Implications For Patient Selection Research Articles

Oxygen-enhanced MRI detects incidence, onset and heterogeneity of radiation-induced hypoxia modification in HPV-associated oropharyngeal cancer.

Hypoxia mediates treatment resistance in solid tumors. We evaluated if oxygen-enhanced (OE)-MRI-derived hypoxic volume (HVMRI) is repeatable and can detect radiotherapy-induced hypoxia modification in HPV-associated oropharyngeal head and neck squamous cell cancer (HNSCC). 27 patients were recruited prospectively between March 2021 and January 2024. HVMRI was measured in primary and nodal tumors prior to standard-of-care (chemo)radiotherapy then at weeks 2 and 4 (W2, W4) into therapy. Two pre-treatment scans assessed biomarker within-subject coefficient of variation (wCV) and repeatability coefficient (RC). Cohort treatment response was measured using mixed-effects modelling. Responding lesions were identified by comparing HVMRI change to RC limits of agreement (LOA). OE-MRI identified hypoxia in all lesions. HVMRI wCV was 24.6% and RC LOA were -45.7% to 84.1%. Cohort median pre-treatment HVMRI of 11.3 cm3 reduced to 6.9 cm3 at W2 and 5.9 cm3 at W4 (both p < 0.001). HVMRI was reduced in 54.5% of individual lesions by W2 and in 88.2% by W4. All lesions with W2 hypoxia reduction showed persistent modification at W4. HVMRI reduced in some lesions that showed no overall volume change. Hypoxia modification was discordant between primary and nodal tumors in 50.0% of patients. Radiation-induced hypoxia modification can occur as early as W2, but onset varies between patients and was not necessarily associated with overall size change. Half of all patients had discordant changes in primary and nodal tumors. These findings have implications for patient selection and timing of dose de-escalation strategies in HPV-associated oropharyngeal carcinoma.

Utility of the 70-Gene MammaPrint Assay for Prediction of Benefit From Extended Letrozole Therapy in the NRG Oncology/NSABP B-42 Trial.

MammaPrint (MP) determines distant metastatic risk and may improve patient selection for extended endocrine therapy (EET). This study examined MP in predicting extended letrozole therapy (ELT) benefit in patients with early-stage breast cancer (BC) from the NSABP B-42 trial. MP was tested in 1,866 patients randomly assigned to receive ELT or placebo. The primary end point was distant recurrence (DR). Secondary end points were disease-free survival (DFS) and BC-free interval (BCFI). Tumors were classified as MP high risk (MP-HR) or low risk (MP-LR). MP-LR tumors were further classified as ultralow risk (MP-UL) or low non-ultralow risk (MP-LNUL). There was no statistically significant difference in ELT benefit on DR between MP-HR and MP-LR (interaction P = .38). MP-LR tumors (n = 1,160) exhibited a statistically significant 10-year benefit of 3.7% for DR (hazard ratio [HR], 0.43 [95% CI, 0.25 to 0.74]; P = .002), whereas MP-HR tumors (n = 706) exhibited a nonsignificant 2.4% benefit (HR, 0.65 [95% CI, 0.34 to 1.24]; P = .19). The 10-year ELT benefit was significant for DFS (7.8%) and BCFI (7.0%) for MP-LR tumors, whereas MP-HR tumors did not significantly benefit (interaction DFS: P = .015, BCFI: P = .006). In exploratory analysis, the 10-year ELT benefit was significant and more pronounced in MP-LNUL (n = 908) tumors: 4.0% for DR, 9.5% for DFS, and 7.9% for BCFI; the benefit in MP-UL (n = 252) tumors was not significant: 3% for DR, 1.8% for DFS, and 4.1% for BCFI. The primary hypothesis of predictive ability of MP on DR was not confirmed. However, the secondary outcomes demonstrated MP was predictive of ELT response and identified a subset of patients with early-stage hormone receptor-positive BC (MP-LR) with improved outcomes from ELT. These data could have important clinical implications in patient selection beyond clinical risk assessment for EET.

Abstract 315: Endovascular Aortic Occlusion Preferentially Improves Hemodynamics and Return of Spontaneous Circulation After Longer Periods of Cardiopulmonary Resuscitation: A Translational Study in Swine

