Optimal Cut-point Research Articles

Interim FDG-PET/CT for predicting response of HER2-positive breast cancer to neoadjuvant therapy: ECOG-ACRIN EA1211/DIRECT trial.

TPS614 Background: Strategies to optimize treatment decision-making in early stage HER2-positive breast cancer are a priority. Recent studies suggest that early metabolic changes on FDG-PET/CT predict response to HER2-directed therapy. The TBCRC026 trial showed that participants not obtaining a 40% reduction in SULmax by cycle 1 day 15 (C1D15) following neoadjuvant trastuzumab/pertuzumab (HP) were unlikely to obtain pCR [negative predictive value (NPV) 91%]. This trial aims to validate FDG-PET/CT as a neoadjuvant interim (niFDG-PET/CT) imaging integral biomarker in patients treated with standard HER2-directed regimens (NCT05710328). Methods: Trial design: EA1211/DIRECT is a multicenter, single-arm, primary imaging phase 2 study enrolling patients with stage II/III HER2-positive breast cancer. Patients undergo standard skull base-thigh FDG-PET/CT at baseline and C1D15 and receive standard of care pertuzumab-based neoadjuvant therapy followed by surgery. Eligibility: Age ≥18 years, ECOG performance status 0-2, stage IIa-IIIc, untreated HER2-positive breast cancer with known hormone receptor status, suitable to undergo FDG-PET/CT imaging and neoadjuvant therapy. Statistical methods: ΔSULmaxD15 will be computed as: (D15 SULmax – baseline SULmax)/baseline SULmax. The primary objective is to estimate the NPV of niFDG-PET/CT for pCR using ΔSULmaxD15 of the primary breast cancer at a threshold of 40%. NPV is defined as the probability that pCR will not be achieved by participants with ΔSULmaxD15 <40%. Secondary endpoints include evaluating sensitivity, specificity, and positive predictive value of ΔSULmaxD15 of the primary breast cancer at a threshold of 40% and ability of the niFDG-PET/CT biomarker to predict 3-year event free survival (EFS). Sample size: We expect that 50% of patients will not reach the ΔSULmax threshold of 40% and a pCR rate of 40-60%. The proposed sample size is 210 participants, adjusted to 235 to account for missing data in 10% of cases. Computation of exact, two-sided 95% confidence intervals (CI) for NPV determined the lower limit of the CI is at least 80% when the true NPV is at least 88%. The lower limit is 84% when the true NPV has the value of 91%, which was estimated in the TBCRC026 study. Current status: EA1211/DIRECT was activated in May 2023 across the NCI National Clinical Trials Network (NCTN) and is anticipated to complete in March 2025. Those interested in the clinical trial can email ea1211team@ecog-acrin.org. The EA1211/DIRECT trial is the first step in implementing a Response-Guided Treatment Strategy by validating the ΔSULmax threshold of 40% as the optimum cut point across standard of care HER2-directed neoadjuvant regimens. If EA1211/DIRECT meets its objectives, the results will be used to design clinical utility studies, thus hoping to change practice. Clinical trial information: NCT05710328 .

Objective sonographic measurements of renal pelvic diameter and renal parenchymal thickness can identify renal hypofunction and poor drainage in patients with antenatally detected unilateral ureteropelvic junction obstruction

INTRODUCTIONHydronephrosis grading systems risk stratify patients with potential ureteropelvic junction obstruction, but only some criteria are measured objectively. Most notably, there is no consensus definition of renal parenchymal thinning. OBJECTIVESThe objective of this study was to assess the association between sonographic measures of renal length, renal pelvic diameter, and renal parenchymal thickness and the outcomes of a)renal hypofunction(differential renal function{DRF} <40%) and b)high-risk renal drainage(T1/2 >40 minutes). STUDY DESIGNAn institutional database of patients who had diuretic renograms(DR) for unilateral hydronephrosis was reviewed. Only infants with Society for Fetal Urology(SFU) grades 3/4 hydronephrosis without hydroureter on postnatal sonogram and had a DR within 120 days were included. The following measurement variables were analyzed: anterior posterior renal pelvic diameter(APRPD), renal length(RL), renal parenchymal thickness(PT), minimal renal parenchymal thickness(MPT=shortest distance from mid-pole calyx to parenchymal edge), and renal pyramidal thickness(PyrT). RL, PT, MPT, PyrT measurements were expressed as ratios (hydronephrotic kidney/contralateral kidney). Multivariate logistic regression was performed for each outcome by comparing three separate renal measurement models. Model 1: RLR, APRPD, MPTR; Model 2: RLR, APRPD, PTR, Model 3: RLR, APRPD, PyrTR. Individual performance of variables from the best performing model were assessed via ROC curve analysis. RESULTS196 patients were included (107 with SFU grade 3, 89 with SFU grade 4) hydronephrosis. Median patient age was 29[IQR 16,47.2] days. 10% had hypofunction, and 20% had T1/2 >40 minutes. 90% with hypofunction and 87% with high-risk drainage had SFU4 hydronephrosis. Model 1 exhibited the best performance, but on multivariate analysis, only APRPD and MPTR were independently associated with both outcomes. No other measure of parenchymal thickness reached statistical significance. The odds of hypofunction and high-risk drainage increase 10% per 1mm increase in APRPD(aOR 1.1 [CI 1.03-1.2], p=0.005; aOR 1.1 [CI 1.03-1.2], p=0.003). For every 0.1unit increase in MPTR the odds of hypofunction decrease by 40%(aOR 0.6 [CI 0.4-0.9], p=0.019); and the odds of high-risk drainage decrease by 30%(aOR 0.7 [CI 0.5-0.9], p=0.011). Optimal statistical cut-points of APRPD >16mm and/or MPTR <0.36 identified patients at risk for obstructive parameters on DR. DISCUSSION AND CONCLUSIONOf the sonographic hydronephrosis measurement variables analyzed, only APRPD and MPTR were independently associated with objective definitions of obstruction based on renal function and drainage categories. Patients who maintain APRPD <16mm and/or MPTR >0.36 can potentially be monitored with renal sonograms as there is >90% chance that they will not have DRF<40% or T1/2>40 minutes.

