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Item A Phase II Trial of Adjuvant Durvalumab Following Trimodality Therapy for Locally Advanced Esophageal and Gastroesophageal Junction Adenocarcinoma: A Big Ten Cancer Research Consortium Study(Frontiers Media, 2021-09-17) Mamdani, Hirva; Schneider, Bryan; Perkins, Susan M.; Burney, Heather N.; Kasi, Pashtoon Murtaza; Abushahin, Laith I.; Birdas, Thomas; Kesler, Kenneth; Watkins, Tracy M.; Badve, Sunil S.; Radovich, Milan; Jalal, Shadia I.; Surgery, School of MedicineBackground: Most patients with resectable locally advanced esophageal and gastroesophageal junction (GEJ) adenocarcinoma (AC) receive concurrent chemoradiation (CRT) followed by esophagectomy. The majority of patients do not achieve pathologic complete response (pCR) with neoadjuvant CRT, and the relapse rate is high among these patients. Methods: We conducted a phase II study (ClinicalTrials.gov Identifier: NCT02639065) evaluating the efficacy and safety of PD-L1 inhibitor durvalumab in patients with locally advanced esophageal and GEJ AC who have undergone neoadjuvant CRT followed by R0 resection with evidence of persistent residual disease in the surgical specimen. Patients received durvalumab 1500 mg IV every 4 weeks for up to 1 year. The primary endpoint was 1-year relapse free survival (RFS). Secondary endpoint was safety and tolerability of durvalumab following trimodality therapy. Exploratory endpoints included correlation of RFS with PD-L1 expression, HER-2 expression, and tumor immune cell population. Results: Thirty-seven patients were enrolled. The majority (64.9%) had pathologically positive lymph nodes. The most common treatment related adverse events were fatigue (27%), diarrhea (18.9%), arthralgia (16.2%), nausea (16.2%), pruritus (16.2%), cough (10.8%), and increase in AST/ALT/bilirubin (10.8%). Three (8.1%) patients developed grade 3 immune mediated adverse events. One-year RFS was 73% (95% CI, 56-84%) with median RFS of 21 months (95% CI, 14-40.4 months). Patients with GEJ AC had a trend toward superior 1-year RFS compared to those with esophageal AC (83% vs. 63%, p = 0.1534). There was a numerical trend toward superior 1-year RFS among patients with PD-L1 positive disease compared to those with PD-L1 negative disease, using CPS of ≥10 (100% vs. 66.7%, p = 0.1551) and ≥1 (84.2% vs. 61.1%, p = 0.1510) cutoffs. A higher relative proportion of M2 macrophages and CD4 memory activated T cells was associated with improved RFS (HR = 0.16; 95% CI, 0.05-0.59; p = 0.0053; and HR = 0.37; 95% CI, 0.15-0.93, p = 0.0351, respectively). Conclusions: Adjuvant durvalumab in patients with residual disease in the surgical specimen following trimodality therapy for locally advanced esophageal and GEJ AC led to clinically meaningful improvement in 1-year RFS compared to historical control rate. Higher PD-L1 expression may have a correlation with the efficacy of durvalumab in this setting. Higher proportion of M2 macrophages and CD4 memory activated T cells was associated with superior RFS.Item Acceptance and commitment therapy for symptom interference in metastatic breast cancer patients: a pilot randomized trial(Springer Nature, 2018-06) Mosher, Catherine E.; Secinti, Ekin; Li, Ruohong; Hirsh, Adam T.; Bricker, Jonathan; Miller, Kathy D.; Schneider, Bryan; Storniolo, Anna Maria; Mina, Lida; Newton, Erin V.; Champion, Victoria L.; Johns, Shelley A.; Psychology, School of SciencePURPOSE: Breast cancer is the leading cause of cancer mortality in women worldwide. With medical advances, metastatic breast cancer (MBC) patients often live for years with many symptoms that interfere with activities. However, there is a paucity of efficacious interventions to address symptom-related suffering and functional interference. Thus, this study examined the feasibility and preliminary efficacy of telephone-based acceptance and commitment therapy (ACT) for symptom interference with functioning in MBC patients. METHODS: Symptomatic MBC patients (N = 47) were randomly assigned to six telephone sessions of ACT or six telephone sessions of education/support. Patients completed measures of symptom interference and measures assessing the severity of pain, fatigue, sleep disturbance, depressive symptoms, and anxiety. RESULTS: The eligibility screening rate (64%) and high retention (83% at 8 weeks post-baseline) demonstrated feasibility. When