Introduction: Non-traumatic cardiac arrest (NTCA) is associated with low survival and substantial societal cost. Standard-of-care treatments, such as cardiopulmonary resuscitation (CPR) and advanced cardiac life support (ACLS), have limitations in restoring cardiac function and improving outcomes. Resuscitative endovascular balloon occlusion of the aorta (REBOA) has emerged as an adjunct to CPR for NTCA. However, the optimal patient population that will benefit most from REBOA remains uncertain. Goals: This translational study investigated the impact of varying low-flow duration (15- vs 30-mins) on REBOA's hemodynamic performance and ability to achieve return of spontaneous circulation (ROSC) in a swine model of NTCA. Methods: Thirty-two swine were anesthetized and placed into ventricular fibrillation. All animals received a 4-min “no-flow” period before mechanical CPR was initiated. Animals were randomized into four groups to receive: 1) 15- vs 30-minutes of CPR; 2) REBOA vs. no-REBOA (control). After completion of the 15- or 30-minute low-flow period, ACLS was initiated and REBOA was fully-inflated in experimental animals. Results: There were no differences in demographics or hemodynamics at baseline (T = -10-mins) or at randomization (T = +10-mins). In the 15-mins groups, there were no differences in the rates of ROSC between REBOA (4 / 8, 50%) and control (4 / 8, 50%; p = 0.99). However, in the 30-min group the REBOA animals had a significantly higher rate of ROSC (6 / 8, 75%) compared to control (1 / 8, 12.5%; p = 0.04). In the 7-mins (T = 34 - 41 mins) after REBOA deployment in the 30-min animals there was a statistically significant difference in diastolic blood pressure (repeated measures ANOVA; p = 0.027). Importantly, 5 / 6 (83%) animals that received ROSC in the 30-min group with REBOA re-arrested at least once with 3 / 6 (50%) maintaining ROSC until study completion. Conclusion: In our swine model of NTCA, REBOA preferentially improved hemodynamics and ROSC after a 30-mins period of low-flow CPR, compared to 15-mins of low-flow CPR. REBOA may be a viable strategy to improve ROSC after prolonged downtime. More hemodynamic support will be required to maintain ROSC. This has implications for patient selection in upcoming human trials of REBOA in NTCA.

Non-surgical Aesthetic Treatment Conversion to Surgery: Implications for Patient Selection and Practice Modeling

Non-surgical Aesthetic Treatment Conversion to Surgery: Implications for Patient Selection and Practice Modeling

Predicting Severe Complications from Cytoreductive Surgery with Hyperthermic Intraperitoneal Chemotherapy: A Data-Driven, Machine Learning Approach to Augment Clinical Judgment.

CRS-HIPEC provides oncologic benefit in well-selected patients with peritoneal carcinomatosis; however, it is a morbid procedure. Decision tools for preoperative patient selection are limited. We developed a risk score to predict severity of 90day complications for cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS-HIPEC). Adults who underwent CRS-HIPEC at the University of Pittsburgh Medical Center (March 2001-April 2020) were analyzed as part of this study. Primary endpoint was severe complications within 90days following CRS-HIPEC, defined using Comprehensive Complication Index (CCI) scores as a dichotomous (determined using restricted cubic splines) and continuous variable. Data were divided into training and test sets. Several machine learning and traditional algorithms were considered. For the 1959 CRS-HIPEC procedures included, CCI ranged from 0 to 100 (median 32.0). Adjusted restricted cubic splines model defined severe complications as CCI > 61. A minimum of 20 variables achieved optimal performance of any of the models. Linear regression achieved the highest area under the receiving operator characteristic curve (AUC, 0.74) and outperformed the NSQIP Surgical Risk calculator (AUC 0.80 vs. 0.66). Factors most positively associated with severe complications included peritoneal carcinomatosis index score, symptomatic status, and undergoing pancreatectomy, while American Society of Anesthesiologists 2 class, appendiceal diagnosis, and preoperative albumin were most negatively associated with severe complications. This study refines our ability to predict severe complications within 90days of discharge from a hospitalization in which CRS-HIPEC was performed. This advancement is timely and relevant given the growing interest in this procedure and may have implications for patient selection, patient and referring provider comfort, and survival.

Considering Diastolic Dyssynchrony as a Predictor of Favorable Response in LV-Only Fusion Pacing Cardiac Resynchronization Therapy

Background: CRT improves systolic and diastolic function, increasing cardiac output. Aim of the study: to assess the outcome of LV diastolic dyssynchrony in a population of fusion pacing CRT. Methods: Diastolic dyssynchrony was measured by offline speckle-tracking-derived TDI timing assessment of the simultaneity of E″ and A″ basal septal and lateral walls. New parameters introduced: E″ and, respectively, A″ time (E″T/A″T) as the time difference between E″ (respectively, A″) peak septal and lateral wall. Patients were divided into super-responders (SR), responders (R), and non-responders (NR). Results: Baseline characteristics: 62 pts (62 ± 11 y.o.) with idiopathic DCM, EF 27 ± 5.2%; 29% type III diastolic dysfunction (DD), 63% type II, 8% type I. Average follow-up 45 ± 19 months: LVEF 37 ± 7.9%, 34%SR, 61%R, 5%NR. The E″T decreased from 90 ± 20 ms to 25 ± 10 ms in SR with significant LV reverse remodeling (LV end-diastolic volume 193.7 ± 81 vs. 243.2 ± 82 mL at baseline, p < 0.0028) and lower LV filling pressures (E/E' 13.2 ± 4.6 vs. 11.4 ± 4.5, p = 0.0295). DD profile improved in 65% of R with a reduction in E/E' ratio (21 ± 9 vs. 14 ± 4 ms, p < 0.0001). Significant cut-off value calculated by ROC curve for LV diastolic dyssynchrony is E″T > 80 ms and A″T > 30 msec. Conclusions: The study identifies the cut-off values of diastolic dyssynchrony parameters as predictors of favorable outcomes in responders and super-responder patients with fusion CRT pacing. These findings may have important implications in patient selection and follow-up.