Burn Mortality in an Appalachian Referral Center: An Examination of Mortality Prediction Scores in a 13-Year Retrospective Study.

Introduction Burn injuries have profound implications, prompting the use of various mortality scoring systems. This study aimed to evaluate their effectiveness within our Appalachian burn referral center, which serves as the sole burn center in the state of West Virginia. Given this unique status, understanding the efficacy of mortality scoring systems within our center is crucial for resource allocation and optimizing patient outcomes in our region. Methods A retrospective analysis of patients admitted to Cabell Huntington Hospital Burn Intensive Care Unit (BICU) from January 2010 to June 2023 was conducted, assessing Baux (B), revised Baux (rB), Belgian Outcome in Burn Injury (BOBI), and Abbreviated Burn Severity Index (ABSI) scores. Logistic regression and receiver operating characteristic analysis were employed to examine survival status and determine optimal cut points. Results Among 1,104 patients, 57 died (5% mortality rate). Deceased patients had significantly higher B/rB/BOBI scores (mean: 98/98/92) than survivors (45/46/4.19) (p < 0.001), with ABSI showing no significance (p = 0.079). Each one-point increase in B/rB/BOBI scores correlated with a 1.09/1.09/2.34 times higher mortality risk (p < 0.001). The AUC for B score in predicting mortality was 0.926 (95% CI: 0.890, 0.962), with sensitivity and specificity values of 0.789 and 0.92, respectively, and an optimal cutoff point of 79. The AUC for the rB score was 0.927 (95% CI: 0.892, 0.962), with sensitivity and specificity values of 0.789 and 0.926, respectively, and an optimal cutoff point of 80. The AUC for the BOBI score was 0.901 (95% CI: 0.865, 0.937), with sensitivity and specificity values of 0.895 and 0.775, respectively, and an optimal cutoff point of 2. For patients with B scores above 79, their odds of mortality were 42.6 times higher than those with B scores of 79 or lower (95% CI: 22.6, 85.6, p < 0.001). Similarly, for patients with rB scores exceeding 80, their odds of mortality were 42.9 times higher than those with rB scores of 80 or lower (95% CI: 22.9, 84.8, p < 0.001). Finally, for patients with BOBI scores greater than 2, their odds of mortality were 17.8 times higher than those with BOBI scores of 2 or lower (95% CI: 9.88, 33.4, p < 0.001). Conclusion Our study underscores the vital role of mortality scoring systems in guiding clinical decision-making and resource allocation for burn patients, particularly within the Appalachian region served by the Cabell Huntington Hospital BICU. By leveraging tools such as the Baux, revised Baux, and BOBI scores, healthcare providers can identify high-risk patients early in their treatment course, facilitating personalized interventions and improving overall patient outcomes. Moreover, our findings highlight the significance of age and total body surface area burned as key determinants of mortality risk, emphasizing the need for tailored approaches to care for elderly patients and those with extensive burns. Continued research and refinement of mortality scoring systems are essential to further enhance their effectiveness and ensure optimal patient care in the challenging field of burn management.

Volumetric quantification of epicardial fat using semiautomated atrial CT segmentation in patients with atrial fibrillation: the Prospective AFAT study

Abstract Background Epicardial fat or epicardial adipose tissue (EAT) is most commonly defined as adipose tissue between the myocardium and the visceral pericardium. Previous studies have suggested EAT to be an important contributor to the pathogenesis of atrial fibrillation (AF) as well as a plausible predictor for AF recurrences after ablation. However, data on EAT using precise volumetric quantification is limited. Methods and Results AFAT is a prospective observational study conducted at a heart centre in our city with 200 patients aimed to be included. We conducted an interim analysis of the first 75 patients enrolled in the AFAT study. All patients received delayed dual source cardiac computer tomography (CT) imaging which was analysed using semi-automated 3D segmentation (Figure 2) to quantify left atrial (LA) and right atrial (RA) EAT prior to ablation (52.5 % persistent AF). The mean age was 67 ± 8.7 years with 46.9 % (n=35) being female. Mean BMI was 28 ± 4.5. The Mean LA EAT was 33.1 ml ± 13.2 ml and RA EAT was 32.7 ml ± 12.2ml. Median follow up after AF catheter ablation was 163 days. The optimal cut point for the total atrial EAT was estimated at 50.2 ml. In patients with total atrial EAT ≤ 50 ml recurrence of any atrial arrythmia after catheter ablation occurred in 8% (6 patients) compared to 25.3% (19 patients) recurrence rates in patients with a total atrial EAT &amp;gt; 50 ml. Kaplan-Meyer estimates showed no statistical difference between groups (log rank p=0.063) as this analysis is under-powered with more patients being enrolled for the final results (Figure 1). Conclusion The use of semi-automated CT based atrial segmentation presents a novel highly accurate and reproducible method to reliably identify atrial EAT. Increased atrial EAT is likely to play an important role for arrythmia recurrences after catheter ablation. Final results of the AFAT study will provide further evidence to this important subject.Arrhythmia recurrences depending on EATBiatrial 3D Segmentation of EAT

Warning signs in a period of acute risk for suicide attempt: The utility of count- and combination-based classification

ObjectiveThis study sought to establish if models involving the specific combinations of identifiable behavioral warning signs (WS; i.e., alcohol use, suicidal communications, preparation of personal affairs, experiencing negative interpersonal life events) for a suicide attempt outperformed a simpler count model of WS to distinguish an acute risk period (the six hours prior to a suicide attempt) from a control period (a matched six-hour period the day prior). MethodGeneralized linear mixed models tested all logical combinations of four behavioral WS in addition to a count variable of the number of behavioral warning signs. For the count variable, receiver operating characteristic curve analysis was utilized to determine the optimal cut point for the number of endorsed WS. ResultsArea under the curve (AUC) compared classification across all models, with the count model demonstrating similar classification performance to the best multivariate model (AUCs of 0.72 and 0.73, respectively), with an optimal cut point of endorsing one or more WS. ConclusionAlthough determinations of acute risk should be informed by multiple sources of information, this study suggests a relatively simple count-based approach that considers the presence of one (or more) behavioral WS may be used as a potential indication of increased acute risk for suicide attempt.

