A Novel Approach to Computing Preference Estimates for Different Treatment Pathways: An Application in Oncology.

BACKGROUND: Patients with cancer may progress through multiple treatments with differing adverse effect profiles. Moreover, pathways may be fixed or flexible in allowing for escalation or de-escalation of treatment depending on interim outcomes. We sought to develop a methodology capable of estimating preferences for the entirety of a pathway involving a sequence of different treatments. METHODS: Patients with early breast cancer completed an online discrete choice experiment to assess preferences for eight key early breast cancer attributes. Hierarchical Bayesian modeling was used to calculate attribute-level preference weights. Preference weights for hypothetical pathways were estimated by summing the respective weights for efficacy, flexible or fixed pathway, duration, administration regimen, and adverse event risk, the last two of which were time-adjusted by multiplying each weight by the proportion of time spent on a selected treatment. RESULTS: Increases in the risk of a serious adverse event were most influential in treatment pathway preferences, followed by increases in efficacy and decreases in overall pathway duration. Patients preferred a flexible pathway versus a fixed pathway. Pathway preference estimates fluctuated in a logically consistent manner. Switching from a flexible to a fixed pathway yielded a significantly lower pathway preference. For this same pathway, when adjuvant treatment was replaced with a treatment with a more favorable toxicity profile and shorter duration, it offset the negative impact of the more toxic neoadjuvant chemotherapy. CONCLUSIONS: This novel methodology accounts for patient preference throughout a sequence of treatments, allowing for comparison of preferences across complex treatment pathways.

Evaluating Oncologists' Practice Patterns and Decision-Making in Locally Advanced or Metastatic Urothelial Carcinoma: The US Physician PARADIGM Study.

BACKGROUND: The treatment landscape for locally advanced/metastatic urothelial carcinoma (la/mUC) has evolved. This study examined US prescribing patterns and clinical decision-making for first-line (1L) and first-line maintenance (1LM) treatment. MATERIALS AND METHODS: US-based oncologists (N = 150) completed an online survey on patient demographics, practice patterns, and important factors considered in 1L/1LM selection. Multivariable logistic regression was used to assess factors associated with more vs less frequent 1L/1LM prescribing. RESULTS: Physician reports estimated that 23% of patients with la/mUC had not received any systemic therapy in the previous 6 months; however, 46% received 1L, 32% received second-line, and 22% received subsequent-line systemic treatments. Of patients who were receiving 1L treatment, 72% were estimated to be receiving 1L platinum-based chemotherapy. Around 69% of patients eligible for 1LM received the treatment. Physicians categorized as frequent prescribers reported overall survival (OS), disease control rate (DCR), and rate of grade 3/4 adverse events (AEs) as factors associated with 1L treatment selection (all P < .05). OS, rate of grade 3/4 immune-mediated AEs, and inclusion in institutional guidelines were reported as attributes used in 1LM treatment selection (all P < .05). Multivariable analysis revealed OS, DCR, and rate of grade 3/4 AEs as important factors in oncologists' 1L treatment selection; academic practice setting and use of Response Evaluation Criteria in Solid Tumors version 1.1 were associated with 1LM use (all P < .05). CONCLUSION: OS and AEs were found to be relevant factors associated with offering 1L and 1LM treatment. Variability exists in physicians' decision-making in the real-world setting for la/mUC.

The burden of anxiety among a nationally representative US adult population.

BACKGROUND: Anxiety disorders are highly prevalent and are associated with a significant humanistic and economic burden. This study evaluates the impact of anxiety symptoms on direct and indirect costs and quality of life in individuals with self-reported and unrecognized anxiety symptoms. METHODS: The 2019 US National Health and Wellness Survey database was analyzed to compare individuals with anxiety symptoms to individuals without symptoms, stratified by responses to a yes/no question about experiencing anxiety symptoms, and further stratified by severity of symptoms based on GAD-7 scores. Individuals who responded 'yes' were characterized as having self-reported anxiety symptoms, and those who responded 'no' were screened for unrecognized anxiety symptoms. RESULTS: Overall, 44.0 % of the population experienced anxiety symptoms, of which 32.5 % self-reported experiencing anxiety, while an additional 11.5 % had mild to severe symptoms but did not self-identify as having anxiety. Both groups experienced significantly worse quality of life, and higher direct and indirect costs than a control group who had no anxiety symptoms (GAD-7 ≤ 4). Individuals with more severe anxiety symptoms experienced worse outcomes. LIMITATIONS: The data were cross-sectional, so causality could not be determined. Outcomes were based on self-report, and are therefore subject to reporting and recall bias. Prevalence and severity were assessed using the GAD-7, and not clinically validated. CONCLUSION: A substantial proportion of the population experiences anxiety symptoms without recognizing it. Anxiety symptoms had a significant impact on quality of life, direct costs, and indirect costs, representing a considerable burden that increased with severity of illness.