Abstract GS5-10: Utility of the 70-gene MammaPrint test for prediction of extended endocrine therapy benefit in patients with early-stage breast cancer in the IDEAL Trial

Abstract Background: The IDEAL trial showed no significant benefit of 5 years extended endocrine therapy (EET) using letrozole in postmenopausal patients with hormone receptor positive (HR+) breast cancer (BC) versus 2.5 years. Genomic classifiers may assist with treatment decisions by predicting EET benefit. The 70-gene MammaPrint (MP) test classifies tumors as having a higher or lower risk of distant metastasis in HR+ early-stage BC. A MP lower risk result can be further classified as either Ultra-Low risk or Low risk of distant metastasis. In the NSABP B42 trial, MP predicted a statistically significant absolute benefit from EET in patients with a MP Low Risk result. Here, we aimed to determine the utility of MP in identifying a subgroup of patients enrolled in the IDEAL trial for which 5 years of EET is beneficial compared to 2.5 years. Methods: A total of 869 patients had available primary tumor tissue for testing. MP results were available for 545/869 patients, of which 515 did not have an event at 2.5 year after randomization and were used for our analyses. The MP result for each patient was calculated by Agendia while blinded to patient clinical outcomes. The primary endpoint was distant recurrence (DR). Secondary endpoints were recurrence free interval (RFI) and breast cancer free interval (BCFI) as defined by STEEP criteria. Patients were classified as higher risk (score -1.000 - 0) or lower risk (score 0.001 - 1.000). Lower risk tumors were further classified as either MP Ultra-Low (score &amp;gt; 0.355) or MP Low Risk (score ≥ 0.001, ≤ 0.355). Likelihood ratio test based on stratified Cox proportional hazards (PH) model were used to evaluate treatment by risk group interaction. Differences in endpoints between treatment groups were assessed by stratified log-rank tests. Hazard ratios (HR) and 95% Confidence Intervals (CI) were computed based on the stratified Cox PH model. Results: The clinical characteristics of the 515 IDEAL samples with a MP result were comparable to the whole IDEAL cohort (n=1820). Within the 2.5 year EET group, 50.6% (n=134) were MP higher risk and 49.4% (n=131) MP lower risk, of which 14.5% (n=19/131) were MP Ultra-Low. Within the 5 year EET group, 50.0% (n=125) were MP higher risk and 50.0% (n=125) MP lower risk, of which 11.2% (n=14/125) were MP Ultra-Low. Among patients with MP lower risk tumors, 5 years vs. 2.5 years of EET resulted in a significant absolute benefit of 9.8% for DR (HR=0.42, [95% CI 0.174-0.996]), 9.8% for RFI (HR=0.43, [95% CI 0.198-0.934]), and 8.8% (HR=0.53, [95% CI 0.264-1.055]) for BCFI, whereas patients with MP higher risk tumors did not derive significant benefit (Table 1). Within the MP lower risk group, 5 year vs 2.5 year EET benefit was more pronounced in MP Low tumors, which exhibited a significant benefit of 10.1% for DR (HR=0.32, [95% CI 0.116-0.866]), 11.7% for RFI (HR=0.35, [95% CI 0.147-0.824]), and 9.7% for BCFI (HR=0.48, [95% CI 0.225-1.015]); MP Ultra Low tumors did not derive significant benefit. Treatment-by-risk group interaction was statistically significant for RFI. Conclusion: A significant EET benefit was observed for MammaPrint lower risk tumors but not for MP higher risk tumors. MammaPrint Low tumors exhibited the largest absolute benefit of 5 years of EET compared to 2.5 years. Consistent with the findings in the NSABP B42 trial, the results from this second randomized trial provide clinically meaningful implications in patient selection for extended endocrine therapy. Table 1. IDEAL: 10-year outcome analysis comparing 5 years vs. 2.5 years of EET using letrozole stratified by MP risk. **MammaPrint Lower Risk &amp; Higher Risk (n=515) and *** MammaPrint Low Risk &amp; High Risk (n=482) Citation Format: Gerrit-Jan Liefers, Elma Meershoek-Klein Kranenbarg, Marjolijn Duijm-de Carpentier, Cornelis J.H. van de Velde, Miranda Kleijn, Christa Dreezen, Andrea Menicucci, Laura van’t Veer, William Audeh. Utility of the 70-gene MammaPrint test for prediction of extended endocrine therapy benefit in patients with early-stage breast cancer in the IDEAL Trial [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr GS5-10.

Role of PD-1 Inhibitors in the Treatment of Esophagogastric Adenocarcinoma: Patient Selection and Reported Outcomes.

