predictive value (PPV) and 81% negative predictive value (NPV) to predict recurrence at <6 m. In pts who were undetectable at pre-Tx but became positive at w3 and remained positive at w7, PPV increased to 62% and NPV increased to 90%. Conclusions: Incorporating quantitative measurements of cfDNA with ctDNA detection in the evaluation of pre-Tx and on- Tx plasma samples improves the clinical performance of mutation-specific ddPCR assays to detect MRD in patients with resected stage III and stage IV melanoma. Citation Format: Mahrukh M Syeda, Jennifer M Wiggins, Josephine Alegun, Saim Ali, Soutrik Mandal, Tracy (Hao) Tang, Keyur Desai, Sonia Dolfi, Daniel J Tenney, Paolo A Ascierto, James Larkin, Michele Del Vecchio, Jeffrey S Weber, David Polsky. Combining total cell-free DNA (cfDNA) and circulating tumor (ctDNA) to enhance the clinical sensitivity of ddPCR assays to detect minimal residual disease (MRD) in stage IIIB/C/IV melanoma patients on adjuvant immunotherapy in CheckMate 238 [abstract]. In: Proceedings of the AACR Special Conference: Liquid Biopsy: From Discovery to Clinical Implementation; 2024 Nov 13-16; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(21_Suppl):Abstract nr B027.

Hemoglobin/creatinine ratio as long- term prognostic marker in acute coronary syndromes: a praise registry study

Abstract Introduction Anemia and renal impairment are key determinants of adverse outcomes in patients with acute coronary syndrome (ACS). The hemoglobin/creatinine (Hb/Cr) ratio, a simple and universally accessible index that combines these two factors, was found to predict adverse outcomes in patients with cardiovascular disease. There is limited evidence on the performance of the Hb/Cr ratio in predicting long-term adverse outcomes in the specific setting of ACS. Purpose To evaluate the long-term prognostic impact of the Hb/Cr ratio in patients with ACS. Methods Out of the 23,270 ACS patients enrolled in the international PRAISE registry between 2003 and 2019, 3.465 were excluded due to missing data and 19.805 were included in this analysis. The primary endpoint was all-cause mortality at one year follow-up. Secondary endpoints were major bleeding and the composite of all-cause mortality or reinfarction at one year follow-up. A cut-point analysis according to Liu’s method was run to evaluate the best discriminative value of the Hb/Cr ratio for the prediction of all-cause mortality. Results The cut-point analysis showed that a cut-off value of 13.79 represented the most discriminative in predicting all-cause mortality at one year (CI 13.35–14.23; AUC 0.66), and that mortality increased exponentially when the ratio was <12.4. On the basis of this discriminative value, we divided our population into low vs. high Hb/Cr groups. The former included 5,874 (29.7%) patients, while the latter included 13,931 (70.3%). Patients in the low Hb/Cr group were older, more frequently female, and had a higher prevalence of cardiovascular risk factors, comorbidities, and history of coronary artery disease. Conversely, patients in the high Hb/Cr group were mostly men and more frequently admitted with a STEMI diagnosis. One year post-discharge from ACS, all-cause mortality (8.3% vs. 2.3%; p < 0.001), major bleeding (5.4% vs. 2.2%; p < 0.001) and the composite of all-cause mortality or reinfarction (11.6% vs. 4.7%; p < 0.001) were significantly higher in the low Hb/Cr group. Bivariate regression analysis showed that Hb/Cr ratio was inversely associated with all-cause mortality (OR 0.85; CI 0.84 – 0.86; p < 0.0001), major bleeding (OR 0.91; CI 0.89-0.92; p < 0.0001), and the composite of all-cause mortality or reinfarction (OR 0.89; CI 0.88-0.90; p < 0.0001). This association held strongly true even after an extensive adjustment for several covariates, including cardiovascular risk factors, comorbidities, and discharge medical therapy: all-cause mortality (OR 0.95; CI 0.92 – 0.97; p < 0.0001), major bleeding (OR 0.92; CI 0.89-0.95; p < 0.0001), composite of all-cause mortality or reinfarction (OR 0.96; CI 0.94-0.98; p < 0.0001). Conclusions HB/Cr ratio appears to be inversely associated with long-term adverse outcomes among ACS patients. Further research is warranted before routinely considering this index in clinical practice.

Longitudinal evaluation of iron status during pregnancy: a prospective cohort study in a high-resource setting

BackgroundIron deficiency affects a large proportion of pregnant women worldwide, with potentially serious consequences for perinatal and infant outcomes, but well-powered, comprehensive analyses of longitudinal iron status during pregnancy are scarce. ObjectivesThis study aimed to evaluate the longitudinal changes in iron biomarkers across pregnancy and prevalence of iron deficiency in primiparous women in a high-resource setting and propose early pregnancy iron status cutoffs that predict iron deficiency in the third trimester. MethodsIn a prospective cohort of primiparous women with low-risk, singleton pregnancies in Ireland, iron [ferritin, soluble transferrin receptors (sTfR), total body iron (TBI)] and inflammatory markers (C-reactive protein, α-glycoprotein) were measured at 3 study visits: 15, 20, and 33 wk of gestation. Women with anemia (hemoglobin < 110g/L) at their first routine antenatal visit were excluded from this analysis. ResultsParticipants (N = 629) were Caucasian (98.2%) and born in Ireland (80.6%). The prevalence of iron deficiency (ferritin < 15 μg/L) increased throughout pregnancy, at 4.5%, 13.7% and 51.2% at 15, 20, and 33 wk of gestation, respectively. Using a ferritin threshold of <30 μg/L, rates of deficiency were 20.7%, 43.7%, and 83.8% across these time points, respectively. Application of sTfR of >4.4 mg/L generated similar prevalence data as ferritin of <15 μg/L at 7.2%, 12.6%, and 60.9%, respectively. Using TBI of <0 mg/kg, deficiency rates were lower than using ferritin or sTfR (P < 0.001). Using a cutpoint analysis method (area under the curve = 0.750), ferritin of <60 μg/L emerged as the ferritin threshold at 15 wk that predicted the presence of iron deficiency (ferritin < 15 μg/L) at 33 wk. Iron-containing supplements (mainly multivitamins) taken prepreganancy/early pregnancy was associated with reduced risk of deficiency throughout pregnancy, including the third trimester (odds ratio: 0.57; 95% confidence interval: 0.39, 0.82; P = 0.002). ConclusionsPregnancy places a remarkable strain on maternal iron status even in a high-resource, generally iron-supplemented population. Women should be screened early in pregnancy for iron status, with a suggested target ferritin concentration of >60 μg/L.This trial was registered at clinicaltrials.gov as NCT01891240 (IMPROvED Study; ==https://www.clinicaltrials.gov/study/NCT01891240?cond=NCT01891240&rank=1).

