Pretreatment Baseline Research Articles

Experience With the Routine Use of Electronic Patient-Reported Outcome Measures for Patients With Lung Cancer.

The Christie NHS Foundation Trust launched their electronic patient-reported outcome measures (ePROMs) service in January 2019 in the routine clinical setting. The lung cancer questionnaires consist of 14 symptom items, adapted from the Common Terminology Criteria for Adverse Events (version 5.0) and the EuroQol EQ-5D-5L quality-of-life (QoL) tool. Patients with lung cancer are invited to complete questionnaires assessing their symptoms and QoL using an online platform. The ePROM responses and clinical, pathologic, and treatment data for patients who completed the questionnaires between January 2019 and December 2020 were extracted from electronic medical records. The symptom and QoL scores of patients who completed baseline pretreatment ePROMs and also those who completed ePROMs pre- and postpalliative lung systemic anticancer therapy (SACT) or radical thoracic radiotherapy were evaluated. Pretreatment questionnaires were analyzed according to age, Eastern Cooperative Oncology Group performance status (ECOG PS), and Adult Comorbidity Evaluation-27 (ACE-27) comorbidity score. One thousand four hundred eighty patients with lung cancer were included. There were no statistically significant differences in symptoms and QoL scores between age groups. Cough (P = .006) and EQ-5D-5L mobility scores (P = .006) were significantly worse for patients with an ECOG PS of 0-1. Dyspnea (P = .035), hemoptysis (P = .023), nausea (P = .041), mobility (P = .004), and self-care (P = .0420) were significantly worse for those with higher ACE-27 scores (2-3 v 0-1). Palliative SACT was associated with a significant improvement in cough (P < .001) and hemoptysis (P = .025), but significantly negatively affected mobility (P = .013). Patients receiving radical thoracic radiotherapy reported a significant improvement in hemoptysis (P = .042) but worse pain (P = .002) and fatigue (P = .01). Other changes in symptom and QoL scores were not significant. The symptoms and QoL reported at baseline and before and after both palliative SACT and radical thoracic radiotherapy are clinically relevant and meaningful. We have demonstrated that routine implementation of ePROMs into clinical practice is feasible and can inform clinical practice and future research.

Comparison of Hearing Thresholds among Patients on Treatment for Drug-Resistant Versus Drug-Susceptible Pulmonary Tuberculosis in A SubSaharan African Healthcare Setting

Background: Pulmonary tuberculosis is a debilitating infectious disease that affects all age groups and sadly, a leading cause of death in developing countries particularly in sub-Saharan Africa. One major challenge facing the global efforts against tuberculosis is drug-resistance, which necessitates the use of aminoglycoside-based second line drugs that are known to have ototoxic potentials. Hearing impairment can be a source of social distress, professional disability and in some cases, litigation. This research compared the pure tone audiometric patterns of patients on treatment for drug-resistant versus drug-susceptible pulmonary tuberculosis. The incidence of hearing loss between the groups was assessed. Patients and Method: The research was a prospective comparative study of all eligible newly diagnosed pulmonary tuberculosis patients admitted into the Pulmonology unit of Federal Medical Centre, Owerri, Nigeria. Pre-treatment (baseline) and monthly pure tone audiometry was done for each patient before and during treatment respectively. The patients were followed up and assessed for three months. Data collected was analyzed with Statistical Package for Social Sciences (SPSS) version 20.0 software for Windows. Statistical significance was set at p&lt; 0.05. Results: A total of 76 patients (38 in each group) completed the study. The M:F ratio was 1.53:1 and 1.24:1 for the drug resistant and drug susceptible groups respectively while the mean duration of presenting symptoms were 11.7 ± 7.8 and 7.4 ± 5.1 weeks for the groups respectively. The prevalence of baseline hearing impairment was 73.7% among both groups while by the third month it was 89.5% among the dug-resistant group and 78.9% among the drug-susceptible group implying a cumulative incidence of hearing loss of 15.8% and 5.3% respectively over three months. This difference was statistically significant. Conclusion: The incidence of hearing impairment among patients on treatment for drug-resistant pulmonary tuberculosis was approximately three-fold higher than their drug susceptible counterparts after three months of treatment; this was statistically significant.

Potential predictive value of circulating tumor DNA (ctDNA) mutations for the efficacy of immune checkpoint inhibitors in advanced triple-negative breast cancer.

Background: In recent years, tumor immunotherapy has become a viable treatment option for triple negative breast cancer (TNBC). Among these, immune checkpoint inhibitors (ICIs) have demonstrated good efficacy in advanced TNBC patients with programmed death-ligand 1 (PD-L1) positive expression. However, only 63% of PD-L1-positive individuals showed any benefit from ICIs. Therefore, finding new predictive biomarkers will aid in identifying patients who are likely to benefit from ICIs. In this study, we used liquid biopsies and next-generation sequencing (NGS) to dynamically detect changes in circulating tumor DNA (ctDNA) in the blood of patients with advanced TNBC treated with ICIs and focused on its potential predictive value. Methods: From May 2018 to October 2020, patients with advanced TNBC treated with ICIs at Shandong Cancer Hospital were included prospectively. Patient blood samples were obtained at the pretreatment baseline, first response evaluation, and disease progression timepoints. Furthermore, 457 cancer-related genes were evaluated by NGS, and patients' ctDNA mutations, gene mutation rates, and other indicators were determined and coupled with clinical data for statistical analysis. Results: A total of 11 TNBC patients were included in this study. The overall objective response rate (ORR) was 27.3%, with a 6.1-month median progression-free survival (PFS) (95% confidence interval: 3.877-8.323months). Of the 11 baseline blood samples, 48 mutations were found, with the most common mutation types being frame shift indels, synonymous single-nucleotide variations (SNVs), frame indel missenses, splicing, and stop gains. Additionally, univariate Cox regression analysis revealed that advanced TNBC patients with one of 12 mutant genes (CYP2D6 deletion and GNAS, BCL2L1, H3F3C, LAG3, FGF23, CCND2, SESN1, SNHG16, MYC, HLA-E, and MCL1 gain) had a shorter PFS with ICI treatment (p < 0.05). To some extent, dynamic changes of ctDNA might indicate the efficacy of ICIs. Conclusion: Our data indicate that ICI efficacy in patients with advanced TNBC may be predicted by 12 mutant ctDNA genes. Additionally, dynamic alterations in peripheral blood ctDNA might be used to track the effectiveness of ICI therapy in those with advanced TNBC.