Esophagogastric cancers are aggressive malignancies, with poor prognosis despite current standard-of-care therapies. PD-1 inhibitors are a newer class of antitumor agents with the potential to improve outcomes among appropriately selected patients. This review provides an overview of the key trials that have guided the use of PD-1 and PD-L1 inhibitors in the refractory and first-line settings. We highlight recent studies investigating the role of genomic classification in predicting therapeutic activity of PD-1 inhibitors. In addition, there is a discussion of the use of different scoring systems and criteria to determine PD-L1 positivity, the impact on the therapeutic use of immune checkpoint inhibition with anti-PD-1 agents, and the controversies in current methods of PD-L1 testing and their implications in patient selection for anti-PD-1 therapy.

Amyloid-Related Imaging Abnormalities: An Update.

Amyloid-related imaging abnormalities (ARIA) is a term introduced in 2010 to encompass a spectrum of MRI findings observed in patients receiving investigational anti-amyloid beta (Aβ) immunotherapies for Alzheimer disease (AD). The entity can be broadly categorized into ARIA characterized by edema and effusion (ARIA-E) and ARIA characterized by microhemorrhages and superficial siderosis (ARIA-H). ARIA typically occurs early in the treatment course and has a higher incidence in patients who are apolipoprotein E ε4 allele carriers. ARIA-E has an additional dose dependence, with higher incidence in patients receiving higher doses of anti-Aβ immuno-therapies. ARIA is often asymptomatic and self-resolving. The recognition of ARIA has implications for patient selection and monitoring for Aβ immunotherapies, and its development can potentially lead to a pause or discontinuation of therapy. The FDA's first approval of an Aβ-targeting monoclonal antibody for AD treatment in 2021 will lead to such therapy's expanded use beyond the clinical trial setting and to radiologists more commonly encountering ARIA in clinical practice. This review explores the theorized pathophysiologic mechanisms for ARIA, describes the MRI findings and grading schemes for ARIA-E and AREA-H, and summarizes relevant Aβ immunotherapies. Through such knowledge, radiologists can optimally impact the management of patients receiving targeted AD therapies.

Coaptation Length as Predictor of Recurrent Mitral Regurgitation After Surgical Repair for Degenerative Mitral Valve Disease: Meta-Analysis of Reconstructed Time-to-Event Data

Coaptation Length as Predictor of Recurrent Mitral Regurgitation After Surgical Repair for Degenerative Mitral Valve Disease: Meta-Analysis of Reconstructed Time-to-Event Data

Clonal Hematopoiesis Detected at the Time of Tyrosine Kinase Inhibitor Cessation Is Associated with Delayed Molecular Recurrence after Treatment-Free Remission in Patients with CML

Background Treatment-free remission (TFR) is a goal of therapy. However, ~50% of patients who attempt TFR will relapse, which mostly occurs by 6 months. The acquisition of somatic mutations in hematopoietic cells is common with age (clonal hematopoiesis, CH). Through next-generation sequencing studies we identified CH in patients in deep molecular remission. CH variants provide a selective growth advantage to cells, driving their clonal expansion. The clones also give rise to mutated immune effector cells with a proinflammatory profile that exacerbate diseases with a chronic inflammatory component, such as atherosclerosis. CH variants could potentially influence TFR, either by outcompeting an emerging residual CML clone or by altering immune function, which is known to play an important role in TFR. Aim To determine whether CH variants present at the time of therapy cessation could influence TFR. Methods An RNA-based hybridization capture sequencing method targeting 17 of the most frequently mutated CH genes was developed and applied to samples of 138 patients who attempted TFR. CH variants met strict criteria for pathogenicity based on their potential to confer growth and survival advantages. The CH status was confirmed by repeat testing of samples of 28 patients. The method reproducibly detected variants with a variant allele frequency (VAF) of ≥0.4%. Results The median follow-up for the 138 patients was 66 months from the TFR attempt. Molecular recurrence was defined as loss of major molecular response (MMR, BCR::ABL1 ≤0.1%). The probability of TFR was 64.5% at 6 months, 59.4% at 12 months and 51.0% at 84 months. CH variants were detected in 61/138 patients (44%): 107 variants in 12 genes. Multiple variants, range 2 - 7, were detected in 26 patients (19%). The median VAF was 0.9%, range 0.4 - 44%. Variants most frequently occurred in TET2 (44% of variants), DNMT3A (25%), PPM1D (7.4%) and ASXL1 (6.5%). The average age at cessation was 59.6 years, range 33 - 85. The average age of patients with CH was higher than those without CH: 64.7 versus 55.5 years, P < .0001. Only 3/13 patients (15%) aged ≤40 had CH compared with 6/7 patients (86%) ≥80. CH was significantly associated with TFR to 36 months after cessation. The optimal criteria for TFR prediction were at least one CH variant of VAF >2% or >2 variants (CH >2%/>2). Thirty-one of 138 patients (22%) had CH of VAF >2% (n = 24) or >2 variants (n = 7). The probability of TFR for these 31 patients was significantly higher than for the remaining patients when assessed at 6, 12, 24 and 36 months after cessation, Figure. The probability of TFR at 6 months was 90.3% for patients with CH >2%/>2 versus 57.0% for the remaining patients, P = .001. The probability of TFR at 36 months was 65.9% versus 51.2%, P = .049. A landmark analysis was performed at 12 months for the 74 patients who maintained TFR at 12 months. MMR was subsequently lost in 8/74 patients and the probability of TFR at 84 months was 86.9%. CH >2%/>2 occurred for 23/74 patients (31%). The probability of late molecular recurrence was higher among the patients with CH >2%/>2: 27.3% versus 5.5% for the remaining patients, P = .009. Overall, molecular recurrence occurred for 12/31 patients (39%) with CH >2%/>2 and 53/107 of remaining patients (50%). Time to molecular recurrence after cessation was longer for patients with CH >2%/>2 than the remaining patients: median 12.5 months versus 3.5 months, P < .0001. The longer time to molecular recurrence was linked to a different pattern of loss of MMR. The median time between first loss of MR4 (BCR::ABL1 ≤0.01%) and loss of MMR was 145 days for patients with CH >2%/>2 and 28 days for remaining patients, P = .0007. BCR::ABL1 values more frequently fluctuated before loss of MMR in patients with CH >2%/>2: 8/12 patients (67%, fluctuation over 120-1335 days) versus 6/53 (11%, fluctuation over 85-715 days) in the remaining patients, P =.016. Conclusion CH may improve the probability and duration of TFR, delaying the time to molecular recurrence, which has implications for patient selection and monitoring. Patients with CH who are eligible for therapy cessation have an excellent prospect of remaining drug-free for 1-2 years but their long term prospects of sustained TFR may be less certain compared to other patients, given the slower dynamics of relapse. Delayed relapse could be due to competition for clonal dominance between residual leukemic cells and larger CH clones, or modulation of the immune microenvironment. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Prior ablation and progression of disease correlate with higher tumor-to-normal liver 99mTc-MAA uptake ratio in hepatocellular carcinoma.