The effects of ambient air pollution exposure on Thoroughbred racehorse performance.

Limited research exists on impacts of air pollution on non-human mammals, particularly animal athletes such as Thoroughbred racehorses. Athletes have a greater risk of exposure as heightened exertion and increased airflow carry more pollutants deeper into the respiratory tract. To provide insights into the impact of ambient air pollution, particularly fine particulate matter (PM2.5), on race speed. Retrospective observational study. Data were obtained from The Jockey Club Information Systems, covering 31 407 winning races by Thoroughbred horses in California spanning 10 years (2011-2020) and evaluated the association between air pollution and winning race speeds. For race days, we collected PM2.5 data from the nearest U.S. Environmental Protection Agency (EPA) monitoring site within 100 km of each racetrack (n = 12). We assessed the associations between daily average PM2.5 concentrations and speed of winning horses with linear mixed effects regression. We adjusted for horse characteristics, race-related covariates, temporal indicators (e.g., year), other air pollutants and temperature. We conducted sensitivity analyses by adjusting extreme air pollution days by reassigning values to the 95th percentile value and conducting linear mixed effects regression on series of datasets with incremental cutpoints of PM2.5. In the cutpoint analysis, we found that for PM2.5 between 4 and 23.6 μg/m3, speed decreased 0.0008 m/s (95% CI: -0.0014562 to -0.00018) for every 1 μg/m3 increase of PM2.5. Limitations include the use of offsite monitors leading to imprecise exposure measurements, not using training practice data, and generalisability as the study focuses on California racetracks. This study highlights the need to create advisories to safeguard the performance of horses during periods of poor air quality. Further research is recommended to explore additional factors influencing the relationship between air pollution and equine welfare.

Social Vulnerability Index Is Associated With Major Morbidity After Lung Resection

BackgroundLittle is known about the prognostic impact of the Social Vulnerability Index (SVI) in patients with early-stage non-small cell lung cancer (NSCLC) who are undergoing video-assisted thoracoscopic lung resection. MethodsPatients who underwent lung resection for stage IA-IIB NSCLC at a single institution between 2010 and 2021 were included in the study. The Society of Thoracic Surgeons definition of major morbidity, consisting of 14 postoperative events, was used. The SVI was determined by geocoding the permanent addresses of Illinois residents and using the Centers for Disease Control and Prevention calculator for a census-tract level SVI. Univariate and multivariate logistic regression analyses were used to examine the association between the SVI and major morbidity. Cut-point analysis was performed to determine the SVI cutoff that most strongly correlated with major morbidity. ResultsA total of 551 patients met inclusion criteria, and 65% (356 of 551) of these patients underwent lobectomy. The SVI cutoff was determined to be 0.831 (P = .010). In the high-SVI cohort , 58% (26 of 45) were Black, compared with 9% (45 of 506) in the low-SVI cohort (P < .001). For high-SVI patients, the major morbidity rate was 27% vs 9% for low-SVI patients (P = .0174), and the 1-year mortality rate was 8.9% vs. 3.0% for those with a low SVI (P = .061). On univariate analysis, high SVI status was associated with 30-day major morbidity (odds ratio, 2.84; CI, 1.28-6.29; P = .010). On multivariate analysis, after controlling for age, race, sex, tumor histologic type, procedure type, preoperative comorbidities, smoking history, and forced expiratory volume in 1 second, this association persisted (odds ratio, 3.16; CI, 1.11-8.99; P = .031). ConclusionsA high SVI is associated with major morbidity after video-assisted thoracoscopic lung resection for NSCLC.

Early Opioid Use and Postoperative Delirium Following Open Abdominal Aortic Aneurysm Repair

Postoperative delirium is a common complication following open abdominal aortic aneurysm repair (OAR). Opioids have been found to contribute to delirium, especially at higher doses. This study assessed the impact of early postoperative opioid analgesia on postoperative delirium incidence and time to onset. We hypothesized that higher early postoperative opioid utilization would be associated with increased postoperative delirium incidence. This was a retrospective analysis of OAR cases at a single quaternary care center from years 2012-2020. The primary exposure was oral morphine equivalents use (OME), calculated for postoperative days 1-7. A cut point analysis using a receiver operator curve for postoperative delirium determined the threshold for high OME (OME>37mg). The primary outcome was postoperative delirium incidence identified via chart review. Multivariable logistic regression was performed for postoperative delirium and adjusted for covariates meeting P<0.1 on bivariate analysis. Among 194 OAR cases, 67 (35%) developed postoperative delirium with median time to onset of 3days (IQR=2-6). Patients with postoperative delirium were older (74years vs. 69years), more frequently presented with symptomatic AAA (47% vs. 27%) and had a higher proportion of comorbidities (all P<0.05). Cases with high OME utilization on postoperative day 1 (55%) were younger (69 vs. 73years), less frequently had an epidural (46% vs. 77%), and more frequently developed delirium (42% vs. 25%, all P<0.05). Epidural use was associated with a significant decrease in OME utilization on postoperative day 1 (33 vs. 83, P<0.01). Postoperative delirium onset was later in those with high OME use (4 vs. 2days, P=0.04). On multivariable analysis, high OME remained associated with postoperative delirium (Table II). High opioid utilization on postoperative day 1 is associated with increased postoperative delirium and epidural along with acetaminophen use reduced opioid utilization. Future study should examine the impact of opioid reduction strategies on outcomes after major vascular surgery.