Efficacy and safety of gluten peptide-based antigen-specific immunotherapy (Nexvax2) in adults with coeliac disease after bolus exposure to gluten (RESET CeD): an interim analysis of a terminated randomised, double-blind, placebo-controlled phase 2 study

A gluten-free diet is insufficient to treat coeliac disease because intestinal injury persists and acute reactions with cytokine release follow gluten exposure. Nexvax2 is a specific immunotherapy using immunodominant peptides recognised by gluten-specific CD4+ T cells that might modify gluten-induced disease in coeliac disease. We aimed to assess the effects of Nexvax2 on gluten-induced symptoms and immune activation in patients with coeliac disease. This was a randomised, double-blind, placebo-controlled phase 2 trial done at 41 sites (29 community, one secondary, and 11 tertiary centres) in the USA, Australia, and New Zealand. Patients with coeliac disease aged 18-70 years who had excluded gluten for at least 1 year, were HLA-DQ2.5 positive, and had a worsening of symptoms after an unmasked 10 g vital gluten challenge were eligible for inclusion. Patients were stratified by HLA-DQ2.5 status (HLA-DQ2.5 non-homozygous vs homozygous). Patients who were non-homozygous were centrally (ICON; Dublin, Ireland) randomly assigned (1:1) to receive subcutaneous Nexvax2 (non-homozygous Nexvax2 group) or saline (0·9% sodium chloride; non-homozygous placebo group) twice a week escalating from 1 μg to 750 μg during the first 5 weeks followed by 11 weeks of maintenance therapy at 900 μg per dose. The exploratory homozygous group was centrally randomly assigned (2:1) to receive Nexvax2 (homozygous Nexvax2 group) or placebo (homozygous placebo group); patients who were homozygous received the same doseage as those who were non-homozygous. The primary endpoint was change in coeliac disease patient reported outcomes (total gastrointestinal domain) from pretreatment baseline to the day of masked bolus 10 g vital gluten challenge given in week 14 analysed in the non-homozygous intention-to-treat population. The trial is registered with ClinicalTrials.gov, NCT03644069. Between Sept 21, 2018, and April 24, 2019, 383 volunteers were screened for inclusion, of whom 179 (47%; 133 [74%] women, 46 [26%] men; median age 41 years [IQR 33-55]) were randomly assigned. One (1%) of 179 patients was excluded from analysis due to misassignment of genotype. The non-homozygous Nexvax2 group included 76 patients, the non-homozygous placebo group included 78 patients, the homozygous Nexvax2 group included 16 patients, and the homozygous placebo group included eight patients. The study was discontinued after planned interim analysis of 66 patients who were non-homozygous. We report an unmasked post-hoc analysis of all available data for the primary endpoint and secondary symptom-based endpoints combining data from 67 (66 were assessed in the planned interim analysis for the primary endpoint). Mean change from baseline to day of first masked gluten challenge in total gastrointestinal score for the non-homozygous Nexvax2 group was 2·86 (SD 2·28) compared with 2·63 (2·07) for the non-homozygous placebo group (p=0·43). Adverse events were similar between all patients who received Nexvax2 and those who received placebo. Serious adverse events were reported in five (3%) of 178 patients (two [2%] of 92 who received Nexvax2 and three [4%] of 82 who received placebo). One patient in the non-homozygous Nexvax2 group had a serious adverse event that occurred during gluten challenge (left-sided mid-back muscle strain with imaging suggestive of partial left kidney infarction). Serious adverse events were reported for three (4%) of 78 patients in the non-homozygous placebo group (one each with exacerbation of asthma and appendicitis, and one who had forehead abscess, conjunctivitis, and folliculitis) and one (1%) patient in the non-homozygous Nexvax2 group developed a pulmonary embolism. The most frequent adverse events in all 92 patients who received Nexvax2 compared with all 86 patients who received placebo were nausea (44 [48%] of 92 patients who received Nexvax2 vs 29 (34%) of 86 patients who received placebo), diarrhoea (32 [35%] vs 25 [29%]), abdominal pain (31 [34%] vs 27 [31%]), headache 32 [35%] vs 20 [23%]), and fatigue (24 [26%] vs 31 [36%]). Nexvax2 did not reduce acute gluten-induced symptoms. Masked bolus vital gluten challenge provides an alternative to extended gluten challenge in efficacy studies for coeliac disease. ImmusanT.

Changes in Sonographic Thickness with Identification of Nine Layers, Roughness, and Hydration in the Dorsal Hand after Injectables.

With the use of sonography, soft-tissue thickness can be measured accurately to assess the volumizing effects of fillers. In this prospective study, monophasic stabilized hyaluronic acid filler (1 cc) was injected into the dorsal superficial and intermediate laminae of 20 patients using a subdermal scraping fanning injection technique. Sonograms and topographic computer analyses were used to measure soft-tissue thickness, skin roughness, and stratum corneum hydration (SCH) at 1 week and 1, 2, 3, and 6 months. Hand appearance and skin roughness improved in all patients. Sonography showed that soft-tissue thickness was increased by 4.52 mm (immediately after treatment), 5.52 mm (1 week), 4.89 mm (1 month), 4.25 mm (2 months), 4.08 mm (3 months), and 3.86 mm (6 months) from the pretreatment baseline of 3.20 mm. Roughness was reduced by 15.39 au (16.17%) at 1 month, 21.5 (18.12%) at 2 months, 22.7 (23.91%) at 3 months, and 27.16 (38.12%) at 6 months, indicating improvements in fine wrinkles. SCH also improved during follow-up. Detailed subdivision of nine layers of hand dorsum was established in this sonography study for the first time. Soft-tissue thickness was increased more than 207% during follow-up, and placement of hyaluronic acid materials was confirmed in the dorsal superficial and dorsal intermediate laminae. Hand appearance and skin roughness improved in all patients. Veins and tendons became less apparent, with volumizing effects. All patients stated that their skin became more moisturized, youthful, and smooth during the follow-up period after only one session of the subdermal scraping, fanning injection technique. Therapeutic, IV.

TOLERANCE AND ACCEPTABILITY OF INTRAVENOUS KETAMINE THERAPY FOR TREATMENT RESISTANT DEPRESSION: A MIXED METHODS ASSESSMENT

Objectives: This study was conducted to evaluate the response of treatment resistant depression to IV ketamine therapy protocol and explore the perspectives of patients regarding the acceptability of this treatment modality. Study Design: Mixed methods assessment including Quasi experimental design and Qualitative interviews. Place and Duration of Study: The study was conducted at Department of Psychiatry, Fauji Foundation Hospital, Rawalpindi from Jan to Jun 2022. Subjects and Methods: Through purposive sampling, 14 patients of treatment resistant depression were made part of the sample. Hamilton Rating scale for Depression (HAM-D) was used to measure response to 6 Ketamine infusions administered over 2 weeks. Paired t-test was applied to analyze changes in HAM-D scores compared to pretreatment baseline at 1 hour, 2 weeks and 1 month after last dose of ketamine using SPSS 26.0. Semi structured interviews were conducted to explore the attitudes of patients regarding ketamine treatment. Thematic analysis was carried out and data driven themes were identified. Results: There was a statistically significant improvement in severity of depression scores at 1 hour and 2 weeks after the last dose of ketamine. This effect was not significantly sustained at 1 month after the last dose. Some patients expressed initial hesitation related to safety of this treatment, citing comparisons with General anesthesia. By the end of treatment, most patients were keen to be advocates for the access to Ketamine therapy due to experiencing rapid transformational effects on severe depressive symptoms. Conclusion: IV Ketamine therapy was found to be a rapid, effective and acceptable tool for treatment resistant depression; however its longer-term effects could not be established.