Factors affecting tumor-to-normal tissue ratio (T:N) have implications for patient selection, dosimetry, and outcomes when considering radioembolization for HCC. This study sought to evaluate patient, disease specific, and technical parameters that predict T:N as measured on planning pre-90Y radioembolization 99mTc-MAA scintigraphy for hepatocellular carcinoma (HCC). 99mTc-MAA hepatic angiography procedures with SPECT/CT over a 4-year period were reviewed. Data recorded included patient demographics, details of underlying liver disease, tumor size, history of prior treatments for HCC and technical parameters from angiography. Anatomic-based segmentation was performed in 93 cases for measurement of tumor and perfused liver volumes and SPECT counts. T:N were calculated and correlated with collected variables. Mean calculated T:N was 2.52. History of prior ablation was significantly correlated with higher T:N (mean 3.39 vs 2.24, p = 0.003). Cases in which mapping was being performed for treatment of disease progression was significantly correlated with higher T:N (mean 3.35 vs 2.14, p = 0.001). Larger tumor size trended toward lower T:N (p = 0.052). Patients with history of ablation and those undergoing treatment for disease progression have higher T:N and, therefore, could be considered for radioembolization preferentially over alternative treatments.

P153 - Stage dependent survival in patients treated with NAC and RC: Implications for patient selection and adjuvant therapy

P153 - Stage dependent survival in patients treated with NAC and RC: Implications for patient selection and adjuvant therapy

Interpretable Machine Learning Model for Predicting Pathologic Complete Response in Patients with Rectal Adenocarcinoma Treated with Chemoradiation Therapy

<h3>Purpose/Objective(s)</h3> Following neoadjuvant chemoradiotherapy (nCRT), pathologic complete response (pCR) strongly influences the decision to proceed with surgery versus "watchful waiting" in rectal cancer (RC) patients. The purpose of this study is to predict pCR without using invasive procedures. An interpretable machine learning model trained with clinical and imaging data from diagnosis and treatment, with extracted radiomics (R) and dosiomics (D) features is utilized to gain insight into contributing factors. <h3>Materials/Methods</h3> This study used multi-institutional datasets, including a training set of 180 patients from our institution and an independent test set of 37 patients from the RTOG 0822 clinical trial. Each patient had a radiotherapy planning CT and the associated contours of the gross tumor volume (GTV) and the organ-at-risks (OARs) including the bladder, bowel_samll, and femur_heads. A total of 296 features including clinical parameters (CP), GTV and OAR dose-volume histogram (DVH), GTV R, and GTV D features were extracted. R and D features were subcategorized into the first- (L1), second- (L2), and higher-order (L3) local texture features. Multiview input data analysis was performed to identify an optimal set of input feature categories by using an exhaustive search. For each input, feature selection was performed using Boruta, followed by collinearity removal based on the variance inflation factor. Explainable boosting machine (EBM), an interpretable glass-box model, was trained using selected features. The performance of EBM on the test set was evaluated using the area under the receiver operating characteristic curve (AUC) and compared with that of 3 state-of-the-art black-box models: extreme gradient boosting (XGB), random forest (RF), and support vector machine (SVM). <h3>Results</h3> Selected features included two shape (elongation, maximum2DDiameterColumn) and one first-order (variance) features in R. Global explanations of EBM showed that tumors with maximum2DDiameterColumn <40 or >90 mm, elongation <0.55, and higher variance of CT intensities were associated with unfavorable outcomes. For all 4 models, the best predictive performance was obtained with an optimal input feature subset of CP+DVH+L1_R+L1_D, which significantly outperformed a full feature set of CP+DVH+R_all+D_all (AUC=0.602 to 0.618). The EBM had the best performance for predicting pCR (AUC=0.855), followed by RF, SVM, and XGB (AUC=0.839, 0.822, and 0.809). <h3>Conclusion</h3> EBM has the potential to improve the predictability of pCR while also enhancing model interpretability, which can aid in radiotherapy decision-making. Using an optimal input feature set selected by multi-view input analysis can lead to improved performance compared to concatenating all available features, which may, in turn, have implications in patient selection for a "watchful-waiting" approach in RC management.