Prevalence of alopecia areata in Japan: Estimates from a nationally representative sample.

Data on the prevalence of alopecia areata (AA) in Japan is limited and the epidemiology of the disease there is not well understood; therefore, it is critical to examine the prevalence and severity of AA in Japan to inform the need for future treatments and research. A cross-sectional, web-based survey was conducted in Japan from January through March 2021. A total of 45 006 participants were identified through general population survey panels and asked about their experience with AA and hair loss. The Alopecia Assessment Tool and the Scalp Hair Assessment PROTM were adopted to screen for history of AA and assess disease severity, respectively. Eligible participants submitted photos of their scalp, which were reviewed by three board-certified dermatologists to evaluate the presence and severity of AA. Prevalence and severity estimates were calculated using participants' self-reported data and verified through the dermatologists' assessments. The participant-reported point prevalence of AA was 2.18%. The adjusted point prevalence following physician adjudication using participant-submitted photos was 1.45%. Topical corticosteroids were the most commonly used treatments, with 34.6% of participants diagnosed with AA reported having ever used them. Participants also reported negative impacts on their mood (70.2%), self-esteem (55.8%), and social interactions (48.9%). Despite the social and emotional impact of hair loss, more than one third of those reporting a physician diagnosis of AA were not currently seeking treatment. The current study identified an estimated prevalence of AA in Japan between 1.45% and 2.18% based on the survey results and physician-adjudication of those findings. Considering the impactful psychological burden of AA, the survey results showing that 38.90% of surveyed patients do not currently seek treatment may indicate an unmet need for remedies.

A global perspective in second-line treatment patterns for patients with advanced esophageal squamous cell carcinoma.

BACKGROUND: Esophageal cancer is a highly prevalent cancer associated with low survival, especially among those with advanced disease. Second-line (2L) treatment patterns and related clinical outcomes of patients with advanced esophageal squamous cell carcinoma (advESCC) treated in routine clinical care were examined globally and regionally. METHODS: A retrospective, noninterventional study collected physician-provided chart data of patients aged ≥20 years receiving either 2L active systemic therapy or BSC following first-line active therapy for advESCC from 11 countries in Asian and Western regions (September-October 2018). Bivariate analyses examined treatment and outcomes by region. RESULTS: AdvESCC patients (Asia = 192; West = 195) were examined, of which 58.1% (Asia n = 101; West n = 124) received active systemic therapy. While regional differences in tumor classification and staging at diagnosis were observed with less advanced tumors in Asia, no regional differences for these characteristics at 2L initiation were reported. Both taxane- and nontaxane-based therapies were used as 2L therapy among Asian and Western patients, although more western than Asian patients received immuno- or targeted therapies (17.0% vs. 3.0%; p = 0.001). Alopecia (10.7%), neutropenia (9.3%), and fatigue (9.3%) were the most-commonly reported adverse events (AEs) in both regions. Significantly higher 2L AE-related emergency room visits (Asia = 22.5% vs. West = 8.0%; p < 0.001) and hospitalizations (Asia = 25.9 ± 31.2 vs. West = 4.7 ± 7.0, p < 0.001) were observed in Asian than in Western patients. No regional differences were reported for response to 2L treatment or the percent of patients who received third-line treatment/died. CONCLUSIONS: While regional variations were observed throughout the course of a patient's advESCC journey, disease response and treatment outcomes were similar.

Patient and Neurologist Preferences in the United States for Relapsing-Remitting Multiple Sclerosis Treatments: Findings from a Discrete Choice Experiment.