Pretreatment Depressive Status Associated with Poor Nutrition and Prognosis in Breast Cancer Patients Receiving Neoadjuvant Chemotherapy

The prevalence of pretreatment depression in breast cancer patients and its impact on nutrition and prognosis during neoadjuvant chemotherapy remain unknown. One hundred twenty-one patients with previously untreated breast cancer undergoing neoadjuvant chemotherapy (NAC) were enrolled. Patients completed the Self-rating Depressive symptoms Scale (SDS) before treatment and were divided into two groups (non-depressive group and depressive group). The nutrition risk screening-2002 (NRS-2002), and nutritional and prognostic indicators, including neutrophil-to-lymphocyte ratio (NLR) and prognostic nutritional index (PNI), were collected at baseline (pretreatment) and post-treatment. One- and two-year progression-free survival (PFS) in both groups were also calculated. We found that 38.84% patients experienced pretreatment depressive symptoms. Patients in the depressive group had higher nutritional risk and lower body mass index, potassium, sodium, total cholesterol, total protein, and fasting blood glucose levels than those in pretreatment non-depressive group after NAC (all p < 0.05). And higher NLR (p = 0.039) and lower PNI level (p = 0.0021) after NAC were found in patients with pretreatment depressive status. Multivariable Cox analysis showed pretreatment depressive status (HR: 1.893; 95% CI: 1.047-3.426; p = 0.034) were a significant predictor of PFS. This study provides evidence for early identification of pretreatment depression in patients receiving NAC, which would certainly favor nutrition and survival outcome.

Improving mother-infant bonding in postnatal depression − The SURE MUMS study

To study the effectiveness of the Sure Mums intervention in improving mother-baby bonding in a group of new mothers in Singapore. Over a period of 2 years from 2017 to 2019, thirty-two mothers were identified from our clinic population seeking treatment for postnatal mental health difficulties - these included depressive or anxiety symptoms, together with bonding difficulties. They received home-based mother-infant therapy sessions, and scores for the Postpartum Bonding Questionnaire (PBQ), Global Assessment of Functioning (GAF), and Edinburgh Postnatal Depression Scale (EPDS) were taken pre- and post-intervention. In all, twenty-five mothers completed measures for baseline characteristics, pretreatment scores and post-treatment scores. Paired sample t-tests were conducted for the 4 subscales of the PBQ, the GAF rating score, and the EPDS score. Postintervention scores noted a reduction in the mean of all of the 4 PBQ subscales, and 3 of the 4 scores had differences that were shown to be statistically significant improvement. The EPDS pre-intervention mean score was 17.72, while mean postintervention EPDS score was 9.2. Total GAF scores showed an mean uptrend by 12-14 points, likely indicating significant improvement in the mothers' functioning post intervention. The results of this programme shows promising evidence of its effectiveness in improving the quality of bonding in mothers with postnatal mental health difficulties. For future direction, we hope to offer the SURE MUMS programme to more mothers who are struggling to bond with their baby amidst the challenges of becoming a parent.

Abstract P5-02-31: Genetic determinants of response to patritumab deruxtecan (HER3-DXd) in hormone receptor-positive/HER2-negative (HR+/HER2-) breast cancer: a correlative analysis from SOLTI TOT-HER3 trial

Abstract Background: Baseline HER3 protein or ERBB3 mRNA levels do not seem to predict efficacy from HER3-DXd in early-stage and advanced HR+/HER2- breast cancer (Prat et al. ESMO Breast 2022; Krop et al. ASCO 2022). Here, we evaluated potential baseline pre-treatment genetic determinants of efficacy to HER3-DXd. Methods: SOLTI TOT-HER3 (NCT04610528) is a window of opportunity, multicenter, pre-operative trial which enrolled, in part A, 77 evaluable patients with untreated HR+/HER2- operable (≥1 cm) breast cancer. Patients received a single dose of HER3-DXd (6.4 mg/kg). The primary objective was to evaluate the CelTIL score variation between pre- and post-treatment (day 21) samples. CelTIL combines % of tumor cellularity and % of tumor-infiltrating lymphocytes into a single score. DNA and RNA were purified from pre-treatment baseline FFPE tumor samples. Gene expression was evaluated using a custom 67-gene panel on the nCounter. NGS-based DNA-seq was performed using the VHIO-300 panel, which estimates tumor mutational burden (TMB), identifies copy-number aberrations (CNAs) across the entire genome and calls mutational status of &amp;gt;300 genes. From CNA data, 150 previously defined DNA-based signatures (Xia et al. Nat Comm 2019) trained to capture RNA- and protein-based phenotypes such as the PAM50-related biology were evaluated. Associations of each variable with efficacy (i.e., CelTIL relative changes, and tumor cellularity relative changes) were adjusted for multiple-testing (false discovery rate [FDR] &amp;lt; 5%). The area under the ROC Curve (AUC) was used to estimate the discrimination performance of each variable. Results: RNA and DNA data were obtained from 45 (58%) patients. Baseline characteristics in this subset of patients were generally similar to the original TOT-HER3 population. Among 228 variables (single mutation status, single gene expression, PAM50 signatures, TMB, and DNA CNA-based signatures), 139 (61%) were found significantly associated (FDR&amp;lt; 5%) with CelTIL changes at day 21. Among them, TP53 mutations (n=7) were found associated with higher CelTIL response compared to TP53 wild type (71% [95% CI=-5.4-17.8] vs. 24% [95% CI=15.9-55.4], FDR=2.1%). In addition, RNA-based genes tracking Basal-related biology (e.g., CCNE1, AUC=0.71) or immune expression (e.g., PDCD1, AUC=0.73, or CD68, AUC=0.62), together with RNA/DNA-based signatures tracking proliferation and/or basal-related biology (e.g., retinoblastoma loss-of-heterozygozity [RB-LOH], AUC=0.76), were associated with high CelTIL response. Conversely, RNA/DNA-based signatures tracking endocrine sensitivity/Luminal A-related biology (e.g., Scorr_IE_Correlation, AUC=0.76) were associated with low/lack of CelTIL response. PIK3CA somatic mutations (n=14, 31% of cases), and TMB (range 2.2-12.7) were not found associated with CelTIL response. Similar overall results were obtained when relative changes in tumor cellularity (instead of CelTIL) was evaluated as the efficacy endpoint. Conclusions: TP53 mutations, immune-related genes, and DNA/RNA-based phenotypic signatures tracking Basal- or Luminal A-related biology such as the DNA-based RB-LOH score or the endocrine sensitivity score (Scorr_IE_Correlation) are associated with CelTIL changes in response to HER3-DXd in HR+/HER2- breast cancer. Further RNA- and DNA-based analyses will be evaluated. Citation Format: Fara Brasó-Maristany, Claudette Falato, Olga Martínez-Sáez, Juan Miguel Cejalvo, Mireia Margelí, Pablo Tolosa, Francisco Javier Salvador Bofill, Josefina Cruz, Blanca González-Farré, Esther Sanfeliu, Míriam Arumí, Guillermo Villacampa, Eva Ciruelos, Martín Espinosa-Bravo, Yann Izarzuzaga, Patricia Galván, Judit Matito, Sonia Pernas, Anu Santhanagopal, Stephen Esker, Parul Patel, Pang-Dian Fan, Juan Manuel Ferrero-Cafiero, Ana Vivancos, Tomás Pascual, Aleix Prat, Mafalda Oliveira. Genetic determinants of response to patritumab deruxtecan (HER3-DXd) in hormone receptor-positive/HER2-negative (HR+/HER2-) breast cancer: a correlative analysis from SOLTI TOT-HER3 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 P5-02-31.