Reconstructive Burnout after Mastectomy: Implications for Patient Selection.

The reconstructive journey after mastectomy can be a long road, with many hurdles to achieve an ideal aesthetic result. Cancer therapy, operative complications, and comorbidities impact patients physically and emotionally. This study introduces the term reconstructive burnout and aims to evaluate which factors predict and contribute to patients prematurely stopping reconstruction. The authors performed a retrospective review of patients undergoing breast reconstruction after skin-sparing mastectomy from 2014 to 2017 performed by two senior surgeons (N.T.H. and S.S.T.) at a single institution. Reconstructive burnout is defined as either no breast mound creation or completion of the breast mound without completion of all major revisions. A total of 530 patients were included, with 76.6% completing reconstruction. In patients undergoing delayed-immediate reconstruction, patients with wounds ( P = 0.004), infections ( P = 0.037), or a complication requiring operative intervention ( P < 0.001) were correlated with incomplete reconstruction; explantation of expanders was highly correlated with reconstructive burnout ( P < 0.001). Implant-based and autologous reconstruction had comparable burnout rates (17.1% versus 19.1%; P = 0.58). Logistic regression models found high body mass index, radiation therapy, any tissue expander complication, and tissue expander explantation to be significant predictors of burnout. Autologous reconstruction was the strongest predictor of completion of reconstruction in both univariable and multivariable models. Reconstructive burnout in breast reconstruction is associated with tissue expander complications, high body mass indices, and radiation therapy. Overall rates of burnout were comparable between autologous and implant-based reconstruction, with autologous reconstruction being the strongest predictor of completion of reconstruction. It is critical to tailor each patient's reconstructive journey to meet both their emotional and physical needs to avoid reconstructive burnout.

Differential effects of teprotumumab treatment based on fat-to-muscle ratio in patients with thyroid eye disease

ABSTRACT Purpose To characterize the distribution of fat-to-muscle ratio (FMR) across patients with thyroid eye disease (TED) and to assess the association between FMR and therapeutic response to teprotumumab. Methods A retrospective cohort study of patients completing a full course of teprotumumab for TED between January 2020 and March 2022 at a single tertiary referral center. Patients without baseline orbital imaging were excluded. Quantitative analysis of FMR was performed by manual segmentation of patients’ imaging using OsiriX software. The primary outcome measure was change in clinical measurement of proptosis. Linear regression modelled change in proptosis against FMR. Statistical significance was set at p < .05. Results Twenty-two patients (3 M:19F) were included with a mean age of 49.4 ± 15.5 years. The FMR ranged from 1.11 to 6.54, mean 3.15 ± 1.30. The data did not deviate from a normal distribution (Shapiro–Wilk test for normality, p = .18). Pre- and post-treatment average proptosis measurements were 21.72 ± 3.56 mm and 18.81 ± 3.07 mm, respectively. Univariable linear regression demonstrated a 0.78 ± 0.36 mm greater reduction in proptosis for every 1 unit decrease in FMR (p = .038). Conclusions Contrary to the traditional dichotomous characterization of TED into type 1 and type 2 phenotypes, orbital FMR may represent a continuum of disease manifestation, more closely following a normal rather than bimodal distribution. Furthermore, pre-treatment FMR is associated with response to teprotumumab; those with lower FMR experiencing a greater reduction in proptosis. This has implications for patient selection and counselling regarding the expected treatment outcome.

Stable cerebrospinal fluid neurogranin and β-site amyloid precursor protein cleaving enzyme 1 levels differentiate predementia Alzheimer's disease patients.