Clinical and health care utilization variables can predict 90-day hospital re-admission in adults with Crohn’s disease for point of care risk evaluation

BackgroundHospital re-admission for persons with Crohn’s disease (CD) is a significant contributor to morbidity and healthcare costs. We derived prediction models of risk of 90-day re-hospitalization among persons with CD that could be applied at hospital discharge to target outpatient interventions mitigating this risk.MethodsWe performed a retrospective study in persons with CD admitted between 2009 and 2016 for an acute CD-related indication. Demographic, clinical, and health services predictor variables were ascertained through chart review and linkage to administrative health databases. We derived and internally validated a multivariable logistic regression model of 90-day CD-related re-hospitalization. We selected the optimal probability cut-point to maximize Youden’s index.ResultsThere were 524 CD hospitalizations and 57 (10.9%) CD re-hospitalizations within 90 days of discharge. Our final model included hospitalization within the prior year (adjusted odds ratio [aOR] 3.27, 95% confidence interval [CI] 1.76–6.08), gastroenterologist consultation within the prior year (aOR 0.185, 95% CI 0.0950–0.360), intra-abdominal surgery during index hospitalization (aOR 0.216, 95% CI 0.0500–0.934), and new diagnosis of CD during index hospitalization (aOR 0.327, 95% CI 0.0950–1.13). The model demonstrated good discrimination (optimism-corrected c-statistic value 0.726) and excellent calibration (Hosmer-Lemeshow goodness-of-fit p-value 0.990). The optimal model probability cut point allowed for a sensitivity of 71.9% and specificity of 70.9% for identifying 90-day re-hospitalization, at a false positivity rate of 29.1% and false negativity rate of 28.1%.ConclusionsDemographic, clinical, and health services variables can help discriminate persons with CD at risk of early re-hospitalization, which could permit targeted post-discharge intervention.

The relationship between liver stiffness by two-dimensional shear wave elastography and iron overload status in transfusion-dependent patients

Increased liver stiffness (LS) can be result of increased liver iron concentration (LIC) which may not yet be reflected in the liver fibrotic status. The objective of our study was to examine relationship between hemochromatosis, LS, and serum ferritin level in transfusion-dependent patients. We recruited all 70 transfusion-dependent patients, whose median age was 15, referred for evaluating LIC status by magnetic resonance imaging (MRI) followed by two-dimensional ultrasonography shear wave elastography (2D-SWE). Thalassemia beta affected the majority of the patients. The optimal cut point for prediction of severe hemochromatosis using median SWE (kPa) and SWV (m/s) was ≥ 7.0 kPa and ≥ 1.54 m/s, respectively, with sensitivity of 0.76 (95% confidence interval [CI] 0.55, 0.91) and, specificity of 0.69 (95%CI 0.53, 0.82). When combing the optimal cut point of SWE (kPa) at ≥ 7.0 and serum ferritin ≥ 4123 ng/mL, the sensitivity increased to 0.84 (95%CI 0.64, 0.95) with specificity of 0.67 (95%CI 0.50, 0.80), positive predictive value (PPV) of 0.60 (95%CI 0.42, 0.76), and negative predictive value (NPV) of 0.88 (95%CI 0.71, 0.96). Simultaneous tests of 2D-SWE and serum ferritin for prediction of severe hemochromatosis showed the highest sensitivity of 84% (95%CI 0.64–0.95), as compared to 2D-SWE alone at 76% (95%CI 0.55, 0.91) or serum ferritin alone at 44% (95%CI 0.24–0.65). We recommend measuring both 2D-SWE and serum ferritin in short interval follow up patients. Adding 2D-SWE to management guideline will help in deciding for aggressive adjustment of iron chelating medication and increased awareness of patients having severe hemochromatosis.

Improving alcohol and substance use screening in school-age children: translation, adaptation and psychometric evaluation of the CRAFFT tool for Lumasaaba, Uganda

BackgroundChildren at risk of substance use disorders (SUD) should be detected using brief structured tools for early intervention. This study sought to translate and adapt the Car, Relax, Alone, Forget, Family/Friends, Trouble (CRAFFT) tool to determine its diagnostic accuracy, and the optimum cut-point to identify substance use disorders (SUD) risk in Ugandan children aged 6 to 13 years.MethodsThis was a sequential mixed-methods study conducted in two phases. In the first qualitative phase, in Kampala and Mbale, the clinician-administered CRAFFT tool version 2.1 was translated into the local Lumasaaba dialect and culturally adapted through focus group discussions (FGDs) and in-depth interviews, in collaboration with the tool’s authors. Expert reviews and translations by bilingual experts provided insights on linguistic comprehensibility and cultural appropriateness, while pilot testing with the target population evaluated the tool’s preliminary effectiveness. In the second phase, the CRAFFT tool, adapted to Lumasaaba, was quantitatively validated against the Mini International Neuropsychiatric Interview for Children and Adolescents (MINI-KID) for diagnosing SUD in Mbale district, through a survey. Participants, chosen randomly from schools stratified according to ownership, location, and school size, were assessed for the tool’s reliability and validity, including comparisons to the MINI KID as the Gold Standard for diagnosing SUD. Data were analyzed using STATA-15. Receiver-operating-characteristic analysis was performed to determine the sensitivity, specificity, and criterion validity of the CRAFFT with the MINI-KID.ResultsOf the 470 children enrolled, 2.1% (n = 10) had missing data on key variables, leaving 460 for analysis. The median age and interquartile range (IQR) was 11 (9–12) years and 56.6% were girls. A total of 116 (25.2%) children had consumed alcohol in the last twelve-month period and 7 (1.5%) had used other substances. The mean CRAFFT score for all the children (n = 460) was 0.32 (SD 0.95). The prevalence of any alcohol use disorder (2 or more positive answers on the MINI KID) in the last 12 months was 7.2% (n = 32). The Lumasaaba version of the CRAFFT tool demonstrated good internal consistency (Cronbach’s α = 0.86) and inter-item correlation (Spearman correlation coefficient of 0.84 (p < 0.001). At a cut-off score of 1.00, the CRAFFT had optimal sensitivity (91%) and specificity (92%) (Area Under the Curve (AUC) 0.91; 95% CI 0.86–0.97) to screen for SUD. A total of 62 (13.5%) had CRAFFT scores of > 1.ConclusionThe Lumasaaba version of the CRAFFT tool has sufficient sensitivity and specificity to identify school-age children at risk of SUD.