Abstract P6-01-46: Independent validation of the HER2DX genomic test in HER2-positive breast cancer treated with neoadjuvant docetaxel, carboplatin, trastuzumab +/- pertuzumab (TCH/TCHP): a correlative analysis from a multicenter academic study

Abstract Background: HER2DX (Prat et al. EBiomedicine 2022) is a 27-gene prognostic (risk-score) and predictive (pathological complete response [pCR]-score) assay in early-stage HER2+ breast cancer based on clinical data and the expression of 4 gene signatures (immune, proliferation, luminal differentiation and HER2 amplicon). Here, we aim to evaluate, for the first time, the ability of HER2DX to predict pCR following neoadjuvant TCH or TCHP in HER2+ disease. Methods: Standardized HER2DX was performed in a central lab on baseline pre-treatment FFPE tumor biopsies from the GOM-HGUGM-2018-05 study in Spain, a consecutive retrospective series of patients (pts) with newly diagnosed stage I-III HER2+ breast cancer eligible for neoadjuvant therapy. Pts received standard 6 cycles of docetaxel, carboplatin and trastuzumab (TCH) or TCH with pertuzumab (TCHP) regimens. Primary aim was to test the ability of HER2DX pCR score to predict pCR (ypT0/is ypN0). Secondary objectives were to test the ability of HER2DX pCR score to predict pCR independently of clinical-pathological variables and the PAM50 subtype (HER2-enriched versus not), and to evaluate the association of HER2DX pCR score with the HER2DX risk-score. Logistic regression and receiver-operator curve (ROC) analysis were assessed. Statistical analyses were performed in R code 4.0.5. Results: HER2DX was evaluated in 155 pts (97%) enrolled in the study with available RNA (as of June 2022). Mean age of pts was 50 (range 22-74) and 55.2% of pts (n=85) were pre-menopausal. Clinical T2-4 disease represented 77.4% of cases (n=120), clinical node-positive disease (cN1-3) represented 63.9% of cases (n=99), and 68.0% of tumors (n=105) were hormone receptor-positive. The overall pCR rate was 57.4% (95% confidence interval [CI] 50-65): 52.2% (95% CI 40-64) with TCH (n=67) and 61.4% (95% CI 50-72) with TCHP (n=88). The proportion of HER2DX low-, medium- and high-pCR groups was 34.2%, 34.8% and 31.0%, respectively. HER2DX pCR score (as a continuous variable from 0 to 100) was significantly associated with pCR (odd ratio [OR]=1.03, p=5.91e-07). The pCR rates in HER2DX pCR-high and pCR-low groups were 75.0% and 28.0% (OR=7.6, 95% CI 3.2-19.1, p=7.14e-06), respectively. In pts treated with TCHP, the pCR rates in HER2DX pCR-high and pCR-low groups were 85.7% and 27.3% (OR=16.0, 95% CI 4.3-59.01, p=3.2e-05), respectively. The AUC ROC of HER2DX pCR score (as a continuous variable) and pCR status was 0.746 (in all pts) and 0.812 (in pts treated with TCHP). HER2DX pCR score was significantly associated with pCR independently of hormone receptor status, Ki67, age, menopausal status, pertuzumab use, clinical stage and PAM50 HER2-enriched subtype. The proportion of HER2DX low- and high-risk of relapse disease was 32.0% and 68.0%, respectively. The correlation of HER2DX pCR score and HER2DX risk-score was weak (coefficient=-0.17), as previously described. Proportion of cases according to both HER2DX scores and absolute difference of pCR rates between TCHP and TCH in each combined group is shown in Table. Conclusion: The HER2DX genomic test predicts pCR following neoadjuvant TCH or TCHP regimens independently of clinical-pathological variables and intrinsic subtype. The combination of both HER2DX scores might help better tailor systemic therapy in patients with newly diagnosed stage I-III HER2+ breast cancer. Citation Format: Coralia Bueno-Muiño, Isabel Echavarria, Sara López-Tarruella, Roche-Molina Marta, María del Monte-Millán, Tatiana Massarrah, Yolanda Jerez Gilarranz, Blanca Herrero, Salvador Gámez, Iván Márquez-Rodas, María Cebollero-Presmanes, Nevado Santos Manuel, Pilar de la Morena Barrio, Francisco Ayala de la Peña, José Ángel García-Sáenz, Fernando Moreno Antón, Álvaro Rodríguez Lescure, Teresa Quintanar, Diego Malón-Giménez, Laura Rodriguez-Lajusticia, Ana Isabel Ballesteros García, Dulce Bañón Torres, Lucía Villarejo, Nerea Lobato, Ainhoa Arias, Inmaculada Ocaña, Enrique Álvarez, Laia Paré, Mercedes Marín-Aguilera, Patricia Galván, Fara Brasó-Maristany, Ana Vivancos, Patricia Villagrasa, Joel S Parker, Charles M. Perou, Aleix Prat, Miguel Martín. Independent validation of the HER2DX genomic test in HER2-positive breast cancer treated with neoadjuvant docetaxel, carboplatin, trastuzumab +/- pertuzumab (TCH/TCHP): a correlative analysis from a multicenter academic study [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 P6-01-46.