Abstract PO2-01-14: Development of Artificial Intelligence-based Machine Learning Models for Predicting Survival In Hormone-Receptor-Positive/HER2-Negative Early Breast Cancer undergoing Neoadjuvant Chemotherapy

Abstract Background. In hormone-receptor positive (HoR)/HER2 negative early breast cancer (BC) multiple efforts have been made to predict disease recurrence and survival. Machine learning techniques have been used but few studies have looked into their applicability in predicting survival on the basis of clinico-pathological characteristics. The aim of this study was to evaluate a random survival forest model to predict the prognosis of this specific BC subtype. Methods. In this multicenter, retrospective study, patients who fulfilled the following inclusion criteria were included: (1) diagnosis of pathologically confirmed HoR-positive/HER2-negative invasive BC; (2) early or locally advanced, stage I-II-III (3) patients receiving neoadjuvant anthracycline and/or taxane-based chemotherapy, concurrently or sequentially; (4) patients undergoing surgery for primary BC. Survival endpoints were disease-free survival (DFS) and overall survival (OS). A random survival forest algorithm was used to develop the predictive model. Ten-fold cross-validation was performed. The C-index and the continuous rank probability score (CRPS) were used to evaluate the discrimination of the predictive model, and a ROC curve was used to evaluate model precision. A cut point analysis based on maximally selected rank statistics was conducted to evaluate the best cut-off in the out-of-bag (OOB) mortality that could maximize DFS and OS prediction. Variable importance was assessed using Breiman-Cutler permutation importance. Results. Overall, 572 patients with HoR-positive/HER2-negative early BC were included. At univariate analysis age, T stage, N stage, grading, ER, PR and Ki67 were found to be significantly associated with DFS and ER, PgR, HER2, pCR ypT and ypN retained statistical significance at multivariate analysis. ER, pCR, pathological T and N stage were found to be significantly associated with OS at univariate and multivariate analysis. The following variables were included in the final model: menopausal status, age, histology, grade, clinical T/N, ER/PgR, Ki67 and HER2, pathological complete response (pCR), ypT and ypN. For DFS, the cross-validated C-index was 0.68 (95% CI 0.63-0.73) and the OOB CRPS was 0.15, with a OOB performance error of 0.31. The AUC calculated at 60 months was 0.91 (95% CI 0.88-0.94). Out-of bag RSF-based risk scores for individual patients were calculated and an optimal cut-off of 22.58 was identified. The HR between high risk and low risk group was 3.08 (95% CI 2.16-4.39, p&amp;lt; 0.001). For OS, the cross-validated C-index was 0.66 (95% CI 0.60-0.71) and the OOB CRPS was 0.17, with a OOB performance error of 0.35. The AUC calculated at 60 months 0.91 (95% CI 0.88-0.95). An optimal cut-off of 21.54 was identified and the HR between low risk and high risk group was 2.50 (95% CI 1.73-3.61, p&amp;lt; 0.001). For DFS, the most important variables were cN (9.00), ypN (7.35), ER (7.21), ypT (5.38), PgR (4.11), pCR (4.01) and age (2.82) while for OS the most important variables were cN (7.88), ER (5.37), PgR (3.61), age (3.37), pCR (2.80), ypT (2.64) and ypN (2.60). Discussion. We analyzed the performance of RSF in the prediction of DFS and OS based on the contribution of clinico-pathological features commonly available at the baseline of the NCT and post-surgery. By selecting patients with HoR-positive HER2-negative disease, we were able to show which clinico-pathological features within a ML model have greater predictive importance. The model could be integrated with image-based tumor and radiology features to improve its predictive accuracy. This retrospective multicenter study suggests that the combination of easily accessible clinico-pathological features within a ML model may reliably predict DFS and OS in the context of HoR-positive/HER2-negative BCs. Citation Format: Luca Mastrantoni, Giovanna Garufi, Noemi Maliziola, Elena Di Monte, Giorgia Arcuri, Valentina Frescura, Angelachiara Rotondi, Giulia Giordano, Luisa Carbognin, Alessandra Fabi, Ida Paris, Gianluca Franceschini, Armando Orlandi, Antonella Palazzo, Giovanni Scambia, Giampaolo Tortora, Emilio Bria. Development of Artificial Intelligence-based Machine Learning Models for Predicting Survival In Hormone-Receptor-Positive/HER2-Negative Early Breast Cancer undergoing Neoadjuvant Chemotherapy [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-01-14.