Preoperative fasting glucose value can predict acute kidney injury in non-cardiac surgical patients without diabetes but not in patients with diabetes

BackgroundPostoperative acute kidney injury (AKI) is a common and costly complication after non-cardiac surgery. Patients with or without diabetes could develop hyperglycemia before surgery, and preoperative hyperglycemia was closely associated with postoperative poor outcomes, but the association between preoperative fasting blood glucose level and postoperative AKI is still unclear.MethodsData from patients undergoing non-cardiac surgery in Chongqing University Cancer Hospital from January 1, 2017, to May 31, 2023, were collected, preoperative glucose value and perioperative variables were extracted, the primary exposure of interest was preoperative glucose value, and the outcome was postoperative AKI.ResultsData from 39,986 patients were included in the final analysis, 741(1.9%) patients developed AKI, 134(5.6%) in the cohort with DM, and 607(1.6%) in the cohort without DM(OR 1.312, 95% CI 1.028–1.675, P = 0.029). A significant non-linear association between preoperative glucose and AKI exists in the cohort without DM after covariable adjustment (P = 0.000), and every 1 mmol/L increment of preoperative glucose level increased OR by 15% (adjusted OR 1.150, 95% CI 1.078–1.227, P = 0.000), the optimal cut-point of preoperative fasting glucose level to predict AKI was 5.39 mmol/L (adjusted OR 1.802, 95%CI 1.513–2.146, P = 0.000). However, in the cohort with DM, the relation between preoperative glucose and postoperative AKI was not significant after adjusting by covariables (P = 0.437). No significance exists between both cohorts in the risk of AKI over the range of preoperative glucose values.ConclusionA preoperative fasting glucose value of 5.39 mmol/L can predict postoperative acute kidney injury after non-cardiac surgery in patients without diagnosed diabetes, but it is not related to AKI in patients with the diagnosis.

Diffusion-Weighted Imaging Fluid-Attenuated Inversion Recovery Mismatch on Portable, Low-Field Magnetic Resonance Imaging Among Acute Stroke Patients.

For stroke patients with unknown time of onset, mismatch between diffusion-weighted imaging (DWI) and fluid-attenuated inversion recovery (FLAIR) magnetic resonance imaging (MRI) can guide thrombolytic intervention. However, access to MRI for hyperacute stroke is limited. Here, we sought to evaluate whether a portable, low-field (LF)-MRI scanner can identify DWI-FLAIR mismatch in acute ischemic stroke. Eligible patients with a diagnosis of acute ischemic stroke underwent LF-MRI acquisition on a 0.064-T scanner within 24 h of last known well. Qualitative and quantitative metrics were evaluated. Two trained assessors determined the visibility of stroke lesions on LF-FLAIR. An image coregistration pipeline was developed, and the LF-FLAIR signal intensity ratio (SIR) was derived. The study included 71 patients aged 71 ± 14 years and a National Institutes of Health Stroke Scale of 6 (interquartile range 3-14). The interobserver agreement for identifying visible FLAIR hyperintensities was high (κ = 0.85, 95% CI 0.70-0.99). Visual DWI-FLAIR mismatch had a 60% sensitivity and 82% specificity for stroke patients <4.5 h, with a negative predictive value of 93%. LF-FLAIR SIR had a mean value of 1.18 ± 0.18 <4.5 h, 1.24 ± 0.39 4.5-6 h, and 1.40 ± 0.23 >6 h of stroke onset. The optimal cut-point for LF-FLAIR SIR was 1.15, with 85% sensitivity and 70% specificity. A cut-point of 6.6 h was established for a FLAIR SIR <1.15, with an 89% sensitivity and 62% specificity. A 0.064-T portable LF-MRI can identify DWI-FLAIR mismatch among patients with acute ischemic stroke. Future research is needed to prospectively validate thresholds and evaluate a role of LF-MRI in guiding thrombolysis among stroke patients with uncertain time of onset. ANN NEUROL 2024;96:321-331.