Abstract PD11-07: PD11-07 Association of TNBC-DX scores with outcomes in triple-negative breast cancer (TNBC) treated with neoadjuvant pembrolizumab and chemotherapy: a correlative analysis from NeoPACT and NeoSTOP trials

Abstract Introduction: The TNBC-DX risk score includes the 14-gene immunoglobulin (IGG) immune signature, tumor size, and nodal status and has shown prognostic value for survival in early-stage TNBC (B. Conte et al., ESMO Breast 2021). However, currently unknown are the value of the TNBC-DX risk score and IGG immune signature in 1) predicting pathologic complete response (pCR) following neoadjuvant therapy, and 2) predicting outcomes the context of neoadjuvant anti-PD1 treatment. Here, we assessed the IGG signature and the TNBC-DX risk score in patients with TNBC treated with neoadjuvant chemoimmunotherapy (NeoPACT; NCT03639948) and neoadjuvant chemotherapy without immunotherapy (NeoSTOP; NCT02413320). Methods: NeoPACT trial enrolled 120 patients with stage I-III TNBC who received carboplatin (AUC 6) + docetaxel (75 mg/m2) + pembrolizumab (200 mg) every 21 days x 6 cycles. NeoSTOP randomized 100 patients with stage I-III TNBC to two chemotherapy regimens; Arm B of NeoSTOP was included in this correlative study as the chemotherapy regimen was identical to NeoPACT. RNA isolated from pretreatment tumor tissue was subjected to next-generation sequencing. The 14-gene IGG immune signature and TNBC-DX risk score were calculated in silico as previously described. Evaluation of stromal tumor-infiltrating lymphocytes (sTILs) was performed as previously described. Markers were tested for prediction of pCR. Logistic regression analysis was used to examine the effect of multiple variables. Event-free survival (EFS) curves were assessed by the Kaplan-Meier method and groups compared by the log-rank test, followed by Cox regression analysis. Results: In this analysis, 112 patients were treated with chemoimmunotherapy on NeoPACT (node-positive = 38%, pCR rate = 58%). In the NeoPACT trial, the 14-gene IGG signature (as a continuous variable) was significantly associated with improved pCR (odds ratio [OR]=1.105, 95% CI 1.019-1.197, P=0.015 for every 0.2 increment). The pCR rates in IGG-high (≥ median) and IGG-low (&amp;lt; median) groups were 71% and 44%, respectively (OR=3.152, 95% CI 1.420-6.996, P=0.005). In terms of EFS, the 14-gene IGG signature was not prognostic (hazard ratio [HR]=0.507, 95% CI 0.148-1.735, p=0.269). In contrast, TNBC-DX risk score was strongly associated with EFS (HR=5.684, 95% CI 1.226-26.356, P=0.012), even when adjusted for sTILs and pCR status (HR=8.415, 95% CI 1.054-67.169, P=0.044). Estimated 3-year EFS rates in TNBC-DX high and low risk groups (above and below median) were 77% and 89%, respectively (P=0.012). In 43 NeoSTOP patients treated with neoadjuvant chemotherapy only (node-positive = 33%, pCR rate = 53%), no association of IGG signature with pCR or TNBC-DX score with EFS was observed. Finally, we observed a moderate correlation between IGG signature and sTILs in both trial datasets combined (r=0.642, P&amp;lt; 0.001). Conclusions: High expression of the 14-gene IGG immune signature in baseline pretreatment tumor samples in early-stage TNBC is significantly associated with pCR following pembrolizumab-based neoadjuvant chemotherapy. The combination of this signature with tumor burden as assessed by TNBC-DX is prognostic for long-term outcomes. Availability of biomarkers that can predict both pathological response and survival with chemoimmunotherapy can optimize this therapy, and evaluation of this biomarker in larger studies is warranted. Citation Format: Priyanka Sharma, Shane R. Stecklein, Rachel Yoder, Joshua M. Staley, Roberto Salgado, Laia Paré, Benedetta Conte, Fara Brasó-Maristany, Anne O’Dea, Lauren Nye, Manana Elia, Deepti Satelli, Gregory Crane, Richard McKittrick, Qamar Khan, Andrew K. Godwin, Aleix Prat. PD11-07 Association of TNBC-DX scores with outcomes in triple-negative breast cancer (TNBC) treated with neoadjuvant pembrolizumab and chemotherapy: a correlative analysis from NeoPACT and NeoSTOP trials [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 PD11-07.

Abstract P1-04-05: Independent validation of the HER2DX genomic test in HER2-positive breast cancer treated with neoadjuvant paclitaxel, trastuzumab and pertuzumab (THP): a correlative analysis from the DAPHNe phase II clinical trial

