Cost-utility of Initial Management of High-grade T1 Bladder Cancer With Intravesical BCG vs Immediate Radical Cystectomy.

OBJECTIVE: To compare the cost-utility of initial management of high-grade T1 non-muscle invasive bladder cancer (HGT1 NMIBC) with intravesical BCG vs immediate radical cystectomy. High-risk NMIBC patients may climb a costly ladder of treatments, culminating in radical cystectomy for oncologic or symptomatic benefit in up to one-third. This high healthcare resource utilization presents a challenging dilemma in balancing sufficiently aggressive management with cost, toxicity, and quality-of-life. METHODS: Cost-utility of initially managing HGT1 with intravesical BCG and early radical cystectomy with ileal conduit urinary diversion was compared using decision-analytic Markov models. Five-year oncologic outcomes, adverse event rates, and published utility values were extracted from literature. Costs were calculated from a US Medicare perspective in 2021 US dollars. Sensitivity analysis identified drivers of cost and break-even points for recurrence and progression. RESULTS: Mean costs were $26,093 for intravesical BCG and $39,720 for immediate radical cystectomy, though cystectomy generated a gain of 2.2 quality-adjusted life years (QALYs) compared to intravesical BCG. Immediate cystectomy was a more cost-effective management strategy for HGT1 NMIBC with an incremental CE ratios (ICER) of $7120/QALY. The costs associated with cystectomy, TURBT, and BCG toxicity had the greatest impact on ICER. One-way sensitivity analysis demonstrated that intravesical BCG became a cost-effective management strategy if the 5-year recurrence rate of HG T1 was less than 56% or the 5-year progression rate to MIBC was less than 4%. CONCLUSION: At current prices, treatment of high-grade T1 NMIBC with early radical cystectomy is more cost-effective management strategy than initial treatment with intravesical BCG.

Cost Effectiveness of Treatment Sequences in Advanced Renal Cell Carcinoma.

BACKGROUND: The treatment landscape for metastatic renal cell carcinoma (mRCC) has significantly evolved in recent years. Without direct comparator trials, factors such as cost effectiveness (CE) are important to guide decision-making. OBJECTIVE: To assess the CE of guideline-recommended approved first- and second-line treatment regimens. DESIGN, SETTING, AND PARTICIPANTS: A comprehensive Markov model was developed to analyze the CE of the five current National Comprehensive Cancer Network-recommended first-line therapies with appropriate second-line therapy for patient cohorts with International Metastatic RCC Database Consortium favorable and intermediate/poor risk. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Life years, quality-adjusted life years (QALYs), and total accumulated costs were estimated using a willingness-to-pay threshold of $150 000 per QALY. One-way and probabilistic sensitivity analyses were performed. RESULTS AND LIMITATIONS: In patients with favorable risk, pembrolizumab + lenvatinib followed by cabozantinib added $32 935 in costs and yielded 0.28 QALYs, resulting in an incremental CE ratio (ICER) of $117 625 per QALY in comparison to pembrolizumab + axitinib followed by cabozantinib. In patients with intermediate/poor risk, nivolumab + ipilimumab followed by cabozantinib added $2252 in costs and yielded 0.60 QALYs compared to cabozantinib followed by nivolumab, yielding an ICER of $4184. Limitations include differences in median follow-up duration between treatments. CONCLUSIONS: Pembrolizumab + lenvatinib followed by cabozantinib, and pembrolizumab + axitinib followed by cabozantinib were cost-effective treatment sequences for patients with favorable-risk mRCC. Nivolumab +ipilimumab followed by cabozantinib was the most cost-effective treatment sequence for patients with intermediate-/poor-risk mRCC, dominating all preferred treatments. PATIENT SUMMARY: Because new treatments for kidney cancer have not been compared head to head, comparison of their cost and efficacy can help in making decisions about the best treatments to use first. Our model showed that patients with a favorable risk profile are most likely to benefit from pembrolizumab and lenvatinib or axitinib followed by cabozantinib, while patients with an intermediate or poor risk profile will probably benefit most from nivolumab and ipilimumab followed by cabozantinib.

ERCP for bile duct stones across a national service, demonstrating a high requirement for repeat procedures.