The Roles of NOTCH3 p.R544C and Thrombophilia Genes in Vietnamese Patients With Ischemic Stroke: Study Involving a Hierarchical Cluster Analysis

Background The etiology of ischemic stroke is multifactorial. Several gene mutations have been identified as leading causes of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), a hereditary disease that causes stroke and other neurological symptoms. Objective We aimed to identify the variants of NOTCH3 and thrombophilia genes, and their complex interactions with other factors. Methods We conducted a hierarchical cluster analysis (HCA) on the data of 100 patients diagnosed with ischemic stroke. The variants of NOTCH3 and thrombophilia genes were identified by polymerase chain reaction with confronting 2-pair primers and real-time polymerase chain reaction. The overall preclinical characteristics, cumulative cutpoint values, and factors associated with these somatic mutations were analyzed in unidimensional and multidimensional scaling models. Results We identified the following optimal cutpoints: creatinine, 83.67 (SD 9.19) µmol/L; age, 54 (SD 5) years; prothrombin (PT) time, 13.25 (SD 0.17) seconds; and international normalized ratio (INR), 1.02 (SD 0.03). Using the Nagelkerke method, cutpoint 50% values of the Glasgow Coma Scale score; modified Rankin scale score; and National Institutes of Health Stroke Scale scores at admission, after 24 hours, and at discharge were 12.77, 2.86 (SD 1.21), 9.83 (SD 2.85), 7.29 (SD 2.04), and 6.85 (SD 2.90), respectively. Conclusions The variants of MTHFR (C677T and A1298C) and NOTCH3 p.R544C may influence the stroke severity under specific conditions of PT, creatinine, INR, and BMI, with risk ratios of 4.8 (95% CI 1.53-15.04) and 3.13 (95% CI 1.60-6.11), respectively (Pfisher&lt;.05). It is interesting that although there are many genes linked to increased atrial fibrillation risk, not all of them are associated with ischemic stroke risk. With the detection of stroke risk loci, more information can be gained on their impacts and interconnections, especially in young patients.

Abstract PS06-04: The prognostic and predictive impact of circulating tumour DNA (ctDNA) dynamics in patients with metastatic Triple Negative Breast Cancer (TNBC) on olaparib based therapy: Results from Cohort E of the PlasmaMATCH trial

Abstract Background: Early changes in ctDNA levels, ctDNA dynamics, may help identify which patients are responding to therapy earlier than imaging. Few studies have assessed ctDNA dynamics during PARP inhibitor therapy. Here we report paired baseline and early on treatment ctDNA analysis from cohort E of plasmaMATCH, that recruited patients with TNBC to treatment with olaparib (PARP inhibitor) plus ceralasertib (ATR inhibitor). Methods: The plasmaMATCH trial assessed the ability of ctDNA testing to allocate patients to mutation matched treatment cohorts (A-D). Patients with TNBC, and without mutations matching cohorts B-D, were enrolled on cohort E. Samples were collected for ctDNA analysis pre-treatment at cycle 1-day1 (C1D1) and cycle 2-day 1 (C2D1). A minimum of 14 days of treatment in the first cycle was required for inclusion in this analysis. Samples were sequenced using error-corrected gene targeted panels (Guardant360, or GuardantOMNI, Guardant Health). Circulating DNA ratio (CDR) was calculated as the ratio of C2D1 ctDNA level to C1D1, pre-specified using the weighted mean of variant allele fractions (AF) of clonal mutations at C1D1, excluding variants with AF &amp;lt; 0.3%, and variants in genes frequently mutated in clonal haematopoesis (GNAS, JAK2, IDH1, IDH2 and ATM). The optimal cut-point for predicting progression free survival (PFS) was assessed as the cut-point with the highest Harrell’s C-index. Results: Of the 75 patients that were enrolled into cohort E, 53 patients had samples sent for paired C1D1-C2D1 ctDNA sequencing, 2 failed sequencing, and all 51 (68%) patients had detectable ctDNA at C1D1. The ctDNA analysis set was representative of the overall enrolled population. The optimal ctDNA dynamics C-index cut-point for predicting PFS was 0 (undetectable ctDNA at C2D1). Median PFS with ctDNA CDR &amp;gt;0 (detectable ctDNA at C2D1) was 4.3 months (95% CI 2.4-5.8), and with undetectable ctDNA was 12 months (95% CI 8-NA) (HR 4.02, 95% CI 1.22-13.23, p=0.01). Splitting patients by median CDR was not predictive (HR=0.98; 95%CI: 0.52-1.82, p=0.94). Confirmed objective response rate was 85.7% (42.1-99.6) in patients with undetectable ctDNA at C2D1, and with detectable ctDNA was 11.4% (3.8-24.6) (OR 4.02, 95% CI 1.22-13.23, p=0.01). Of the 7 patients with undetectable ctDNA at C2D1, one had a BRCA2 germline mutation, and all other patients were wildtype for BRCA1/2 mutations in tumour and germline. All patients with undetectable ctDNA and BRCA1/2 wildtype had a confirmed response.In cohorts A-D (mutation targeted therapies, in predominantly ER positive cancer), the optimal ctDNA dynamics C-index CDR cut-point was 0.165 (HR 3.44, 95%CI: 2.06-5.75, p&amp;lt; 0.001), with median CDR cut-point also highly predictive (HR=2.14, 95%CI:1.36-3.36, p=0.001). Undetectable ctDNA was also strongly predictive (HR=4.41; 95%CI: 1.97-9.87, p&amp;lt; 0.001) in cohort A-D.In cohort E, a significant association was found between baseline ctDNA and PFS, with an optimal C-index cutpoint of 6.81% (HR=3.02, 95% CI: 1.39-6.56, p=0.001). Median PFS for baseline ctDNA ≤ 6.81% was 10.2 months (95% CI 3.7-17.2), and for baseline ctDNA &amp;gt;6.81% was 4.4 months (95% CI 2.2-5.5). Conclusions: ‘Clearance’ of ctDNA to become undetectable at C2D1 identified sporadic TNBC patients who benefited from olaparib and ceralasertib. Although ‘clearance’ of ctDNA was associated with good outcome on olaparib plus ceralasertib, median CDR was not predictive of treatment benefit. This contrasts the results of ctDNA dynamic assessment of cohort A-D, where median CDR was highly predictive of treatment benefit. ctDNA dynamic assessment may differ between mutation targeted therapies (cohorts A-D) that induce cell-cycle arrest, and PARP inhibitors (cohort E) that inhibit DNA repair mechanisms. Implementing ctDNA dynamics into clinical trials and care may require distinct analysis for different therapies. Citation Format: Iseult Browne, Javier Pascual, Rosalind Cutts, Belinda Kingston, Sarah Hrebien, Lucy Kilburn, Alex Pearson, Laura Moretti, Andrew Wardley, Iain Macpherson, Richard Baird, Rebecca Roylance, Iris Faull, Kimberly C Banks, Isaac Garcia-Murillas, Judith Bliss, Alistair Ring, Nicholas Turner. The prognostic and predictive impact of circulating tumour DNA (ctDNA) dynamics in patients with metastatic Triple Negative Breast Cancer (TNBC) on olaparib based therapy: Results from Cohort E of the PlasmaMATCH trial [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 PS06-04.