Abstract Background: HER2DX is a 27-gene prognostic (risk-score) and predictive (pathological complete response [pCR]-score) assay in early-stage HER2+ breast cancer (BC) based on clinical data and the expression of 4 gene signatures (immune, proliferation, luminal differentiation, and HER2 amplicon). Here we aim to evaluate, for the first time, the ability of HER2DX to predict pCR following neoadjuvant THP in HER2+ BC. Methods: Standardized HER2DX was evaluated centrally on baseline pre-treatment FFPE tumor biopsies from the DAPHNe phase II trial (Waks et al. NPJ Breast 2022; NCT03716180), in which patients (pts) with newly diagnosed stage II-III HER2+ BC were treated with neoadjuvant weekly paclitaxel × 12 and HP every 3 weeks × 4. Primary aim was to test the ability of HER2DX pCR-score to predict pCR (ypT0/isN0). Secondary objectives were to test the ability of HER2DX pCR-score to predict pCR independent of clinical-pathological variables and PAM50 subtype (HER2-enriched vs not) and to evaluate the association of HER2DX pCR-score with HER2DX risk-score. Five patients who received additional neoadjuvant chemotherapy after THP were excluded from this analysis. Logistic regression and receiver-operator curve (ROC) analysis were assessed. Statistical analyses were performed in R code 4.0.5. Results: HER2DX was evaluated in 80 of 97 pts (82.5%) enrolled in the DAPHNe trial who received study treatment. Clinical T2-4 disease represented 81.3% of cases (n=65), clinical node-negative disease (cN0) represented 65.0% of cases (n=52), and 70.0% of tumors (n=56) were hormone receptor-positive. The overall pCR rate was 60.0% (95% confidence interval [CI] 49.3-70.7): 87.0% (95% CI 79.6-94.4) in hormone receptor-negative disease and 48.2% (95% CI 37.2-59.1) in hormone receptor-positive disease. The proportion of HER2DX low-, medium- and high-pCR groups was 38.8%, 27.5% and 33.7%, respectively. HER2DX pCR-score (as a continuous variable from 0 to 100) was significantly associated with pCR (odds ratio [OR]=1.05, p&amp;lt; 0.0001). In the overall population, the pCR rates in HER2DX pCR-high, pCR-med and pCR-low groups were 92.6%, 63.6% and 29.0% (pCR-high vs pCR-low OR=30.6, p&amp;lt; 0.0001), respectively. The AUC ROC of HER2DX pCR score (as a continuous variable) and pCR status was 0.835. In the ER-negative population, the pCR rates in HER2DX pCR-high, pCR-med and pCR-low groups were 94.7%, 66.7%, and 0%, respectively (Table 1). HER2DX pCR-score was significantly associated with pCR independent of hormone receptor status, HER2 immunohistochemistry (IHC) score, clinical stage, and PAM50 HER2-enriched subtype. The correlation between HER2DX pCR-score and HER2DX risk-score was weak (Pearson coefficient=-0.12), as previously described (Prat et al. EBiomedicine 2022). 51.3% of patients were categorized as HER2DX low-risk. Conclusion: The 27-gene HER2DX genomic test predicts pCR following neoadjuvant THP in newly diagnosed stage II-III HER2+ BC. Patients with HER2DX pCR-low score and HER2DX high-risk score, representing 22.5% of pts, warrant further attention in order to optimize therapeutic strategies in this subset. The combination of HER2DX pCR-score and risk-score might guide therapeutic decisions by identifying patients who are ideal candidates for de-escalated or escalated systemic and locoregional treatments. Table 1 Citation Format: Adrienne Waks, Esther R. Ogayo, Laia Paré, Mercedes Marín-Aguilera, Fara Brasó-Maristany, Patricia Galván, Oleguer Castillo, Olga Martínez-Sáez, Ana Vivancos, Patricia Villagrasa, Paolo Tarantino, Neelam Desai, Jennifer Guerriero, Otto Metzger, Nadine Tung, Ian Krop, Joel S Parker, Charles M. Perou, Aleix Prat, Eric Winer, Sara Tolaney, Elizabeth A. Mittendorf. Independent validation of the HER2DX genomic test in HER2-positive breast cancer treated with neoadjuvant paclitaxel, trastuzumab and pertuzumab (THP): a correlative analysis from the DAPHNe phase II clinical 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 P1-04-05.

Prognostic value of blood biomarkers in steroid-refractory or steroid-dependent acute graft-versus-host disease: a REACH2 analysis

AbstractSystemic steroids are the standard first-line treatment for acute graft-versus-host disease (aGVHD), but ∼50% of patients become steroid-refractory or dependent (SR/D). Ruxolitinib is the only Food and Drug Administration– and European Medicines Agency–approved therapy for patients with SR/D aGVHD. In the phase 3 REACH2 trial (NCT02913261), ruxolitinib demonstrated superior efficacy in SR/D aGVHD, with a significantly higher overall response rate (ORR) on day 28, durable ORR on day 56, and longer median overall survival compared with the best available therapy (BAT). Identifying biomarkers and clinical characteristics associated with increased probability of response can guide treatment decisions. In this exploratory analysis of the REACH2 study (first biomarker study), we developed baseline (pretreatment) and day 14 models to identify patient characteristics and biomarkers (12 aGVHD-associated cytokines/chemokines, 6 immune cell types, and 3 inflammatory proteins) before and during treatment, which affected the probability of response at day 28. Treatment with ruxolitinib, conditioning, skin involvement, and age were strongly associated with an increased likelihood of response in the ≥1 model. Lower levels of most aGVHD and immune cell markers at baseline were associated with an increased probability of response. In the day 14 model, levels of aGVHD markers at day 14, rather than changes from baseline, affected the probability of response. For both models, the bias-corrected area under the receiver operating characteristic values (baseline, 0.73; day 14, 0.80) indicated a high level of correspondence between the fitted and actual outcomes. Our results suggest potential prognostic value of selected biomarkers and patient characteristics.

A study to determine enzalutamide long term safety and efficacy for men with castration-resistant prostate cancer: A multicenter, prospective DELC study.

66 Background: In the PREVAIL study, enzalutamide was demonstrated to be effective in men with chemo-naïve metastatic castration-resistant prostate cancer (CRPC). In Japan, enzalutamide was introduced in 2014. Real-world evidence is needed for the long-term safety and efficacy of enzalutamide. The aim of this study was to evaluate the efficacy, safety and prognostic factors in CRPC treated with enzalutamide. Methods: This multicenter, prospective, observational study enrolled 163 Japanese CRPC patients between January 2016 and March 2019. Eligibility criteria were men with chemo-naïve CRPC, no prior treatment with novel androgen receptor signaling inhibitors, and an ECOG- Performance Status ≤ 2. The switching of bicalutamide and flutamide was eligible. Written consent for participation has been obtained from the patient. Enzalutamide 160 mg/day was administered once daily according to usual practice. Data were collected from medical records at baseline and every 3 months until march 2021. The primary endpoint was overall survival (OS), and factors associated with OS were examined. Cox proportional hazards model was used for statistics. The secondary endpoints were PSA response and safety. Results: At a median follow-up of 26.0 months, the median OS was 42.1 months and 24-month OS rate was 69%. Univariate analysis showed that time to CRPC, pretreatment serum PSA, baseline NSE, and baseline interleukin-6 (IL-6) levels were associated with OS. Multivariate analysis revealed that pretreatment serum PSA (hazard ratio [HR] 2.30, 95% confidence interval [CI] 1.30-4.10), baseline NSE (HR 2.97, 95%CI 1.24-7.11), and baseline IL-6 (HR 2.32 95%CI 1.32-4.09) were independent risk factors for OS. PSA decline more than 50% was 74% (n=120). Fatigue (30%, n=49), constipation (20%, n=32) and appetite loss (18%, n=29) were the most common adverse events (AEs). Dose reduction/drug discontinuation rates were 20% (n=33) due to AEs and 18% (n=29) due to patient request. Conclusions: The efficacy and safety of enzalutamide in Japanese real clinical practice were comparable to those reported in PREVAIL study. The present analysis also suggests that serum PSA, NSE and IL-6 levels are independent prognostic factors in CRPC patients. Clinical trial information: UMIN000019855 . [Table: see text]

Evaluation of a novel transcriptomic tumor signature (PROSTest) as response biomarker for 177Lu-PSMA therapy in advanced prostate cancer.