examining within-group change, ACT participants showed decreases in symptom interference (i.e., fatigue interference and sleep-related impairment; Cohen's d range = - 0.23 to - 0.31) at 8 and 12 weeks post-baseline, whereas education/support participants showed minimal change in these outcomes (d range = - 0.03 to 0.07). Additionally, at 12 weeks post-baseline, ACT participants showed moderate decreases in fatigue and sleep disturbance (both ds = - 0.43), whereas education/support participants showed small decreases in these outcomes (ds = - 0.24 and - 0.18 for fatigue and sleep disturbance, respectively). Both the ACT and education/support groups showed reductions in depressive symptoms (ds = - 0.27 and - 0.28) at 12 weeks post-baseline. Group differences in all outcomes were not statistically significant. CONCLUSIONS: ACT shows feasibility and promise in improving fatigue and sleep-related outcomes in MBC patients and warrants further investigation.Item Adjuvant Trastuzumab Emtansine Versus Paclitaxel Plus Trastuzumab for Stage I Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer: 5-Year Results and Correlative Analyses From ATEMPT(Wolters Kluwer, 2024) Tarantino, Paolo; Tayob, Nabihah; Villacampa, Guillermo; Dang, Chau; Yardley, Denise A.; Isakoff, Steven J.; Valero, Vicente; Faggen, Meredith; Mulvey, Therese; Bose, Ron; Weckstein, Douglas; Wolff, Antonio C.; Reeder-Hayes, Katherine; Rugo, Hope S.; Ramaswamy, Bhuvaneswari; Zuckerman, Dan; Hart, Lowell; Gadi, Vijayakrishna K.; Constantine, Michael; Cheng, Kit; Merrill Garrett, Audrey; Marcom, P. Kelly; Albain, Kathy; DeFusco, Patricia; Tung, Nadine; Ardman, Blair; Nanda, Rita; Jankowitz, Rachel C.; Rimawi, Mothaffar; Abramson, Vandana; Pohlmann, Paula R.; Van Poznak, Catherine; Forero-Torres, Andres; Liu, Minetta C.; Ruddy, Kathryn J.; Waks, Adrienne G.; DeMeo, Michelle; Burstein, Harold J.; Partridge, Ann H.; Dell'Orto, Patrizia; Russo, Leila; Krause, Emma; Newhouse, Daniel J.; Kurt, Busem Binboğa; Mittendorf, Elizabeth A.; Schneider, Bryan; Prat, Aleix; Winer, Eric P.; Krop, Ian E.; Tolaney, Sara M.; Consortium of the TBCRC Translational Investigators; TBCRC Translational Investigators; Medicine, School of MedicinePurpose: Long-term outcomes of patients with stage I human epidermal growth factor receptor 2 (HER2)-positive breast cancer receiving adjuvant trastuzumab emtansine (T-DM1) remain undefined, and prognostic predictors represent an unmet need. Methods: In the ATEMPT phase II trial, patients with stage I centrally confirmed HER2-positive breast cancer were randomly assigned 3:1 to adjuvant T-DM1 for 1 year or paclitaxel plus trastuzumab (TH). Coprimary objectives were to compare the incidence of clinically relevant toxicities between arms and to evaluate invasive disease-free survival (iDFS) with T-DM1. Correlative analyses included the HER2DX genomic tool, multiomic evaluations of HER2 heterogeneity, and predictors of thrombocytopenia. Results: After a median follow-up of 5.8 years, 11 iDFS events were observed in the T-DM1 arm, consistent with a 5-year iDFS of 97.0% (95% CI, 95.2 to 98.7). At 5 years, the recurrence-free interval (RFI) was 98.3% (95% CI, 97.0 to 99.7), the overall survival was 97.8% (95% CI, 96.3 to 99.3), and the breast cancer-specific survival was 99.4% (95% CI, 98.6 to 100). Comparable iDFS was observed with T-DM1 irrespective of tumor size, hormone receptor status, centrally determined HER2 immunohistochemical score, and receipt of T-DM1 for more or less than 6 months. Although ATEMPT was not powered for this end point, the 5-year iDFS in the TH arm was 91.1%. Among patients with sufficient tissue for HER2DX testing (n = 187), 5-year outcomes significantly differed according to HER2DX risk score, with better RFI (98.1% v 81.8%, hazard ratio [HR], 0.10, P = .01) and iDFS (96.3% v 81.8%, HR, 0.20, P = .047) among patients with HER2DX low-risk versus high-risk tumors, respectively. Conclusion: Adjuvant T-DM1 for 1 year leads to outstanding long-term outcomes for patients with stage I HER2-positive breast cancer. A high HER2DX risk score predicted a higher risk of recurrence in ATEMPT.Item Breast Cancer Disparities Through the Lens of the COVID-19 Pandemic(Springer Nature, 2021) Newman, Lisa; Fejerman, Laura; Pal, Tuya; Mema, Eralda; McGinty, Geraldine; Cheng, Alex; Levy, Mia; Momoh, Adeyiza; Troester, Melissa; Schneider, Bryan; McNeil, Lorna; Davis, Melissa; Babagbemi, Kemi; Hunt, Kelly; Medicine, School