Background and study aims Bile duct stones (BDS) represent approximately 50 % of the requirement for endoscopic retrograde cholangiopancreatography (ERCP) within most services. Significant variation in outcome rates for BDS clearance at ERCP has been reported, and endoscopy societies have set standards for expected clearance rates. The aim of this study was to analyze procedure outcomes across a national service. Patients and methods Using verified hospital episode statistics (HES) data for the National Health Service (NHS) in England, we analyzed all patients having first ERCPs for BDS from 2015 to 2017, and followed these patients for at least 2 years. Results In total 37,468 patients underwent a first ERCP for BDS, with 69.8 % undergoing only one procedure. This figure of less than 70 % of BDS cleared at first ERCP is below the Key Performance Indicators as set by the British Society of Gastroenterology (> 75 %) and the European Society of Gastrointestinal Endoscopy (> 90 %). Of 55,556 ERCPs done for BDS, 52.9 % were repeat procedures, with 11,322 patients needing multiple procedures. For hospitals performing significant numbers of ERCPs (more than 600 for BDS during the study period) patients undergoing repeat ERCPs for BDS ranged from 9 % to 50 %. Conclusions In this nationwide study, the performance at clearing BDS at first ERCP was suboptimal, with high numbers of repeat procedures required. This may have a negative impact on both patient outcomes and experience, and increase pressure on endoscopy services. Apparent variation of outcome between acute hospital care providers requires further analysis.

Pilot Study in Investigating Material Financial Toxicity Markers by Age in Cancer Patients.

Purpose: Studies have shown that financial toxicity can reduce survival, decrease quality of life, and reduce compliance with treatments. The aim of this retrospective study was to investigate material markers of financial toxicity, including insurance coverage, financial assistance, and balances due among adolescent and young adult (AYA) (18-39), adult (40-64), and senior adult (>65) patients with a sarcoma diagnosis after the Affordable Care Act became effective. Methods: This study performed a retrospective analysis of possible indicators within the material domain of financial toxicity in sarcoma patients, a common diagnosis in young adult patients. Indicators of financial toxicity included: insurance status and number of insurances, charity care, accessing financing options, or having an unpaid balance referred to a collection's agency. Results: The cumulative charges per patient were similar between AYA, adult, and senior adult populations at an average of $194,329 (standard deviation [SD] = $321,425), $236,724 (SD = $368,345), and $188,030 (SD = $271,191), respectively. AYA patients were more likely than adult and senior adult patients to have Medicaid coverage (income-based government insurance) (22.1% vs. 8.4% vs. 1.2%), receive charity care (5.3% vs. 2.6% vs. 1.2%), or have a balance referred to a collection's agency (9.2% vs. 5.8% vs. 1.2%). Conclusions: This study suggests that younger cancer patients are more likely to suffer material financial strain and additional financial resources may need to be made available to ensure they can receive care without an increase of financial toxicity markers and undue financial stress.

Association between delays to patient admission from the emergency department and all-cause 30-day mortality.

BACKGROUND: Delays to timely admission from emergency departments (EDs) are known to harm patients. OBJECTIVE: To assess and quantify the increased risk of death resulting from delays to inpatient admission from EDs, using Hospital Episode Statistics and Office of National Statistics data in England. METHODS: A cross-sectional, retrospective observational study was carried out of patients admitted from every type 1 (major) ED in England between April 2016 and March 2018. The primary outcome was death from all causes within 30 days of admission. Observed mortality was compared with expected mortality, as calculated using a logistic regression model to adjust for sex, age, deprivation, comorbidities, hour of day, month, previous ED attendances/emergency admissions and crowding in the department at the time of the attendance. RESULTS: Between April 2016 and March 2018, 26 738 514 people attended an ED, with 7 472 480 patients admitted relating to 5 249 891 individual patients, who constituted the study's dataset. A total of 433 962 deaths occurred within 30 days. The overall crude 30-day mortality rate was 8.71% (95% CI 8.69% to 8.74%). A statistically significant linear increase in mortality was found from 5 hours after time of arrival at the ED up to 12 hours (when accurate data collection ceased) (p<0.001). The greatest change in the 30-day standardised mortality ratio was an 8% increase, occurring in the patient cohort that waited in the ED for more than 6 to 8 hours from the time of arrival. CONCLUSIONS: Delays to hospital inpatient admission for patients in excess of 5 hours from time of arrival at the ED are associated with an increase in all-cause 30-day mortality. Between 5 and 12 hours, delays cause a predictable dose-response effect. For every 82 admitted patients whose time to inpatient bed transfer is delayed beyond 6 to 8 hours from time of arrival at the ED, there is one extra death.

Budget Impact of Adaptive Abiraterone Therapy for Castration-Resistant Prostate Cancer.