183 Background: Radionuclide therapy targeting the prostate specific membrane antigen (177Lu-PSMA therapy) has proven to be an effective treatment in men with metastatic castration resistant prostate cancer (mCRPCs). Despite representing a significant therapeutic breakthrough, a critical unmet need in 177Lu-PSMA therapy, is a prognostic biomarker for treatment optimization. Imaging and standard biomarkers have limited value. The PROSTest is a new 27-gene algorithmic signature originally developed for prostate adenocarcinoma diagnosis (0 to 100, positive score ≥20). We hypothesized that PROSTest would be elevated in mCRPCs and could have utility as a biomarker for mCRPC management. Methods: Prospective enrollment of 113 mCRPC for 177Lu-PSMA therapy (KlbB-5338-0302021 study). Pathology, clinical and biomarker data were available as was PSMA-PET/CT. Blood samples were collected for PROSTest prior to therapy. Target genes were isolated and amplified using qPCR. PROSTest scores (0-100) were obtained following algorithmic analysis. Scores were correlated with mCRPC diagnosis and baseline information. Scores and standard clinical measures were evaluated as prognostic factors with survival as endpoint. Mann-Whitney U-test, Kaplan-Meier survival and Cox proportional hazards regression analysis were utilized. All data: median (IQ range). Results: 89 (79%) patients were evaluable. Age was 75 (68-80). Disease characteristics at time of diagnosis included Gleason scores 8-10 (70%) and TMM: T3-T4 tumors (67%), N1 (53%), M1 (45%). At the time of therapy all patients were metastatic and all exhibited PSMA-positive disease. The highest tumor SUVmax was 51 (28-78). PSA levels were 69ng/mL (18-305). The PROSTest score was 89 (81-92). PROSTest scores were weakly correlated with age (r=0.33, p=0.0015) but not with baseline histopathological parameters (e.g., Gleason score, TNM) or pretreatment imaging results (e.g., SUVmax). Twenty-four (27%) patients have perished. Treatment and follow-up (5 months, 3-18) are ongoing. The mOS was 15 months. No factors were associated with death as an outcome except for the PROSTest score. PROSTest scores ≥79 (based on ROC analysis) were associated with significantly increased risk for mortality (HR: 2.9, 95% CI: 1.5-7.4). The mOS was 14 months in patients with pre-therapy PROSTest scores &gt;79 compared to mOS not reached for PROSTest scores &lt;79 ( p=0.02). In the COX model, baseline PROSTest was confirmed to be significantly predictive of death despite therapy (β = 1.51, p=0.01). Conclusions: The PROSTest blood gene expression score is elevated in mCRPCs. Levels are not associated with baseline clinical, histopathological, pretreatment PSA or imaging parameters. Elevated expression (≥79) of this biomarker prior to treatment was associated with a lower survival and could be used to predict survival in patients undergoing 177Lu-PSMA.

Predictive and prognostic potential of pretreatment 68Ga-PSMA PET tumor heterogeneity index in patients with metastatic castration-resistant prostate cancer (mCRPC).

200 Background: 177Lu-PSMA therapy has been introduced as an effective therapeutic option for metastatic castration resistant prostate cancer (mCRPC). Since about one third of the treated patients show no biochemical response (BCR) after therapy, prediction of treatment outcome is important for patient selection. Therefore, this study was conducted to evaluate to the predictive values of volumetric parameters and radiomic features (RFs) extracted form pretreatment 68Ga-PSMA PET and baseline clinical parameters in response to 177Lu-PSMA therapy. Methods: In this multicenter study, mCRPC patients undergoing 177Lu-PSMA therapy were enrolled from September 2017 to January 2022. The available clinical data of all patients was collected and documented from three different centers. The patients underwent several cycles of therapy. According to the outcome of therapy, the patients were classified into two groups including positive BCR (≥ 50% reduction in the serum PSA value) and negative BCR (&lt; 50%). Sixty-five RFs, eight volumetric parameters and also seventeen clinical parameters were evaluated for prediction of BCR. In addition, the impact of such parameters on overall survival (OS) was evaluated. Results: In this retrospective study, 33 prostate cancer patients with a median age of 69 years (range: 49-89) were enrolled. BCR was observed in 22 cases (66%), and 16 cases (48.5%) died during the follow-up time. The results of Spearman correlation test indicated a significant relationship between BCR and treatment cycle, administered dose, HISTO energy, GLCM entropy, and GLZLM LZLGE (p&lt;0.05). In addition, according to the Mann-Whitney U test, age, cycle, dose, GLCM entropy, and GLZLM LZLGE were significantly different between BCR and non BCR patients (p&lt;0.05). According to the ROC curve analysis for feature selection for prediction of BCR, GLCM entropy, age, treatment cycle, and administered dose showed acceptable results (p&lt;0.05). According to SVM for the assessing of the best model for predication of response to therapy, GLCM entropy alone showed the highest predictive performance in treatment planning. For the entire cohort, the Kaplan-Meier test revealed a median OS of 21 months (95% CI: 12.12-29.88). The median OS was estimated at 26 months (95% CI: 17.43-34.56) for BCR patients and 13 months (95% CI: 9.18-16.81) for non BCR patients. Among all variables included in the Kaplan Meier, only response to therapy was statistically significant (p=0.01) and none of the RFs and other clinical factors achieved a p-value of less than 0.05. Conclusions: This exploratory study showed that heterogeneity parameter of pretreatment 68Ga-PSMA PET images might be a potential predictive value for response to 177Lu-PSMA therapy in mCRPC; however, further prospective studies need to be carried out to verify these findings.

Outcomes Database to Prospectively Assess the Changing Therapy Landscape in Renal Cell Carcinoma (ODYSSEY RCC).