Abstract PO1-01-01: ECOG-ACRIN EA1211: Interim FDG-PET/CT for predicting response of HER2-positive breast cancer to neoadjuvant therapy (DIRECT Trial)

Abstract Background: Strategies to optimize treatment decision-making in early stage HER2-positive breast cancer are a current priority for the oncology and patient advocacy community. Recent studies suggest that early metabolic changes on FDG-PET/CT (imaging biomarker) predict response to HER2-directed therapy. The TBCRC026 trial showed that participants not obtaining a 40% reduction in SULmax by cycle 1 day 15 (C1D15) following neoadjuvant trastuzumab/pertuzumab (HP) were unlikely to obtain pCR [negative predictive value (NPV) 91%]. The ECOG-ACRIN EA1211/DIRECT trial aims to validate FDG-PET/CT as a neoadjuvant interim (niFDG-PET/CT) imaging integral biomarker in patients treated with standard HER2-directed regimens (NCT05710328). Design: EA1211/DIRECT is a multicenter, single-arm, primary imaging phase 2 study enrolling patients with stage II/III HER2-positive breast cancer. Patients undergo standard skull base-thigh FDG-PET/CT at baseline and C1D15 and receive standard of care pertuzumab-based neoadjuvant therapy followed by surgery. Eligibility: Age ≥18 years, ECOG performance status 0-2, stage IIa-IIIc, untreated HER2-positive breast cancer with known hormone receptor status, suitable to undergo FDG-PET/CT imaging and neoadjuvant therapy. Methods: ΔSULmaxD15 will be computed as: (D15 SULmax – baseline SULmax)/baseline SULmax. The primary objective is to estimate the NPV of niFDG-PET/CT for pCR using ΔSULmaxD15 of the primary breast cancer at a threshold of 40%, in patients treated with neoadjuvant HER2-directed therapy. NPV is defined as the probability that pCR will not be achieved by participants with ΔSULmaxD15 &amp;lt; 40%. Secondary endpoints include evaluating the sensitivity, specificity, and positive predictive value of ΔSULmaxD15 of the primary breast cancer at a threshold of 40% and the ability of the niFDG-PET/CT biomarker to predict 3-year event free survival (EFS). Sample Size: We expect that 50% of patients will not reach the ΔSULmax threshold of 40% and a pCR rate of 40-60%. The proposed sample size is 210 participants, adjusted to 235 to account for missing data in 10% of cases. Computation of exact, two-sided 95% confidence intervals (CI) for NPV determined the lower limit of the CI is at least 80% when the true NPV is at least 88%. The lower limit is 84% when the true NPV has the value of 91%, which was estimated in the TBCRC026 study. Current Status: EA1211/DIRECT was activated in May 2023 across the NCI National Clinical Trials Network (NCTN), and accrual is anticipated to complete in March 2025. Those interested in the clinical trial can email ea1211team@ecog-acrin.org. Conclusion: The EA1211/DIRECT trial is the first step in implementing a Response-Guided Treatment Strategy by validating the ΔSULmax threshold of 40% as the optimum cut point across standard of care HER2-directed neoadjuvant regimens. If EA1211/DIRECT meets its objectives, the results will be used to design clinical utility studies, and thus hoping to change practice. Citation Format: Heather Jacene, Constantine Gatsonis, Roisin Connolly, Brian Burnette, Erica Stringer-Reasor, Maeve Hennessy, Justin Romanoff, Alexander Taurone, Ciara O'Sullivan, H. T. Carisa Le-Petross, Courtney Lawhn Heath, Vered Stearns, Amy Fowler, Shou-Ching Tang, Karla A Sepulveda, Angela DeMichele, David Mankoff, Antonio Wolff. ECOG-ACRIN EA1211: Interim FDG-PET/CT for predicting response of HER2-positive breast cancer to neoadjuvant therapy (DIRECT Trial) [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 PO1-01-01.

Postsurgical utility of copeptin for the prediction of postoperative arginine vasopressin deficiency.