BACKGROUND AND OBJECTIVE: Relapsing-remitting multiple sclerosis (RRMS) is a chronic inflammatory disease associated with central nervous system dysfunction and accelerated brain volume loss (BVL). There exists a paucity of research examining the importance of BVL to patients and neurologists and exploring whether such preferences may differ between these two groups. This study sought to evaluate the preferences of patients and neurologists for RRMS treatments by considering benefits and risks associated with novel and common disease-modifying therapies (DMTs). PATIENTS AND METHODS: US patients diagnosed with non-highly active RRMS and US-based neurologists completed an online cross-sectional survey. A discrete choice experiment was used to assess patient and neurologist treatment preferences, with neurologists considering preferences for patients with non-highly active RRMS. Respondents chose between two treatment profiles with seven attributes identified in qualitative research: 2-year disability progression; 1-year relapse rate; rate of BVL; and risks of gastrointestinal symptoms, flu-like symptoms, infection, and life-threatening events. Attribute-level weighted preferences were estimated using a hierarchical Bayesian model. RESULTS: Analyses included 150 patients with non-highly active RRMS (mean age: 54 years) and 150 neurologists (65% in private practice). Among patients, the most important treatment attribute was reducing the rate of BVL, followed by reducing the risk of infection and risk of flu-like symptoms. In contrast, the most important treatment attribute among neurologists was reducing the risk of a life-threatening event, followed by slowing the rate of 2-year disability progression and risk of infection. CONCLUSION: The findings highlight differences in treatment preferences between US patients and neurologists for non-highly active RRMS. The importance placed by patients on slowing the rate of BVL makes this a key topic that should be covered in the shared decision-making process.

Patient and neurologist preferences in the UK for relapsing-remitting multiple sclerosis treatments: findings from a discrete choice experiment.

OBJECTIVE: To evaluate and compare patient and neurologist preferences for relapsing-remitting multiple sclerosis (RRMS) treatments with respect to benefits and risks associated with common and novel disease-modifying therapies, including brain volume loss (BVL). METHODS: Patients with non-highly-active RRMS and neurologists in the United Kingdom completed an online cross-sectional survey. Patients completed one discrete choice experiment (DCE) exercise and providers completed two, one focusing on treatment for non-highly-active RRMS and another focused on highly active RRMS. Respondents chose between two treatment profiles that varied on seven attributes identified in qualitative research: 2 year disability progression; 1 year relapse rate; rate of BVL; and risks of gastrointestinal symptoms, flu-like symptoms, infection and life-threatening event. Bayesian modeling was used to estimate attribute-level weighted preferences. RESULTS: Patients (n = 144) prioritized slowing the rate of BVL, followed by reducing risk of infection, rate of 2 year disability progression and 1 year relapse rate. For non-highly-active patients, neurologists (n = 101) prioritized slowing the rate of BVL, followed by reducing 2 year disability progression, risk of infection and 1 year relapse rate. For highly active patients, neurologists prioritized lowering the 1 year relapse rate, followed by slowing the rate of BVL and 2 year disability progression. In all three DCEs, rate of BVL was approximately twice as important as reducing the risks of flu-like symptoms, gastrointestinal symptoms and life-threatening event. CONCLUSIONS: This study highlights similarities in treatment preferences for non-highly-active RRMS among patients and neurologists and differences in neurologists' preferences for treating non-highly-active vs. highly active RRMS. This research identifies BVL as a treatment outcome that should be discussed when physicians engage in shared decision-making with patients.

Negative Regulation of CARD11 Signaling and Lymphoma Cell Survival by the E3 Ubiquitin Ligase RNF181.

NF-κB activation downstream of antigen receptor engagement is a highly regulated event required for lymphocyte activation during the adaptive immune response. The pathway is often dysregulated in lymphoma, leading to constitutive NF-κB activity that supports the aberrant proliferation of transformed lymphocytes. To identify novel regulators of antigen receptor signaling to NF-κB, we developed bioluminescence resonance energy transfer-based interaction cloning (BRIC), a screening strategy that can detect protein-protein interactions in live mammalian cells in a high-throughput manner. Using this strategy, we identified the RING finger protein RNF181 as an interactor of CARD11, a key signaling scaffold in the antigen receptor pathway. We present evidence that RNF181 functions as an E3 ubiquitin ligase to inhibit antigen receptor signaling to NF-κB downstream of CARD11. The levels of the obligate signaling protein Bcl10 are reduced by RNF181 even prior to signaling, and Bcl10 can serve as a substrate for RNF181 E3 ligase activity in vitro. Furthermore, RNF181 limits the proliferation of human diffuse large B cell lymphoma cells that depend upon aberrant CARD11 signaling to NF-κB for growth and survival in culture. Our results define a new regulatory checkpoint that can modulate the output of CARD11 signaling to NF-κB in both normal and transformed lymphocytes.