BACKGROUND: The use of a novel strategy known as adaptive abiraterone therapy based on mathematical modeling of evolutionary dynamics of tumor subpopulations was shown in a clinical trial to extend the time to disease progression in patients with metastatic castration-resistant prostate cancer (CRPC) and reduced the use of abiraterone therapy. Although the clinical impact of adaptive abiraterone treatment is clear, the economic impact of this strategy has not been investigated. OBJECTIVE: To compare the cost of care with adaptive abiraterone therapy versus standard continuous abiraterone therapy in patients with metastatic CRPC, using patient billing data. METHODS: We performed a retrospective review of billing data for patients with metastatic CRPC who received abiraterone treatment at a large cancer center between June 1, 2012, and August 31, 2018. Patients were divided into 2 groups based on whether they received adaptive abiraterone therapy (N = 15) or continuous abiraterone therapy (N = 21). All patients with refractory, metastatic prostate cancer after castration that was indicated for abiraterone therapy were eligible for this study. Each patient in the adaptive abiraterone therapy cohort received abiraterone plus prednisone treatment until the patient reached a target threshold of 50% or more reduction in prostate-specific antigen (PSA) level compared with his PSA level before abiraterone therapy; treatment was then suspended until the PSA level rose above the 50% of PSA before abiraterone therapy target threshold. The continuous therapy cohort received abiraterone plus prednisone daily until radiographic progression. The primary outcomes were the mean annual cost of care per patient, including and excluding the cost of abiraterone, and the cost of care, by clinical category. RESULTS: The median time to disease progression was 25.8 months for patients who received adaptive abiraterone therapy compared with 12.1 months for patients who received continuous abiraterone therapy. Overall, the mean total, including the cost of drug, annual cost per patient who received adaptive abiraterone therapy was $79,093 compared with $146,782 for patients who received continuous abiraterone therapy (P <.0001). The annual cost of care per patient, excluding the cost of abiraterone, was $13,883 for those who received adaptive therapy versus $22,322 for those who received continuous abiraterone therapy (P = .2757), which was not statistically significant. CONCLUSION: Practical precision medicine strategies, such as adaptive abiraterone treatment or pharmacogenomics-targeted dosing, can use known biomarkers, such as PSA, to tailor therapy, generate improved outcomes, and reduce costs without the need for novel drug and diagnostic discovery and development. The results of this study suggest that a large clinical study of adaptive abiraterone therapy is warranted to validate the potential of this strategy to extend the time to disease progression and reduce costs of treatment of metastatic CRPC.

Trends in Risk-Adjusted 28-Day Mortality Rates for Patients Hospitalized with COVID-19 in England.

Early reports showed high mortality from coronavirus disease 2019 (COVID-19). Mortality rates have recently been lower; however, patients are also now younger, with fewer comorbidities. We explored 28-day mortality for patients hospitalized for COVID-19 in England over a 5-month period, adjusting for a range of potentially mitigating variables, including sociodemographics and comorbidities. Among 102,610 hospitalizations, crude mortality decreased from 33.4% (95% CI, 32.9-34.0) in March 2020 to 15.5% (95% CI, 14.1-17.0) in July. Adjusted mortality decreased from 33.4% (95% CI, 32.8-34.1) in March to 17.4% (95% CI, 11.3-26.9) in July. The relative risk of mortality decreased from a reference of 1 in March to 0.52 (95% CI, 0.34-0.80) in July. This demonstrates that the reduction in mortality is not solely due to changes in the demographics of those with COVID-19.

Pharmacogenomics: An evolving clinical tool for precision medicine.

Pharmacogenomics, ie, the study of how an individual's genomic profile influences his or her response to drugs, has emerged as a clinical tool to optimize drug therapy. Certain variants in some genes increase the risk of severe, life-threatening adverse effects from certain drugs. Integrating pharmacogenomics into clinical practice to assist in drug selection and dosing has the potential to improve the outcomes of treatment, reduce the risk of drug-induced morbidity and death, and be cost-effective.

Key Lessons Learned from Moffitt's Molecular Tumor Board: The Clinical Genomics Action Committee Experience.

BACKGROUND: The increasing practicality of genomic sequencing technology has led to its incorporation into routine clinical practice. Successful identification and targeting of driver genomic alterations that provide proliferative and survival advantages to tumor cells have led to approval and ongoing development of several targeted cancer therapies. Within many major cancer centers, molecular tumor boards are constituted to shepherd precision medicine into clinical practice. MATERIALS AND METHODS: In July 2014, the Clinical Genomics Action Committee (CGAC) was established as the molecular tumor board companion to the Personalized Medicine Clinical Service (PMCS) at Moffitt Cancer Center in Tampa, Florida. The processes and outcomes of the program were assessed in order to help others move into the practice of precision medicine. RESULTS: Through the establishment and initial 1,400 patients of the PMCS and its associated molecular tumor board at a major cancer center, five practical lessons of broad applicability have been learned: transdisciplinary engagement, the use of the molecular report as an aid to clinical management, clinical actionability, getting therapeutic options to patients, and financial considerations. Value to patients includes access to cutting-edge practice merged with individualized preferences in treatment and care. CONCLUSIONS: Genomic-driven cancer medicine is increasingly becoming a part of routine clinical practice. For successful implementation of precision cancer medicine, strategically organized molecular tumor boards are critical to provide objective evidence-based translation of observed molecular alterations into patient-centered clinical action. Molecular tumor board implementation models along with clinical and economic outcomes will define future treatment standards. The Oncologist 2017;22:144-151Implications for Practice: It is clear that the increasing practicality of genetic tumor sequencing technology has led to its incorporation as part of routine clinical practice. Subsequently, many cancer centers are seeking to develop a personalized medicine services and/or molecular tumor board to shepherd precision medicine into clinical practice. This article discusses the key lessons learned through the establishment and development of a molecular tumor board and personalized medicine clinical service. This article highlights practical issues and can serve as an important guide to other centers as they conceive and develop their own personalized medicine services and molecular tumor boards.