Cerebrospinal fluid (CSF) β-site amyloid precursor protein cleaving enzyme 1 (BACE1), neurogranin and the neurogranin/BACE1 ratio are proposed markers for Alzheimer’s disease. BACE1 is also a drug target. However, CSF levels may differ between early-stage amyloid plaque formation (A) and later stage downstream tau-tangle pathology (T) and neurodegeneration (N) and may be expressed as an A/T/N stage (e.g. A+/T−/N or A+/T+/N+). Whether BACE1 and neurogranin levels are persistent traits or change with disease progression is unknown. The aim of this study was to investigate whether CSF neurogranin and BACE1 concentrations differ between A/T/N stages, whether these change over time and correlate with memory decline. This may have implications for patient selection in future trials. We used CSF markers to determine A/T/N stage using amyloid beta42/40 ratio, p-tau181 and total-tau respectively in predementia Alzheimer’s disease cases (n = 176) [including cases that progressed to dementia (n = 10)] and controls (n = 74) from the Norwegian Dementia Disease Initiation cohort. We selected cases at the presumed early (A+/T−/N−, n = 86) and late stages (A+/T+/N+, n = 90) of the Alzheimer’s disease continuum and controlled with normal markers (A−/T−/N−, n = 74). A subset of subjects in all A/T/N groups underwent repeat CSF sampling at approximately 2-year intervals up to 6 years from baseline. Using linear mixed models, longitudinal measurements of CSF BACE1 and neurogranin levels in A+/T−/N− and A+/T+/N+ as compared to A−/T−/N− healthy controls were performed. Next, we measured changes in CSF BACE1 and neurogranin levels in cases that progressed from A−/T−/N− to A+/T−/N− (n = 12), from A+/T−/N− to A+/T or N+ (n = 12), remained stable A+/T−/N− (n = 26), remained stable A+/T+/N+ (n = 28) compared with controls remaining stable A−/T−/N− (n = 33). Lastly, associations between these markers and memory decline were assessed. Compared with A−/T−/N− healthy controls, neurogranin was unaltered in A+/T−/N− (n.s.) but higher in A+/T+/N+ (P < 0.0001). In contrast, BACE1 was lower in A+/T−/N− (P < 0.05) and higher in A+/T+/N+ (P < 0.0001). The neurogranin/BACE1 ratio was increased in both A+/T−/N− (P < 0.05) and A+/T+/N+ (P < 0.0001) groups as compared to A-/T-/N- healthy controls and was more strongly associated with memory decline (b = −0.29, P = 0.0006) than neurogranin (b = −0.20, P = 0.002) and BACE1 (b = −0.13, P = 0.046). Neurogranin and BACE1 level differences remained stable over time not only within A/T/N groups but also in patients progressing to more pathological A/T/N stages (e.g. progressing from A+/T−/N− to A + T or N+) and in cases progressing to dementia. Our results suggest that neurogranin and BACE1 levels may differentiate pathomechanistic Alzheimer’s disease subgroups, putatively with different options for treatment.

Coaptation Reserve Predicts Optimal Reduction in Mitral Regurgitation and Long-Term Survival With Transcatheter Edge-to-Edge Repair.

Although transcatheter edge-to-edge repair (TEER) is effective and safe, there is a need for better prediction of optimal outcomes. We aimed to determine predictors of optimal reduction in mitral regurgitation (MR) and survival with TEER. We examined mitral anatomy and its change with TEER on outcomes in 183 patients (age, 82 [77-87] years; 53% women). Coaptation reserve was measured as the distance of continuous apposition of the A2 and P2 leaflet segments in 2-dimensional apical long-axis imaging at the site of the predominant jet of MR. Augmentation in coaptation was measured as the total amount of leaflet insertion. Addressable coaptation area was calculated using the physical boundaries of the TEER device. Coaptation reserve, its augmentation, and addressable coaptation area were strong predictors of MR reduction (all P<0.001), as well as heart failure hospitalization and death. For patients with either mild or no residual MR, median values for coaptation reserve, its augmentation, and addressable coaptation area were 3.7 (2.8-4.5) mm, 7.3 (5.2-9.5) mm, and 59.0 (48.0-71.8) mm2, respectively. Receiver operating characteristic analyses determined the best values for optimal MR reduction as a coaptation reserve of >3.0 mm (P<0.001), addressable coaptation area of ≥52 mm2 (P<0.001), and coaptation augmentation of ≥4.7 mm (P<0.001). These values were associated with greater 2-year survival free of all-cause mortality and persisting even in analyses restricted to those with mild or no residual MR after TEER. Coaptation reserve and its augmentation are simple, independent parameters that predict optimal MR reduction and better survival in patients undergoing TEER. These findings may have implications for patient selection and expanded use of the therapy.