Abstract PS04-08: Sociodemographic Risk Factors and Prediction of Aromatase Inhibitor Non-Adherence in Women with Breast Cancer Enrolled in SWOG S1105

Abstract Background: Non-adherence to aromatase inhibitors (AIs) for breast cancer is common and increases risk of recurrence. Few prospective studies have systematically evaluated non-adherence and non-clinical factors associated with it. We analyzed baseline sociodemographic characteristics and financial factors associated with non-adherence to create a baseline composite risk-score for AI non-adherence. Methods: Patients enrolled in S1105 were required to have been on an AI for ≥30 days at enrollment. Patients were assessed for non-adherence of AIs every 3 months for 36 months, with non-adherence defined as urine AI metabolite assay results satisfying any of the following: &amp;lt; 10 ng/mL, undetectable, specimen submitted outside of the ± 21-day follow-up appointment window, or no submitted specimen. Factors included race, Hispanic ethnicity, age, education, income, health insurance type, and prescription cost. We also included socioeconomic deprivation and rural or urban residence using trial participants’ residential zip codes linked to the Area Deprivation Index (ADI) and Rural Urban Continuum codes (RUCC) respectively. For numeric factors and categorical factors with more than two levels, we used cutpoint analysis to determine the highest risk range by optimizing the Chi-squared statistic. For each resulting binary factor, we performed a logistic regression, adjusting for the study stratification factors and stratifying by treatment arm. Factors associated with adherence at the alpha=0.10 level were combined into a composite risk score, with study participants given one point for each baseline adverse risk factor. Secondarily, we examined a composite risk score including all factors, regardless of statistical significance. Results: In total, 724 patients were registered from 40 institutions between May 2012 and September 2013. The median age was 60.9 years, and 64.5% were on AI &amp;lt; 12 months prior to registration. Only 8% had out of pocket (OOP) cost &amp;gt;$30. Observed adherence at 36 months was 35.9%. Patients living in metro areas with populations ≥ 250,000 (RUCC ≤ 3) were more likely to be non-adherent (37.5% vs 28.3%, OR=1.50, p=.08); as were those who were younger, those without a college education, and those with limited (≤$5) OOP cost. ADI, race and ethnicity were not associated with non-adherence. The composite risk score was strongly associated with 36-month adherence. For each 1 unit increase in risk level, the risk of non-adherence increased 47% (OR=1.47, p&amp;lt; .001); the risk increased 64% for those with &amp;gt;2 vs. ≤2 risk factors (OR=1.64, p=.002). Results using all factors regardless of statistical significance were consistent. Conclusions: A composite model comprised of sociodemographic risk factors can identify patients on AI’s at much greater risk of long-term AI non-adherence. In addition to mitigating side effects, targeted interventions to improve adherence should focus on structural barriers among those at highest risk. Non-adherence (+/- 6 months) = factor + AI duration + AI type, stratified by arm Citation Format: Dawn Hershman, Anna Moseley, Kathryn Arnold, Julie Gralow, Alfred Neugut, Scott Ramsey, N. Lynn Henry, Joseph Unger. Sociodemographic Risk Factors and Prediction of Aromatase Inhibitor Non-Adherence in Women with Breast Cancer Enrolled in SWOG S1105 [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PS04-08.

Role of maternal hyperoxygenation in predicting need for postnatal balloon atrial septostomy in fetal d-transposition of the great arteries.

Predicting whether postnatal balloon atrial septostomy (BAS) will be necessary for fetuses with dextro-transposition of the great arteries (d-TGA) remains challenging. We sought to determine whether fetal echocardiographic measurements obtained during maternal hyperoxygenation (MH) can improve our ability to predict the need for postnatal BAS. This was a retrospective, single-institution review of d-TGA fetuses whose mothers had undergone MH at 33-38 weeks' gestation at the Children's Hospital of Philadelphia, between 1 January 2017 and 30March2020. All fetal d-TGA cases had either an intact ventricular septum or small ventricular septal defect measuring < 3 mm. Patent foramen ovale (PFO) size, measured by two-dimensional imaging (2D) and by color Doppler, and patent ductus arteriosus (PDA) shunting (antegrade vs bidirectional) were assessed in room air (RA) and during MH. BAS status and timing were recorded. Of 41 fetal d-TGA cases in the cohort, 23 underwent postnatal BAS, while 18 did not, and 14 subjects underwent emergent BAS within 3 h of delivery. On univariate analysis, PFO size measured both in RA and during MH and antegrade shunting in the PDA during MH predicted BAS. During MH, median PFO size by 2D was significantly smaller in fetuses which underwent emergent BAS compared to fetuses which did not undergo BAS (2.5 (interquartile range (IQR), 2.0-3.0) mm vs 4.1 (IQR, 3.4-5.0) mm; P < 0.001). On cut-point analysis, PFO size by 2D during MH of ≤ 3.2 mm predicted the need for emergent BAS with a sensitivity of 93% (95% CI, 66-100%) and a specificity of 78% (95% CI, 58-91%). In fetuses with d-TGA, measurement of PFO size and direction of PDA shunting during MH improves our ability to predict the need for postnatal BAS, although additional study is needed. We propose incorporating third-trimester MH when planning delivery of a d-TGA fetus. © 2024 International Society of Ultrasound in Obstetrics and Gynecology.