of MedicinePurpose of review: The emergency medicine and critical care needs of the COVID-19 pandemic forced a sudden and dramatic disruption of cancer screening and treatment programs in the USA during the winter and spring of 2020. This review commentary addresses the impact of the pandemic on racial/ethnic minorities such as African Americans and Hispanic-Latina Americans, with a focus on factors related to breast cancer. Recent findings: African Americans and Hispanic-Latina Americans experienced disproportionately higher morbidity and mortality from COVID-19; many of the same socioeconomic and tumor biology/genetic factors that explain breast cancer disparities are likely to account for COVID-19 outcome disparities. Summary: The breast cancer clinical and research community should partner with public health experts to ensure participation of diverse patients in COVID-19 treatment trials and vaccine programs and to overcome COVID-19-related breast health management delays that are likely to have been magnified among African Americans and Hispanic-Latina Americans.Item Evaluating the role of serotonin in hot flashes after breast cancer using acute tryptophan depletion.(Wolters Kluwer, 2009) Carpenter, Janet S.; Yu, Menggang; Wu, Jingwei; Von Ah, Diane; Milata, Jennifer; Otte, Julie L.; Johns, Shelley; Schneider, Bryan; Storniolo, Anna Maria; Salomon, Ronald; Desta, Zeuresenay; Cao, Donghua; Jin, Yan; Philips, Santosh; Skaar, Todd C.OBJECTIVE: Among women with breast cancer, hot flashes are frequent, severe, and bothersome symptoms that can negatively impact quality of life and compromise compliance with life-saving medications (eg, tamoxifen and aromatase inhibitors). Clinicians' abilities to treat hot flashes are limited due to inadequate understanding of physiological mechanisms involved in hot flashes. Using an acute tryptophan depletion paradigm, we tested whether alterations in central serotonin levels were involved in the induction of hot flashes in women with breast cancer. METHODS: This was a within-participant, double-blind, controlled, balanced, crossover study. Twenty-seven women completed two 9-hour test days. On one test day, women ingested a concentrated amino acid drink and encapsulated amino acids (no tryptophan) according to published procedures that have been shown to have specific effects on serotonin within 4.5 to 7 hours. On the other test day, women ingested a control drink. Serial venous blood sampling and objective hot flash monitoring were used to evaluate response to each condition. RESULTS: Response to acute tryptophan depletion was variable and unexplained by use of selective serotonin reuptake inhibitors, antiestrogens, breast cancer disease and treatment variables, or genetic polymorphisms in serotonin receptor and transporter genes. Contrary to our hypothesis, hot flashes were not worsened with acute tryptophan depletion. CONCLUSIONS: Physiologically documented and self-reported hot flashes were not exacerbated by tryptophan depletion. Additional mechanistic research is needed to better understand the etiology of hot flashes.Item Exceptional Response with Immunotherapy in a Patient with Anaplastic Thyroid Cancer(AlphaMed Press, 2017-10) Kollipara, Revathi; Schneider, Bryan; Radovich, Milan; Babu, Sunil; Kiel, Patrick J.; Medicine, School of MedicineChemotherapy with or without radiation is the standard therapy for anaplastic thyroid cancer (ATC), although the response rate is not high and not durable. We describe a 62-year-old male who was diagnosed with ATC and initially treated with a thyroidectomy and lymph node dissection, followed by chemotherapy. Next generation sequencing was then performed to guide therapy and the tumor was found to have BRAF and programmed death-ligand 1 (PD-L1) positivity that was subsequently treated with vemurafenib and nivolumab. This led to substantial regression of tumor nodules. Genomic sequencing-based approaches to identify therapeutic targets has potential for improving outcomes. Currently, the patient continues to be in complete radiographic and clinical remission 20 months after beginning treatment with nivolumab. KEY POINTS: Programmed death-1 (PD-1)/PD-L1 immunotherapy has shown evidence of durable responses in certain malignancies such as melanoma, lung cancer, and renal cell carcinoma.PD-L1 