TPS739 Background: The landscape for treatment of metastatic renal cell carcinoma (mRCC) has changed dramatically over the past 7 years with the approvals of tyrosine kinase inhibitors and immune-oncology (IO) agents alone or in combination for untreated mRCC. However, multiple knowledge gaps remain. While active surveillance remains an option for selected pts, prospective evidence on selection of and outcomes for pts is limited. Recent phase III trials all used a common comparator, sunitinib, so no comparative effectiveness data on the new IO-based regimens exists. There are also no routinely used predictive biomarkers in mRCC pt management. Therefore, a better understanding of the biologic determinants associated with cancer heterogeneity and clinical outcomes through blood, tumor, and radiographic based assessments is needed. Importantly, longitudinal changes in health-related quality of life (QOL) and symptom burden of patients with mRCC initiated on new IO–based regimens outside of an interventional clinical trial are poorly understood. Pt reported outcomes (PRO) are rarely captured in a systematic manner. Addressing the evidence gap for how real world pts symptomatically change with treatment combinations and sequences over time is a pressing unmet need. Methods: This is a prospective, observational cohort, phase IV study of 800 mRCC pts in the US. Pts must: be age ≥19 at informed consent; have a diagnosis of mRCC (any histology) with no prior systemic therapy for mRCC (surgery and radiation therapy, prior neoadjuvant/adjuvant therapy for non-mRCC, and pts currently not on systemic therapy and being observed are all permitted); and be able to comply with completion of PROs. Those being treated for active malignancies other than mRCC or not intending to undergo follow up care at a study site within PCORnet are excluded. Pts will undergo consent and baseline assessments, including research blood collection and processing, by the study site team. A novel aspect of this study is the use of PCORnet and Medicare data to minimize data collection burden on sites. PCORnet, the National Patient-Centered Clinical Research Network, is a network of networks that curates EHR data from multiple health systems using a common data model. This allows subsequent follow up to be centrally coordinated by the coordinating center. PRO will be collected at baseline (pre-treatment), every 3 mos for 2 yrs, and then every 6 mos until end of follow up (minimum 18 mos follow-up; maximum 36 mos follow-up). The primary objective is to determine distinct patterns of change in QOL and symptom burden of mRCC pts receiving therapy. Secondary objectives include quantifying the time to treatment discontinuation of pts, identifying patterns of clinical management in the real world setting of mRCC pts on various treatment regimens, and evaluating overall survival of mRCC pts. ClinicalTrials.gov Identifier: NCT04919122 Clinical trial information: NCT04919122 .

A predictive model of response to metoprolol in children and adolescents with postural tachycardia syndrome

BackgroundThe present work was designed to explore whether electrocardiogram (ECG) index-based models could predict the effectiveness of metoprolol therapy in pediatric patients with postural tachycardia syndrome (POTS).MethodsThis study consisted of a training set and an external validation set. Children and adolescents with POTS who were given metoprolol treatment were enrolled, and after follow-up, they were grouped into non-responders and responders depending on the efficacy of metoprolol. The difference in pre-treatment baseline ECG indicators was analyzed between the two groups in the training set. Binary logistic regression analysis was further conducted on the association between significantly different baseline variables and therapeutic efficacy. Nomogram models were established to predict therapeutic response to metoprolol. The receiver-operating characteristic curve (ROC), calibration, and internal validation were used to evaluate the prediction model. The predictive ability of the model was validated in the external validation set.ResultsOf the 95 enrolled patients, 65 responded to metoprolol treatment, and 30 failed to respond. In the responders, the maximum value of the P wave after correction (Pcmax), P wave dispersion (Pd), Pd after correction (Pcd), QT interval dispersion (QTd), QTd after correction (QTcd), maximum T-peak-to-T-end interval (Tpemax), and T-peak-to-T-end interval dispersion (Tped) were prolonged (all P < 0.01), and the P wave amplitude was increased (P < 0.05) compared with those of the non-responders. In contrast, the minimum value of the P wave duration after correction (Pcmin), the minimum value of the QT interval after correction (QTcmin), and the minimum T-peak-to-T-end interval (Tpemin) in the responders were shorter (P < 0.01, < 0.01 and < 0.01, respectively) than those in the non-responders. The above indicators were screened based on the clinical significance and multicollinearity analysis to construct a binary logistic regression. As a result, pre-treatment Pcmax, QTcmin, and Tped were identified as significantly associated factors that could be combined to provide an accurate prediction of the therapeutic response to metoprolol among the study subjects, yielding good discrimination [area under curve (AUC) = 0.970, 95% confidence interval (CI) 0.942–0.998] with a predictive sensitivity of 93.8%, specificity of 90.0%, good calibration, and corrected C-index of 0.961. In addition, the calibration curve and standard curve had a good fit. The accuracy of internal validation with bootstrap repeated sampling was 0.902. In contrast, the kappa value was 0.769, indicating satisfactory agreement between the predictive model and the results from the actual observations. In the external validation set, the AUC for the prediction model was 0.895, and the sensitivity and specificity were 90.9% and 95.0%, respectively.ConclusionsA high-precision predictive model was successfully developed and externally validated. It had an excellent predictive value of the therapeutic effect of metoprolol on POTS among children and adolescents.

Adjusting for Baseline Measurements of the Mediators and Outcome as a First Step Toward Eliminating Confounding Biases in Mediation Analysis

Mediation analysis prevails for researchers probing the etiological mechanisms through which treatment affects an outcome. A central challenge of mediation analysis is justifying sufficient baseline covariates that meet the causal assumption of no unmeasured confounding. But current practices routinely overlook this assumption. In this article, we suggest a relatively easy way to mitigate the risks of incorrect inferences resulting from unmeasured confounding: include pretreatment measurements of the mediator(s) and the outcome as baseline covariates. We explain why adjusting for pretreatment baseline measurements is a necessary first step toward eliminating confounding biases. We hope that such a practice can encourage explication, justification, and reflection of the causal assumptions underpinning mediation analysis toward improving the validity of causal inferences in psychology research.

Audiologists’ perceived value of ototoxicity management and barriers to implementation for at-risk cancer patients in VA: the OtoMIC survey

PurposePlatinum-based chemotherapies used to treat many types of cancers are ototoxic. Ototoxicity management (OtoM) to mitigate the ototoxic outcomes of cancer survivors is recommended practice yet it is not a standard part of oncologic care. Although more than 10,000 patients each year are treated with platinum-based chemotherapies at the US Veterans Health Administration (VA), the current state of OtoM in VA is not well-defined. This study reports on a national survey of VA audiologists’ perceptions regarding OtoM in cancer patients.MethodsA 26-item online survey was administered to VA audiologists and service chiefs across the VA’s 18 regional systems of care. Descriptive statistics and deductive thematic analysis were used to analyze the data.ResultsThe 61 respondents included at least one from each VA region. All reported they felt some form of OtoM was necessary for at-risk cancer patients. A pre-treatment baseline, the ability to detect ototoxicity early, and management of ototoxic effects both during and after treatment were considered high value objectives of OtoM by respondents. Roughly half reported routinely providing these services for patients receiving cisplatin and carboplatin. Respondents disagreed regarding appropriate hearing testing schedules and how to co-manage OtoM responsibilities with oncology. They identified barriers to care that conformed to three themes: care and referral coordination with oncology, audiology workload, and lack of protocols.ConclusionsAlthough VA audiologists value providing OtoM for cancer patients, only about half perform OtoM for highly ototoxic treatment regimens. The OtoMIC survey provides clinician perspectives to benchmark and address OtoM care gaps.Implications for cancer survivorsCollaboration between oncology and audiology is needed to improve current OtoM processes, so that cancer survivors can have more control over their long term hearing health.