Centiles for the shock index among injured children in the prehospital setting

ObjectiveThe shock index (SI), the ratio of heart rate to systolic blood pressure, is a clinical tool for assessing injury severity. Age-adjusted SI models may improve predictive value for injured children in the out-of-hospital setting. We sought to characterize the proportion of children in the prehospital setting with an abnormal SI using established criteria, describe the age-based distribution of SI among injured children, and determine prehospital interventions by SI. MethodsWe performed a multi-agency retrospective cross-sectional study of children (<18 years) in the prehospital setting with a scene encounter for suspected trauma and transported to the hospital between 2018 and 2022 using the National Emergency Medical Services (EMS) Information System datasets. Our exposure of interest was the first calculated SI. We identified the proportion of children with an abnormal SI when using the SI, pediatric age-adjusted (SIPA); and the pediatric SI (PSI) criteria. We developed and internally validated an age-based distributional model for the SI using generalized additive models for location, scale, and shape to describe the age-based distribution of the SI as a centile or Z-score. We evaluated EMS interventions (basic airway interventions, advanced airway interventions, cardiac interventions, vascular access, intravenous fluids, and vasopressor use) in relation to both the SIPA, PSI, and distributional SI values. ResultsWe analyzed 1,007,863 pediatric EMS trauma encounters (55.0% male, median age 13 years [IQR, 8–16 years]). The most common dispatch complaint was for traffic/transport related injury (32.9%). When using the PSI and SIPA, 13.1% and 16.3% were classified as having an abnormal SI, respectively. There were broad differences in the percentage of encounters classified as having an abnormal SI across the age range, varying from 5.1 to 22.8% for SIPA and 3.7–20.1% for PSI. The SIPA values ranged from the 75th to 95th centiles, while the PSI corresponded to an SI greater than the 90th centile, except in older children. The centile distribution for SI declined during early childhood and stabilized during adolescence and demonstrated a difference of <0.1% at cutoff values. An abnormal PSI, SIPA and higher SI centiles (>90th centile and >95th centiles) were associated with interventions related to basic and advanced airway management, cardiac procedures, vascular access, and provision of intravenous fluids occurred with greater frequency at higher SI centiles. Some procedures, including airway management and vascular access, had a smaller peak at lower (<10th) centiles. DiscussionWe describe the empiric distribution of the pediatric SI across the age range, which may overcome limitations of extant criteria in identifying patients with shock in the prehospital setting. Both high and low SI values were associated with important, potentially lifesaving EMS interventions. Future work may allow for more precise identification of children with significant injury using cutpoint analysis paired to outcome-based criteria. These may additionally be combined with other physiologic and mechanistic criteria to assist in triage decisions.

Network analysis of live pig movements in the Republic of North Macedonia in the period 2019-2020: Identification of key farms and municipalities regar­ding their role in the spread of infectious diseases

Social network analysis could be a useful tool in the understanding of many aspects of animal movements because the movement of pigs between farms is one of the main routes for the spread of infectious diseases. Its outputs may highlight information about pig farms and areas that are highly connected and identify key players in animal traffic. The purpose of the study was to identify key farms in the live pig movement network and detect municipalities in North Macedonia which are at risk of disease transmission due to increased pig movements. To this end, completed live pig movement data in the period 2019-2020 extracted from the electronic national database in the system of identification and registration of animals, from the Food and Veterinary Agency of the Republic of North Macedonia was used. Igraph package in R programming language was used to carry out the analysis and spdep package to test spatial autocorrelation. Our findings showed that the size of the network was 320 nodes and 859 links. It was found that 215 (67.2%) farms had in-degree values in the range 1-164 and 137 (42.8%) farms had out-degree values in range of 1-166. Twenty-four farms (7.5%) showed a betweenness centrality value of 1-72, and the cut-point analysis detected 56 farms (17.5%), with most farms located in central, east, and southeastern parts of the country. Network density showed 0.008 or 0.8% and clustering coefficient (transitivity) of 0.017. Moran’s I statistic for spatial autocorrelation of municipalities with summarised in-degree showed negative value (-0.003, p=0.295) and municipalities with summarised out-degree showed positive value (0.126, p=0.031). This study identified pig farms that could influence the animal flow and their geographical location. The municipality of Veles was identified as the area with the highest arrivals and departures of pig batches. Findings may be useful to inform decision-makers to target farms and municipalities for surveillance and to organise official control and early detection of contagious swine diseases

Establishing outcome-driven vital signs ranges for children in the prehospital setting.

Vital signs are frequently used in pediatric prehospital assessments and guide protocol utilization. Common pediatric vital sign classification criteria identify >80% of children in the prehospital setting as having abnormal vital signs, though few receive lifesaving interventions (LSIs). We sought to identify data-driven thresholds for abnormal vital signs by evaluating their association with prehospital LSIs. We evaluated prehospital care records for children (<18 years) transported to the hospital during 2022 from a large, national repository of emergency medical services (EMS) patient encounters. Predictors of interest were heart rate (HR), respiratory rate (RR), systolic blood pressure (SBP), and pulse oximetry. HR, RR, and SBP were converted to Z-scores using age-based distributional models. Our outcome was potential LSIs, defined as performance of selected respiratory procedures, resuscitative interventions, or medication administrations. Using cut point analysis, we identified higher specificity (maximal specificity with a minimum of 25% sensitivity) and higher sensitivity (maximal sensitivity with a minimum of 25% specificity) ranges for each vital sign and evaluated measures of diagnostic accuracy. We included 987,515 children (median age 10 years, IQR 2-15 years). An LSI occurred in 4.3% (2.1% with respiratory procedures, 1.2% with resuscitative interventions, and 2.0% with medication administration). HR, RR, and SBP demonstrated a U-shaped association with LSIs. Specificities ranged from 84.1% to 93.7% for higher specificity criteria, with RR demonstrating the best performance (sensitivity 84.6%, specificity 27.0%). Sensitivities ranged from 62.3% to 84.4% for higher sensitivity criteria. Cut points for pediatric vital signs were associated with LSIs. Specific age-adjusted ranges can identify children at higher and lower risk for receipt of LSI. These ranges may be combined with other objective measures to improve the assessment of children in the prehospital setting, assist in optimizing protocol utilization, improve transport decision making, and guide destination selection.