Budget impact analysis of CYP2C19-guided voriconazole prophylaxis in AML.

OBJECTIVES: The objective of this study was to determine the economic impact of proactive, CYP2C19 genotype-guided voriconazole prophylaxis in AML. METHODS: An Excel-based model was created to project the cost of treating a simulated cohort of severely neutropenic AML patients undergoing antifungal prophylaxis. The model compares (i) standard prophylactic dosing with voriconazole and (ii) CYP2C19 genotyping of all AML patients to guide voriconazole dosing and prescribing. RESULTS: Based on the model, genotype-guided dosing of voriconazole conservatively spares 2.3 patients per year from invasive fungal infections. Implementing proactive genotyping of all AML patients in a simulated 100 patient cohort is expected to save a total of $41467 or $415 per patient. CONCLUSIONS: The model, based on the robust literature of clinical and economic data, predicts that proactive genotype-guided voriconazole prophylaxis is likely to yield modest cost savings while improving patient outcomes. The primary driver of savings is the avoidance of expensive antifungal treatment and extended hospital stays, costing $30 952 per patient, in patients succumbing to fungal infection.

National-scale metacommunity dynamics of carabid beetles in UK farmland.

1. Understanding the wide-scale processes controlling communities across multiple sites is a foremost challenge of modern ecology. Here, data from a nation-wide network of field sites are used to describe the metacommunity dynamics of arable carabid beetles. This is done by modelling how communities are structured at a local level, by changes in the environment of the sampled fields and, at a regional level, by fitting spatial parameters describing latitudinal and longitudinal gradients. 2. Local and regional processes demonstrated independent and significant capacities for structuring communities. Within the local environment, crop type was found to be the primary determinant of carabid community composition. The regional component included a strong response to a longitudinal gradient, with significant increases in diversity in an east-to-west direction. 3. Carabid metacommunities seem to be structured by a combination of species sorting dynamics, operating at two different, but equally important, spatial scales. At a local scale, species are sorted along a resource gradient determined by crop type. At a wider spatial scale species appear to be sorted along a longitudinal gradient. 4. Nation-wide trends in communities coincided with known gradients of increased homogeneity of habitat mosaics and agricultural intensification. However, more work is required to understand fully how communities are controlled by the interaction of crops with changes in landscape structure at different spatial scales. 5. We conclude that crop type is a powerful determinant of carabid biodiversity, but that it cannot be considered in isolation from other components of the landscape for optimal conservation policy.

The Drosophila SSL gene is expressed in larvae, pupae, and adults, exhibits sexual dimorphism, and mimics properties of the beta subunit of casein kinase II.

Drosophila melanogaster casein kinase II (CKII) is composed of catalytic alpha and regulatory beta subunits that generate the alpha2beta2 holoenzyme. A two-hybrid screen of a Drosophila embryo library using CKIIalpha as bait has resulted in the isolation of multiple cDNAs encoding SSL, a CKIIbeta-like polypeptide. We demonstrate that CKIIbeta, beta', and SSL exhibit robust and comparable interaction with CKIIalpha. Residues in SSL that mediate interaction with CKIIalpha appear similar to those in CKIIbeta, and SSL forms homodimers and heterodimers with CKIIbeta or beta' as well. We have tested all known Drosophila CKIIbeta-like proteins for rescue of the ion-homeostasis defect of yeast lacking beta subunits and find that CKIIbeta and SSL complement, beta' has marginal function, and Stellate appears non-functional. We have used real-time RT-PCR to assess developmental expression, and find that CKIIbeta is robust and ubiquitous, whereas SSL is restricted to males (third-instar-larvae, pupae, and adults), but is nondetectable in females of the corresponding stages. These results indicate that SSL expression encompasses a greater developmental window than that previously suggested and may confer distinct functions to CKII in a sex-specific manner.