Arginine vasopressin deficiency (AVD) following neurosurgical procedures for pituitary disorders is common and can delay discharge. Copeptin, a stable surrogate marker of arginine vasopressin, may predict postoperative AVD. The authors' aim was to assess the optimal postoperative sampling time and cut-point concentration of copeptin to predict the development of postsurgical AVD. Adults without preexisting AVD who were undergoing surgery for a pituitary lesion between February 2020 and April 2022 were eligible for study inclusion. Two samples were drawn from each patient postoperatively to assess the copeptin concentration using an immunofluorescent assay. Samples were denoted as "early" (within 6 hours of extubation) or "postoperative day 1" (POD1; within 10-30 hours of extubation). Patients were evaluated for the development of AVD. One hundred ninety-two patients (54.2% female) with a median age of 54.5 years (IQR 39.8-67.0 years) were included in the study. The median copeptin concentration at both time points was significantly lower in those with AVD (transient or permanent; n = 22, 11.5%) than in those without (early: 4.9 vs 18.7 pmol/L, p < 0.001; POD1: 3.4 vs 4.9 pmol/L, p < 0.001) but did not differ in those who developed transient versus permanent AVD. The optimal copeptin cut point for the prediction of AVD was < 8.5 pmol/L for early samples (sensitivity 0.70, specificity 0.80, positive predictive value [PPV] 0.29, negative predictive value [NPV] 0.96) and < 4.3 pmol/L for POD1 samples (sensitivity 0.82, specificity 0.63, PPV 0.22, NPV 0.96). In early samples, a copeptin cutoff of 22.9 pmol/L increased the sensitivity for the detection of AVD to 95% with an NPV of 99%. The proportion of patients who had AVD was higher (60.0% vs 8.8%, p < 0.001) and the copeptin concentration lower (early: 4.3 vs 17.0 pmol/L, p < 0.001; POD1: 2.7 vs 4.9 pmol/L, p < 0.001) among those who had undergone surgery for a craniopharyngeal duct pathology versus a pituitary adenoma. Although copeptin was lower in patients with persistent Cushing's disease than in those in remission, the difference did not reach statistical significance (early p = 0.11, POD1 p = 0.52). Furthermore, the copeptin concentration could not predict the development of syndrome of inappropriate secretion of antidiuretic hormone. Patients without AVD who had received stress dose steroids intraoperatively had lower median early copeptin (11.7 vs 19.1 pmol/L, p = 0.027). In early postoperative copeptin samples, the optimal copeptin cut point for AVD diagnosis was < 8.5 pmol/L, and a level > 22.9 pmol/L had predicative utility in excluding AVD. Caution should be used when interpreting copeptin results, as patients administered glucocorticoids intraoperatively without AVD had lower median copeptin concentrations.

Cognitive control circuit function predicts antidepressant outcomes: A signal detection approach to actionable clinical decisions

BackgroundWe previously identified a cognitive biotype of depression characterized by dysfunction of the brain’s cognitive control circuit, comprising the dorsolateral prefrontal cortex (dLPFC) and dorsal anterior cingulate cortex (dACC), derived from functional magnetic resonance imaging (fMRI). We evaluate these circuit metrics as personalized predictors of antidepressant remission. MethodsWe undertook a secondary analysis of data from the international Study to Predict Optimized Treatment in Depression (iSPOT-D) for 159 patients who completed fMRI during a GoNoGo task, 8 weeks treatment with one of three study antidepressants and who were assessed for remission status (Hamilton Depression Rating Scale score of ≤ 7). Circuit predictors of remission were dLPFC and dACC activity and connectivity quantified in standard deviations. Using established software implementing receiver operating analysis (ROC) we calculated the sensitivity and specificity of these predictors at every cut-point for every circuit measure. We calculated number needed to treat (NNT) metrics for the ROC model identifying optimal cut-point values. ResultsROC models identified maximum separation of remitters (62.5%) from non-remitters (21.2%) at an initial cut-point of −0.75 standard deviations for dLPFC activity and averaged circuit metrics at secondary cutpoints. The NNT was 3.72, implying that if 4 patients (rounding of 3.72) were randomly selected, one would be likely to remit, but if circuit metrics informed treatment, two would be likely to remit. ConclusionsOur findings contribute to identifying clinically actionable circuit measures for clinical trials and clinical practice. Future studies are needed to replicate these findings and expand the assessment of longer-term outcomes.

Exercise capacity prior to major cancer surgery: A cross-sectional observational study of the validity of the 6-minute walk and 30-second sit-to-stand tests.

Cardiopulmonary exercise testing (CPET) is the gold standard for measuring exercise capacity, however, it is resource intensive and has limited availability. This study aimed to determine: 1) the association between the 6-min walk test (6MWT) and the 30-s sit-to-stand test (30STS) with CPET peak oxygen uptake (VO2peak) and anaerobic threshold (AT) and 2) 6MWT and 30STS cut points associated with a higher risk of postoperative complications. A cross-sectional study, retrospectively analyzing data collected from a tertiary cancer center over a 23-month period. Measures included CPET VO2peak and AT, 6MWT and 30STS test. Correlations were used to characterize relationships between variables. Receiver operating characteristic curve analyses determined 6MWT and 30STS cut points that aligned with CPET variable cut points. Note that, 156 participants were included. The 6MWT and 30STS displayed moderate correlations with VO2peak, rho=0.65, p=0.01 and rho=0.52, p<0.005 respectively. Fair correlations were observed between AT and 6MWT (rho=0.36, p=0.01) and 30STS (rho=0.41, p<0.005). The optimal cut points to identify VO2peak<15mL/kg/min were 493.5m on the 6MWT and 12.5 stands on the 30STS test and for AT<11mL/kg/min were 506.5m on the 6MWT and 12.5 stands on the 30STS test. Both the 6MWT and 30STS test could be used as alternative tools for measuring exercise capacity preoperatively in the cancer setting where CPET is not available. A range of 6MWT and 30STS cut points, according to sensitivity and specificity levels, may be used to evaluate risk of postoperative outcomes.

Quantitative Assessment of Tumor Contact with Neurogenic Zones and Its Effects on Survival: Insights beyond Traditional Predictors.

So far, the cellular origin of glioblastoma (GBM) needs to be determined, with prevalent theories suggesting emergence from transformed endogenous stem cells. Adult neurogenesis primarily occurs in two brain regions: the subventricular zone (SVZ) and the subgranular zone (SGZ) of the hippocampal dentate gyrus. Whether the proximity of GBM to these neurogenic niches affects patient outcome remains uncertain. Previous studies often rely on subjective assessments, limiting the reliability of those results. In this study, we assessed the impact of GBM's relationship with the cortex, SVZ and SGZ on clinical variables using fully automated segmentation methods. In 177 glioblastoma patients, we calculated optimal cutpoints of minimal distances to the SVZ and SGZ to distinguish poor from favorable survival. The impact of tumor contact with neurogenic zones on clinical parameters, such as overall survival, multifocality, MGMT promotor methylation, Ki-67 and KPS score was also examined by multivariable regression analysis, chi-square test and Mann-Whitney-U. The analysis confirmed shorter survival in tumors contacting the SVZ with an optimal cutpoint of 14 mm distance to the SVZ, separating poor from more favorable survival. In contrast, tumor contact with the SGZ did not negatively affect survival. We did not find significant correlations with multifocality or MGMT promotor methylation in tumors contacting the SVZ, as previous studies discussed. These findings suggest that the spatial relationship between GBM and neurogenic niches needs to be assessed differently. Objective measurements disprove prior assumptions, warranting further research on this topic.