Impact of Bone Modifying Agent Initiation Time, Frequency, and Duration on Skeletal-Related Events in Patients with Multiple Myeloma

Background: Skeletal related events (SREs) including pathologic fractures, surgery or radiation to bone, and spinal cord compression contribute to diminished quality of life in patients with multiple myeloma. Bone modifying agents (BMA) such as denosumab or the bisphosphonates zoledronic acid and pamidronate, are used to inhibit osteoclast activity to prevent SREs. The Bone Working Group of the International Myeloma Working Group suggests monthly administration of zoledronic acid for 12 months in newly diagnosed myeloma patients. This is followed by an option to discontinue or decrease administration frequency to every 3, 6, or 12 months if a very good partial response or better is achieved. The ideal start time of BMA from diagnosis and the duration of administration has not been adequately established to optimize reduction of SREs. Methods: This was a retrospective, single-center study that included newly diagnosed myeloma patients treated at the Mayo Clinic between 9/1/2018 and 9/1/2020 who had received at least one dose of a BMA. The primary objective was to evaluate the impact of BMA dosing frequency and duration on SREs. Secondary objectives included time to BMA initiation, time to relapse or progressions following BMA start, and safety. Data was summarized using frequencies and percentages for categorical data, and medians and interquartile ranges (IQR) for continuous data. A spline plot and cut-point analysis were used to assess the association of time from multiple myeloma diagnosis to BMA initiation with skeletal related outcomes. Rates of SREs were estimated using the Aalen-Johansen method, where death was treated as a competing risk. Associations of factors with SREs were assessed using Cox proportional hazards regressions, and these associations were summarized using hazard ratios (HR) and corresponding 95% confidence intervals (CI). Variables that could change throughout follow-up including BMA frequency, cumulative BMA dose, and duration of BMA were treated as time-dependent covariates in the Cox proportional hazards models, where the information for these variables was updated each time an additional dose of BMA was given. All analyses were performed using SAS version 9.4 software (SAS Institute, Inc.; Cary, NC) and R version 4.2.2 (R Core Team, R Foundation for Statistical Computing, Vienna, Austria). Results: Sixty-seven patients were included with a median age of 65 years old. The most frequently used BMA was zoledronic acid (88.1%), followed by pamidronate (7.5%), and denosumab (4.5%). Fifty-five patients (82.1%) had bone disease at baseline. Within 2 years of starting BMA, SREs occurred in 42.2% of patients with baseline bone disease and 8.3% of patients without (p=0.054). Median time to BMA initiation after diagnosis was 45 days (IQR 14-105) in patients with baseline bone disease and 87 (IQR 32-496) in patients without. Among the 26 patients with a SRE, median time from start of BMA to SRE was 170 days (IQR 32-496). No significant association was found between time to initiation and development of a SRE (Figure 1). BMA dosing frequencies of every 3 months and 6 months had a HR for SREs of 1.67 and 0.47, respectively compared to every 1 month, (P-values &amp;gt;0.25). After excluding patients without baseline bone disease, compared to every 1 month dosing, dosing every 3 months and every 6 months increased the risk of SRE, although the differences were not statistically significant (3 months: HR=1.92, 95% CI 0.76-4.88, p=0.17; and 6 months: HR=1.26, 95% CI 0.14-10.94, p=0.84). Patients without bone disease at baseline remained on BMAs for a median of 1.8 years while patients with bone disease received BMAs for a median of 2 years. There was no statistically significant difference found with varying duration or cumulative dose and SRE development (Table 1). Relapse or progression occurred in 32.1% of patients within 2 years of starting BMA, while death occurred in 7.5% of patients. Osteonecrosis of the jaw occurred in 1 patient with bone disease at baseline who received zoledronic acid every 3 months for a duration of 596 days. Conclusions: No significant association between time of BMA initiation, dosing frequency, or duration on development of SREs were observed. This suggests delaying the start time of BMAs to allow for dental clearance and initial treatment would not increase risk of SREs. Prospective trials are needed to confirm these findings.

Accuracy of the Exeter Hospitalizations-Office Visits-Medical Conditions-Extra Care-Social Concerns Index for Identifying Children With Complex Chronic Medical Conditions in the Clinical Setting.

Our objective was to determine the accuracy of a point-of-care instrument, the Hospitalizations-Office Visits-Medical Conditions-Extra Care-Social Concerns (HOMES) instrument, in identifying patients with complex chronic conditions (CCCs) compared to an algorithm used to identify patients with CCCs within large administrative data sets. We compared the HOMES to Feudtner's CCCs classification system. Using administrative algorithms, we categorized primary care patients at a children's hospital into 3 categories: no chronic conditions, non-complex chronic conditions, and CCCs. We randomly selected 100 patients from each category. HOMES scoring was completed for each patient. We performed an optimal cut-point analysis on 80% of the sample to determine which total HOMES score best identified children with ≥1 CCC and ≥2 CCCs. Using the optimal cut points and the remaining 20% of the study population, we determined the odds and area under the curve (AUC) of having ≥1 CCC and ≥2 CCCs. The median (interquartile range [IQR]) age was 4 (IQR: 0, 8). Using optimal cut points of ≥7 for ≥1 CCC and ≥11 for ≥2 CCCs, the odds of having ≥1 CCC was19 times higher than lower scores (odds ratio [OR] 19.1 [95% confidence interval [CI]: 9.75, 37.5]) and of having ≥2 CCCs was 32 times higher (OR 32.3 [95% CI: 12.9, 50.6]). The AUCs were 0.76 for ≥1 CCC (sensitivity 0.82, specificity 0.80) and 0.74 for ≥2 CCCs (sensitivity 0.92, specificity 0.74). The HOMES accurately identified patients with CCCs.