positive tumors promote autoimmunity against the tumor; therefore, PD-1/PD-L1 blockade may be beneficial.Molecular profiling could possibly result in improved targeted therapy for certain malignancies.Item Factors underlying metastatic breast cancer patients' perceptions of symptom importance: a qualitative analysis(Wiley, 2018-01) Mosher, Catherine E.; Daily, Susan; Tometich, Danielle; Matthias, Marianne S.; Outcalt, Samantha D.; Hirsh, Adam; Johns, Shelley A.; Rand, Kevin; Schneider, Bryan; Mina, Lida; Storniolo, Anna Maria; Newton, Erin; Miller, Kathy; Psychology, School of ScienceThe symptom literature in cancer has primarily examined symptom severity, frequency and distress. Assessing cancer patients' perceptions of symptom importance-how important it is for them to see improvement in a symptom following an intervention-and factors influencing these judgments would also inform patient-centred care, but this analysis has not been undertaken. This qualitative study aimed to identify factors underlying perceptions of symptom importance among 25 symptomatic metastatic breast cancer (MBC) patients. Participants were recruited from a cancer centre in the Midwestern USA. Semi-structured interviews focused on patients' rationale for considering common symptoms (i.e., anxiety, sadness, sleep problems, pain or fatigue) to be important. Thematic analyses revealed five interrelated factors underlying MBC patients' perceptions of symptom importance: activity restriction, concentration difficulties, exacerbation of other physical symptoms, symptom-related long-term health concerns and negative impact on their relationships with others. Patients most frequently stated that a physical or psychological symptom was important because of the resulting activity restriction. Additionally, some patients considered pain to be important because it signalled potential long-term health concerns, such as worsening metastatic disease. Findings suggest that clinicians should take into account MBC patients' perceptions of symptom importance and factors underlying these judgments when making shared treatment decisions.Item A large, consistent plasma proteomics data set from prospectively collected breast cancer patient and healthy volunteer samples(BMC, 2011-05-27) Riley, Catherine P; Zhang, Xiang; Nakshatri, Harikrishna; Schneider, Bryan; Regnier, Fred E; Adamec, Jiri; Buck, CharlesBackground Variability of plasma sample collection and of proteomics technology platforms has been detrimental to generation of large proteomic profile datasets from human biospecimens. Methods We carried out a clinical trial-like protocol to standardize collection of plasma from 204 healthy and 216 breast cancer patient volunteers. The breast cancer patients provided follow up samples at 3 month intervals. We generated proteomics profiles from these samples with a stable and reproducible platform for differential proteomics that employs a highly consistent nanofabricated ChipCube™ chromatography system for peptide detection and quantification with fast, single dimension mass spectrometry (LC-MS). Protein identification is achieved with subsequent LC-MS/MS analysis employing the same ChipCube™ chromatography system. Results With this consistent platform, over 800 LC-MS plasma proteomic profiles from prospectively collected samples of 420 individuals were obtained. Using a web-based data analysis pipeline for LC-MS profiling data, analyses of all peptide peaks from these plasma LC-MS profiles reveals an average coefficient of variability of less than 15%. Protein identification of peptide peaks of interest has been achieved with subsequent LC-MS/MS analyses and by referring to a spectral library created from about 150 discrete LC-MS/MS runs. Verification of peptide quantity and identity is demonstrated with several Multiple Reaction Monitoring analyses. These plasma proteomic profiles are publicly available through ProteomeCommons. Conclusion From a large prospective cohort of healthy and breast cancer patient volunteers and using a nano-fabricated chromatography system, a consistent LC-MS proteomics dataset has been generated that includes more than 800 discrete human plasma profiles. This large proteomics dataset provides an important resource in support of breast cancer biomarker discovery and validation efforts.Item Leveraging GWAS data derived from a large cooperative group