124 Numerical Cut Points for Mild, Moderate and Severe Pain in Adult Burn Survivors

Abstract Introduction The optimal numerical cut points for mild, moderate, and severe burn pain have been established. Investigators at a single center determined that average burn pain can be categorized as mild (0-2), moderate (3-5), and severe (6-10). To address concerns about small sample size and limited diversity, we aimed to identify the most suitable average pain intensity rating scores for mild, moderate, and severe pain in a large, diverse cohort of adult burn survivors using a Patient Reported Outcome Measures Pain Interference (PROMIS-PI) short form. Methods Average 11-point pain intensity Visual Analog Scale (VAS) or Numerical Rating Scale (NRS) scores (0-10) and a customized PROMIS-PI 4-question short form were administered to adults with burn injury treated at 5 centers in the US at hospital discharge (baseline) and 6, 12, 24-months and 5-years post-injury. To identify pain intensity scores that best represent mild, moderate, and severe pain, F value statistics associated with multiple ANOVA comparisons for mean pain interference scores by various pain intensity cut points were computed. Based on previous research, 6 possible cut points (CP) were compared: CP 3,6; 3,7; 4,6; 4,7; 2,5; and 3,5. The optimal cut points were considered those with the highest ANOVA F statistic. Results Data from 1,190 participants (68% male, 80% white, 22% Hispanic, mean age 46 years) and 5 study centers with VAS/NRS pain intensity and PROMIS-PI scores at one or more study timepoints were analyzed. The optimal classification for mild, moderate, and severe pain was CP 2,5 at all timepoints (see table). Conclusions This study confirms that for a diverse cohort of burn-injured adults from multiple centers within the United States, burn intensity ratings of mild (0-2), moderate (3-5), and severe (6-10) is appropriate for up to 5 years post-injury. These findings support previous research findings and continue to advance our understanding of burn pain and pain intensity reporting while providing clinicians and researchers with an objective measure that can be used for screening, treatment, quality improvement, and research. Applicability of Research to Practice Use of this numerical classification for burn pain in the adult burn survivor can be used with greater confidence in diverse populations.

Methods of determining optimal cut-point of diagnostic biomarkers with application of clinical data in ROC analysis: an update review

IntroductionAn important application of ROC analysis is the determination of the optimal cut-point for biomarkers in diagnostic studies. This comprehensive review provides a framework of cut-point election for biomarkers in diagnostic medicine.MethodsSeveral methods were proposed for the selection of optional cut-points. The validity and precision of the proposed methods were discussed and the clinical application of the methods was illustrated with a practical example of clinical diagnostic data of C-reactive protein (CRP), erythrocyte sedimentation rate (ESR) and malondialdehyde (MDA) for prediction of inflammatory bowel disease (IBD) patients using the NCSS software.ResultsOur results in the clinical data suggested that for CRP and MDA, the calculated cut-points of the Youden index, Euclidean index, Product and Union index methods were consistent in predicting IBD patients, while for ESR, only the Euclidean and Product methods yielded similar estimates. However, the diagnostic odds ratio (DOR) method provided more extreme values for the optimal cut-point for all biomarkers analyzed.ConclusionOverall, the four methods including the Youden index, Euclidean index, Product, and IU can produce quite similar optimal cut-points for binormal pairs with the same variance. The cut-point determined with the Youden index may not agree with the other three methods in the case of skewed distributions while DOR does not produce valid informative cut-points. Therefore, more extensive Monte Carlo simulation studies are needed to investigate the conditions of test result distributions that may lead to inconsistent findings in clinical diagnostics.

The impact of the length of proximal margin on the prognosis of adenocarcinoma of gastroesophageal junction and strategies:A real-world study

BackgroundThe optimal proximal margin (PM) length for Siewert II/III adenocarcinoma of the esophagogastric junction (AEJ) remains unclear. This study aimed to determine the optimal PM length using an abdominal approach to guide surgical decision-making. MethodsA prospective study analyzed 304 consecutive patients diagnosed with Siewert II/III AEJ between January 2019 and December 2021. Total gastrectomy was performed via the abdominal approach, and PM length was measured on fixed gross specimens. X-Tile software determined the optimal PM cut-point based on progression-free survival (PFS). Univariate analyses compared baseline characteristics across PM groups, while survival analyses utilized Kaplan–Meier estimation and Cox proportional hazards regression for assessing the impact of margin length on survival. Multivariable analyses were conducted to adjust for confounding variables. ResultsThe study included 264 AEJ cases classified as Siewert II (71.97%) or III (28.03%). The median gross PM length was 1.0 cm (IQR: 0.5 cm–1.5 cm, range: 0 cm–6 cm). PM length ≥1.2 cm was associated with a lower risk of disease progression compared to PM length 0.4 cm on PFS (HR = 0.41, 95% CI 0.20–0.84, P = 0.015). Moreover, PM ≥ 1.2 cm improved prognosis in subgroups of T4 or N3, tumor size <4 cm, Siewert II, and Lauren classification. ConclusionsFor Siewert type II/III AEJ, a proximal margin length ≥1.2 cm (1.65 cm in situ) is associated with improved outcomes. These findings offer valuable insights into the association between PM length and outcomes in Siewert II/III AEJ, providing guidance for surgical approaches and aiding clinical decision-making to enhance patient outcomes.