Cognitive Predictors of Responsiveness to Reactive Step Training in People with Parkinson’s Disease at Fall-Risk

Reactive stepping can be improved in people with Parkinson’s Disease (PwPD). However, there is variability in the responsiveness to such training. This study examined if cognition could predict the responsiveness of PwPD to a two-week reactive step training intervention. 25 PwPD (70.52 years ± 7.15; Hoehn & Yahr range 1–3) at risk for falls completed a multiple baseline, open-label, uncontrolled pre-post intervention study. Reactive stepping was trained through a two-week (six-session) intervention with repeated support surface translations. Stepping performance was measured at two baseline assessments (B1 and B2), immediately after the intervention (P1), and two months after training (P2). Primary stepping outcomes were anterior-posterior margin of stability (MOS), step length, and step latency during backward steps. The primary aim assessed whether global cognition (Scales for Outcomes in Parkinson's Disease-Cognition - SCOPA-COG, & Montreal Cognitive Assessment - MoCA) was related to two-month retention of improvements in reactive stepping after practice. The secondary aim explored whether specific cognitive domains predicted retained stepping improvements, including attention/working memory, executive function, language, memory, and visuospatial function. Greater baseline global cognition was related to better two-month retention of step length improvements (SCOPA-COG: p = 0.002, f2 = 0.31; MoCA: p = 0.002, f2 = 0.38). However, only SCOPA-COG retained statistical significance after p-value adjustment for multiple comparisons (p = 0.04). Optimal cut-point analysis revealed that a SCOPA-COG threshold of 31 or higher was optimal for identifying individuals likely to retain improvement. Specific cognitive domains did not predict changes in reactive stepping outcomes. Participants with greater baseline global cognition, particularly as measured by SCOPA-COG, demonstrated greater retention of improvements in reactive stepping. In this cohort, a SCOPA-COG threshold of 31 could predict individuals likely to benefit from the intervention. These findings highlight the potential of cognitive screening to identify people more or less likely to benefit from reactive balance training.

Assessment of Minimum Dose as a Strong Predictor of Local Failure after Spine SBRT

Stereotactic body radiation therapy (SBRT) has demonstrated robust clinical benefits in carefully selected patients, improving local control and even overall survival (OS). Even so, a wide range of dose-fractionation schemes are used in clinical practice. We seek to assess a large database to determine clinical and dosimetric predictors of local failure after spine SBRT. From a large institutional database, spine SBRT treatments with subsequent imaging follow-up to assess local control were identified. Patients were treated with a simultaneous integrated boost technique using 1 or 3 fractions, generally delivering 20-24 Gy in 1 fraction to the high dose volume and 16 Gy to the low dose volume (or 30-36 Gy and 24 Gy for 3 fraction treatments). Exclusions included: lack of imaging follow-up, proton therapy, and benign primary histologies. Statistical analyses included Cox proportional hazards analyses and the robust log-rank statistic for cut-point analysis. The cumulative incidence of local failure with death as a competing risk was considered as the primary endpoint. A total of 522 eligible spine SBRT treatments (68% single fraction) were identified in 377 unique patients. Patients had a median OS of 43.7 months (95% confidence interval: 34.3-54.4). The cumulative incidence of local failure was 19.3% (15.3-23.2) at 1 year and 25.6% (21.1-29.9) at 2 years. Univariate analysis identified that the minimum dose (normalized for the prescription dose) was a strong predictor of local failure (p = 0.0093). Among patients treated with a single fraction, statistical significance was maintained (p = 0.024). No other dosimetric factors were predictive of local failure. In a cut point analysis, the log-rank statistic was maximized at 15.8 Gy minimum dose for single-fraction treatment (HR = 0.51, 95% CI: 0.34 - 0.75, p = 0.0009). Cumulative incidence of local failure was 15.1% (9.8-20.2) vs. 24.7% (17.2-31.5) at 1 year using this cut-off. Comparable local control was demonstrated with a minimum dose of 14 Gy (HR = 0.57, 95%: 0.37 - 0.87, p = 0.009), with reduced local control with lower minimum doses. Among a range of clinical factors assessed, only epidural and soft tissue involvement were predictive of local failure (HR = 1.80 and 1.98, respectively). Multivariable analyses incorporating soft tissue involvement, epidural extension, and multilevel disease confirmed the 15.8 Gy cutoff for single fraction cases (HR = 0.58, 95% CI: 0.38-0.88, p = 0.011). Spine SBRT offers favorable local control using a range of dose-fractionation schemes; however, minimum dose has a strong association with local control, unlike any other dosimetric factors tested. Furthermore, statistical significance was maintained even when considering epidural extension and potential limitations from dose to the spinal cord. Our data suggests that the minimum dose should be prioritized during treatment planning, ideally to at least 14 - 15.8 Gy for single fraction.

Pneumonitis Rates Before and After Adoption of Immunotherapy Consolidation in Patients With Locally Advanced Non-Small Cell Lung Cancer Treated With Concurrent Chemoradiation

We hypothesized that after adoption of immune checkpoint inhibitor (ICI) consolidation for patients with locally advanced non-small cell lung cancer (LA-NSCLC) receiving concurrent chemoradiation therapy (cCRT), rates of symptomatic pneumonitis would increase, thereby supporting efforts to reduce lung radiation dose. This single institution, multisite retrospective study included 783 patients with LA-NSCLC treated with definitive cCRT either before introduction of ICI consolidation (pre-ICI era cohort [January 2011-September 2017]; N=448) or afterward (ICI era cohort [October 2017-December 2021]; N=335). Primary endpoint was grade ≥2 pneumonitis (G2P) and secondary endpoint was grade ≥3 pneumonitis (G3P), per Common Terminology Criteria for Adverse Events v5.0. Pneumonitis was compared between pre-ICI era and ICI era cohorts using the cumulative incidence function and Gray's test. Inverse probability of treatment weighting (IPTW)-adjusted Fine-Gray models were generated. Logistic models were developed to predict the 1-year probability of G2P as a function of lung dosimetry. G2P was higher in the ICI era than in the pre-ICI era (1-year cumulative incidence 31.4% vs 20.1%; P < .001; IPTW-adjusted multivariable subdistribution hazard ratio, 2.03; 95% confidence interval, 1.53-2.70; P < .001). There was no significant interaction between ICI era treatment and either lung volume receiving≥20 Gy (V20) or mean lung dose in Fine-Gray regression for G2P; however, the predicted probability of G2P was higher in the ICI era at clinically relevant values of lung V20 (≥24%) and mean lung dose (≥14 Gy). Cut-point analysis revealed a lung V20 threshold of 28% in the ICI era (1-year G2P rate 46.0% above vs 19.8% below; P < .001). Among patients receiving ICI consolidation, lung V5 was not associated with G2P. G3P was not higher in the ICI era (1-year cumulative incidence 7.5% vs 6.0%; P=.39; IPTW-adjusted multivariable subdistribution hazard ratio, 1.12; 95% confidence interval, 0.63-2.01; P=.70). In patients with LA-NSCLC treated with cCRT, the adoption of ICI consolidation was associated with an increase in G2P but not G3P. With ICI consolidation, stricter lung dose constraints may be warranted.