Feasibility and Optimal Time Point of [68Ga]Gallium-labeled Prostate-specific Membrane Antigen Ligand Positron Emission Tomography Imaging in Patients Undergoing Cytoreductive Surgery After Systemic Therapy for Primary Oligometastatic Prostate Cancer: Implications for Patient Selection and Extent of Surgery

BackgroundProstate-specific membrane antigen (PSMA) targeted molecular imaging using positron emission tomography (PET) has significantly improved the diagnosis and treatment of prostate cancer (PCA). ObjectiveTo assess the feasibility and compare the diagnostic accuracy of [68Ga]Ga-PSMA-11 PET images taken at baseline, before the initiation of systemic treatment and preoperative images, using histopathology after cytoreductive surgery as reference. Design, setting, and participantsWe identified 20 patients in our prospectively maintained database with primary oligometastatic PCA who underwent cytoreductive radical prostatectomy and superextended pelvic lymph node dissection after systemic therapy, who had baseline and preoperative [68Ga]Ga-PSMA-11 PET imaging available. Outcome measurements and statistical analysisWe performed a region-based analysis to determine the diagnostic accuracy of imaging, using pathology as a reference. Regions were predefined as prostate, internal iliac left/right, obturator left/right, external iliac left/right, common iliac left/right, and presacral. Results and limitationsSensitivity, specificity, negative predictive value (NPV), positive predictive value (PPV), and diagnostic effectiveness were, respectively, 95.65%, 78.22%, 98.39%, 57.89%, and 83.00% for baseline [68Ga]Ga-PSMA-11 PET, compared to 56.52%, 98.05%, 88.30%, 89.66%, and 88.50% for preoperative [68Ga]Ga-PSMA-11 PET. On a receiver operating characteristic analysis, the diagnostic accuracy of baseline [68Ga]Ga-PSMA-11 PET with an area under the curve (AUC) of 0.87 (95% confidence interval [CI] 0.83–0.92) was significantly better than that of preoperative [68Ga]Ga-PSMA-11 PET after systemic therapy with an AUC of 0.77 (95% CI 0.70–0.85, p = 0.01). ConclusionsBaseline imaging, [68Ga]Ga-PSMA-11 PET has significantly better diagnostic accuracy, sensitivity, and NPV than images obtained preoperatively, in systemically pretreated patients. If a patient is suitable for local treatment and complete resection of the residual tumor is intended, [68Ga]Ga-PSMA-11 PET images taken prior to systemic therapy are significantly more accurate in selecting the relevant lymph nodes for resection. Patient summaryWe found that prostate-specific membrane antigen positron emission tomography (PSMA-PET) imaging used early, before hormonal therapy or chemotherapy, provides more accurate information about the spread of the disease, than if used immediately before surgery but after hormonal therapy or chemotherapy. Early use of PSMA-PET has the potential to improve therapy also at later stages of the disease.

Radiosensitivity, Immune Activation, and Mutational Frequency of Melanoma Metastases Across Tissue Types

<h3>Purpose/Objective(s)</h3> Melanoma is a more radioresistant and immunogenic histology, associated with a higher mutational burden. However, the influence of metastasis tissue location is unknown. We hypothesize exploiting these differences may allow therapy personalization. <h3>Materials/Methods</h3> We identified metastatic melanoma samples across 6 tissues (brain, liver, lung, lymph node [LN], skin, soft tissue [ST]), which were profiled for gene expression by microarray chips. Intrinsic radiosensitivity was estimated by the radiosensitivity index (RSI), a rank-based gene expression signature, where a higher RSI (scale 0-1) indicates greater radioresistance, with a cut point of 0.375 in other histologies. Degree of inflammation in the microenvironment was calculated by an existing 12-gene chemokine signature (12CK) where a higher 12CK score indicates greater inflammation. A subset (n = 94) underwent targeted exome sequencing (1,327 cancer-associated genes) and somatic mutations (MF) were enriched after filtering known germline/silent mutations and artifacts. Differences by tissue were analyzed with the Kruskal-Wallis H test. Correlations between RSI, 12CK, and MF were tested using Spearman's rho. <h3>Results</h3> From 1995 to 2011, 337 metastatic samples were identified from unique patients. Median age at diagnosis was 61 (range 20-97). With a median follow-up of 162 months (95% CI 142.6-181.4), median survival was 59.8 months (95% CI 49.2-70.4). Median values for RSI, 12CK, and MB were 0.451 (interquartile range [IQR] 0.331-0.552), 8.700 (IQR 7.218-9.746), and 101.5 (IQR 73.75-137), respectively. Significant differences existed among tissues for both RSI (<i>P</i> = 0.003) and 12CK (<i>P</i> < 0.001), but not MF (<i>P</i> = 0.498) (Table 1). No pair-wise comparisons were significant after Bonferroni correction for RSI, but for 12CK, Brain-ST (<i>P</i> = 0.044), Brain-Lung (<i>P</i> = 0.013), Brain-LN (<i>P</i> = 0.000), and Liver-LN (<i>P</i> = 0.023) were significant. Correlation between RSI and 12CK was significant (rho = -0.661, <i>P</i> < 0.001), but correlations between MB and RSI/12CK were not significant. <h3>Conclusion</h3> In this novel composite genomic analysis of melanoma metastases, all were relatively radioresistant, but higher RSI values for liver and skin metastases may warrant radiotherapy dose escalation. Similarly, the lower inflammatory scores of liver and brain metastases may have implications for selection of patients for immunotherapy. More inflamed tumors may be more responsive to radiation. In contrast to current homogenous approaches to metastases, these results indicate personalized approaches to types/sequencing of therapy for melanoma metastases by tissue type may be warranted.