trial to assess the risk of taxane-induced peripheral neuropathy (TIPN) in patients being treated for breast cancer: Part 2—functional implications of a SNP cluster associated with TIPN risk in patients being treated for breast cancer(Springer, 2023-02-21) Lustberg, Maryam; Wu, Xuan; Fernández-Martínez, Juan Luis; de Andrés-Galiana, Enrique J.; Philips, Santosh; Leibowitz, Jeffrey; Schneider, Bryan; Sonis, Stephen; Medicine, School of MedicineIntroduction: Using GWAS data derived from a large collaborative trial (ECOG-5103), we identified a cluster of 267 SNPs which predicted CIPN in treatment-naive patients as reported in Part 1 of this study. To assess the functional and pathological implications of this set, we identified collective gene signatures were and evaluated the informational value of those signatures in defining CIPN's pathogenesis. Methods: In Part 1, we analyzed GWAS data derived from ECOG-5103, first identifying those SNPs that were most strongly associated with CIPN using Fisher's ratio. After identifying those SNPs which differentiated CIPN-positive from CIPN-negative phenotypes, we ranked them in order of their discriminatory power to produce a cluster of SNPs which provided the highest predictive accuracy using leave-one-out cross validation (LOOCV). An uncertainty analysis was included. Using the best predictive SNP cluster, we performed gene attribution for each SNP using NCBI Phenotype Genotype Integrator and then assessed functionality by applying GeneAnalytics, Gene Set Enrichment Analysis, and PCViz. Results: Using aggregate data derived from the GWAS, we identified a 267 SNP cluster which was associated with a CIPN+ phenotype with an accuracy of 96.1%. We could attribute 173 genes to the 267 SNP cluster. Six long intergenic non-protein coding genes were excluded. Ultimately, the functional analysis was based on 138 genes. Of the 17 pathways identified by Gene Analytics (GA) software, the irinotecan pharmacokinetic pathway had the highest score. Highly matching gene ontology attributions included flavone metabolic process, flavonoid glucuronidation, xenobiotic glucuronidation, nervous system development, UDP glycosyltransferase activity, retinoic acid binding, protein kinase C binding, and glucoronosyl transferase activity. Gene Set Enrichment Analysis (GSEA) GO terms identified neuron-associated genes as most significant (p = 5.45e-10). Consistent with the GA's output, flavone, and flavonoid associated terms, glucuronidation were noted as were GO terms associated with neurogenesis. Conclusion: The application of functional analyses to phenotype-associated SNP clusters provides an independent validation step in assessing the clinical meaningfulness of GWAS-derived data. Functional analyses following gene attribution of a CIPN-predictive SNP cluster identified pathways, gene ontology terms, and a network which were consistent with a neuropathic phenotype.Item Relations of Mindfulness and Illness Acceptance With Psychosocial Functioning in Patients With Metastatic Breast Cancer and Caregivers(Oncology Nursing Society, 2020-11-01) Chinh, Kelly; Secinti, Ekin; Johns, Shelly A.; Hirsh, Adam T.; Miller, Kathy D.; Schneider, Bryan; Storniolo, Anna Maria; Mina, Lida; Newton, Erin V.; Champion, Victoria L.; Mosher, Catherine E.; Psychology, School of ScienceObjectives: To examine relationships in mindfulness and illness acceptance and psychosocial functioning in patients with metastatic breast cancer and their family caregivers. Sample & setting: 33 dyads from an academic cancer center in the United States. Methods & variables: Participants completed questionnaires on mindfulness, illness acceptance, relationship quality, anxiety, and depressive symptoms. Dyadic, cross-sectional data were analyzed using actor-partner interdependence models. Results: Greater nonjudging, acting with awareness, and illness acceptance among caregivers were associated with patients' and caregivers' perceptions of better relationship quality. Higher levels of these processes were associated with reduced anxiety and depressive symptoms in patients and caregivers. Implications for nursing: Aspects of mindfulness and illness acceptance in dyads confer benefits that are primarily intrapersonal in nature. Nurses may consider introducing mindfulness and acceptance-based interventions to patients and caregivers with adjustment difficulties.