Smoothed empirical likelihood for optimal cut point analysis

In diagnostic studies, a continuous biomarker is often dichotomized for the diagnosis of binary disease status. Various criteria have been studied for the cut point selection of the continuous biomarker in receiver operating characteristic (ROC) analysis, in particular, the Youden index, the closest-to-(0,1) index, and the concordance probability index. Recently, Wang, Tian, and Zhao (2017) established a Wilks theorem for a smoothed empirical likelihood ratio statistic of Youden index. However, it is not directly useful for statistical inference compared to the cut point. In addition, the optimal cut point may vary with different criteria. In this article, we study smoothed empirical likelihood for optimal cut point selection with Youden index, closest-to-(0,1) criterion, and concordance probability. We develop confidence estimation for the optimal cut points based on the smoothed empirical likelihood ratio statistics. We examine the empirical performance by extensive simulation studies. We also illustrate the method with a real dataset.

Optimal examined lymph node number for accurate staging and long-term survival in rectal cancer: a population-based study.

Although the recommended minimal examined lymph node (ELN) number in rectal cancer (RC) is 12, this standard remains controversial because of insufficient evidence. We aimed to refine this definition by quantifying the relationship between ELN number, stage migration and long-term survival in RC. Data from a Chinese multi-institutional registry (2009-2018) and the Surveillance, Epidemiology, and End Results (SEER) database (2008-2017) on stages I-III resected RC were analysed to determine the relationship between ELN count, stage migration, and overall survival (OS) using multivariable models. The series of odds ratios (ORs) for negative-to-positive node stage migration and hazard ratios (HRs) for survival with more ELNs were fitted using a Locally Weighted Scatterplot Smoothing (LOWESS) smoother, and structural breakpoints were determined using the Chow test. The relationship between ELN and survival was evaluated on a continuous scale using restricted cubic splines (RCS). The distribution of ELN count between the Chinese registry ( n =7694) and SEER database ( n =21332) was similar. With increasing ELN count, both cohorts exhibited significant proportional increases from node-negative to node-positive disease (SEER, OR, 1.012, P <0.001; Chinese registry, OR, 1.016, P =0.014) and serial improvements in OS (SEER: HR, 0.982; Chinese registry: HR, 0.975; both P <0.001) after controlling for confounders. Cut-point analysis showed an optimal threshold ELN count of 15, which was validated in the two cohorts, with the ability to properly discriminate probabilities of survival. A higher ELN count is associated with more precise nodal staging and better survival. Our results robustly conclude that 15 ELNs are the optimal cut-off point for evaluating the quality of lymph node examination and stratification of prognosis.

Optimal number of lymph node stations associated with improved survival among patients with non-small cell lung cancer (NSCLC).

8571 Background: Good quality pathologic nodal evaluation is associated with improved long-term survival in NSCLC after surgical resection. However, there is no universal definition of quality. We examined the association between number of lymph node stations (NLNS) sampled and overall survival. Methods: We examined the population-based Mid-South Quality of Surgical Resection (MS-QSR) cohort, excluding patients with neoadjuvant therapy, positive margins, and secondary resections. We summarized demographic and clinical characteristics with appropriate statistics. We employed four Cox regression models: 1) including NLNS as the only predictor; 2) model 1, adjusting for age, sex, histology, clinical stage, extent of resection, and surgical technique; 3) examined the impact of pathologic staging (pStage in 3 groups: IA/IB[&lt;4cm tumor size]; IB[&gt;4cm]/II/IIIA[pN2-]; pN2]) by modeling interaction with pStage and NLNS; 4) model 3 plus adjustments (no clinical stage). In a cut point analysis to identify the optimal NLNS for improved survival, we dichotomized the NLNS for cut points 0 to 12. Hazard ratios (HR) were calculated (as above) and plotted for each dichotomization. Results: The 3916 eligible patients were 21% Black, 54% male, 15% on Medicaid and 49% Medicare; 84% and 85% had clinical and pathologic stage I/II, respectively; 84% had no invasive staging; 84% had a PET-CT scan. For every additional lymph node station sampled, the HR decreased by 0.94 (95% confidence interval: 0.92, 0.96). After adjustments, the HR remained significant (Table). Our pStage cohorts comprised of 2474 (64%) IA/IB[&lt;4cm]; 1080 (28%) IB[&gt;4cm]/II/IIIA[pN2-]; and 290 (8%) pN2+. Once stratified, HRs remained significant among those with early stage but not for pN2+ (Table). When further adjusted, only pStage IA/IB[&lt;4cm] patients had a significant HR, 0.94 (0.91, 0.97). The cut point analysis indicated sequential survival improvement up to ≥ 7 total stations sampled, consistently across all models/adjustments. Conclusions: The number of lymph node stations examined is directly associated with survival after lung cancer resection. Examination of a total of 7 intrapulmonary, hilar and mediastinal stations seems optimal. Hazard ratios (95% confidence intervals) for modeling hazards as a function of lymph node stations sampled (model 1), further adjusted for age, sex, histology, clinical stage, extent of resection, and surgical technique (model 2), including interaction with pathologic stage with no adjustments (model 3), and interaction with pathological stage with adjustments (no clinical stage) (model 4). [Table: see text]