Real-World Progression-Free Survival as an Endpoint in Lung Cancer: Replicating Atezolizumab and Docetaxel Arms of the OAK Trial Using Real-World Data.

Evaluating cancer treatments in real-world data (RWD) requires informative endpoints. This study replicated the atezolizumab and docetaxel arms of the OAK trial using RWD and compared progression-free survival (PFS) outcomes derived from abstracted physician's notes in RWD (rwPFS) against PFS outcomes derived from the clinical trial PFS (ctPFS). Atezolizumab and docetaxel arms of the phase III OAK randomized controlled trial (RCT; NCT02008227) were replicated in a US nationwide real-world database using selected OAK inclusion/exclusion criteria and propensity score-based adjustment for baseline prognostic variables. Concordance of outcomes was assessed using Kaplan-Meier medians and hazard ratios (HRs). The RWD cohorts comprised 133 patients on atezolizumab and 479 patients on docetaxel. After adjustment, prognostic variables were balanced between RCT arms and corresponding RWD cohorts. The rwPFS and ctPFS outcomes showed better concordance for docetaxel (2.99 vs. 3.52 months; HR: 0.99, 95% confidence interval (CI): 0.85-1.15) than for atezolizumab (3.71 vs. 2.76 months; HR: 0.8, 95% CI: 0.61-1.02). Excluding events labeled "pseudo-progression" from both RWD and RCT improved concordance for atezolizumab (4.24 vs. 4.14 months; HR: 0.95, 95% CI: 0.70-1.25). These findings were robust across sensitivity analyses. Replicating RCTs using RWD and comparing outcomes can help characterize RWD endpoints. Similarity of results between rwPFS and ctPFS at the cohort level may depend on drug category, highlighting the need for further studies to verify and understand when the corresponding outcomes can be compared, including within the same patient.

Clinico-Genomic Characterization of Patients with Metastatic Urothelial Carcinoma in Real-World Practice Identifies a Novel Bladder Immune Performance Index (BIPI).

PURPOSE: This retrospective analysis of the largest available clinico-genomic database used de-identified patient-level electronic health record-derived real-world data (RWD) combined with FoundationOne comprehensive genomic profiling (CGP) to characterize patients with metastatic urothelial carcinoma (mUC) treated in the real-world setting, detect potential biomarkers, and develop a bladder immune performance index (BIPI). EXPERIMENTAL DESIGN: Patients with mUC who started front-line single-agent immune checkpoint inhibitors (ICI) and an unmatched group treated with front-line platinum-based chemotherapy between January 1, 2011, and September 30, 2019, were selected. Clinical and genomic data were correlated with overall survival (OS). A novel BIPI predicting outcome with ICIs was developed using machine learning methods and validated using data from a phase II trial (NCT02951767). RESULTS: In ICI-treated patients (n = 118), high tumor mutational burden (≥10 mutations/megabase) was associated with improved OS (HR, 0.58; 95% CI, 0.35-0.95; P = 0.03). In chemotherapy-treated patients (n = 268), those with high APOBEC mutational signature had worse OS (HR, 1.43; 95% CI, 1.06-1.94; P = 0.02). Neither FGFR3 mutations nor DNA damage-repair pathway alterations were associated with OS. A novel BIPI combining clinical and genomic variables (nonmetastatic at initial diagnosis, normal or above normal albumin level at baseline, prior surgery for organ-confined disease, high tumor mutational burden) identified ICI-treated patients with longest OS and was validated in an independent dataset. CONCLUSIONS: Contemporary RWD including FoundationOne CGP can be used to characterize outcomes in real-world patients according to biomarkers beyond PD-L1. A validated, novel clinico-genomic BIPI demonstrated satisfactory prognostic performance for OS in patients with mUC receiving front-line ICI therapy.

Replication of Overall Survival, Progression-Free Survival, and Overall Response in Chemotherapy Arms of Non-Small Cell Lung Cancer Trials Using Real-World Data.

PURPOSE: The utility of real-world data (RWD) for use as external controls in drug development is informed by studies that replicate trial control arms for different endpoints. The purpose of this study was to replicate control arms from four non-small cell lung cancer (NSCLC) randomized controlled trials (RCT) to analyze overall survival (OS), progression-free survival (PFS), and overall response rate (ORR) using RWD. PATIENTS AND METHODS: This study used RWD from a nationwide de-identified database and a clinico-genomic database to replicate OS, PFS, and ORR endpoints in the chemotherapy control arms of four first-line NSCLC RCTs evaluating atezolizumab [IMpower150-wild-type (WT), IMpower130-WT, IMpower131, and IMpower132]. Additional objectives were to develop a definition of real-world PFS (rwPFS) and to evaluate the real-world response rate (rwRR) endpoint. RESULTS: Baseline demographic and clinical characteristics were balanced after application of propensity score weighting methods. For rwPFS and OS, RWD external controls were generally similar to their RCT control counterparts. Across all four trials, the hazard ratio (HR) point estimates comparing trial controls with external controls were closer to 1.0 for the PFS endpoint than for the OS endpoint. An exploratory assessment of rwRR in RWD revealed a slight but nonsignificant overestimation of RCT ORR, which was unconfounded by baseline characteristics. CONCLUSIONS: RWD can be used to reasonably replicate the OS and PFS of chemotherapy control arms of first-line NSCLC RCTs. Additional studies can provide greater insight into the utility of RWD in drug development.

Real-world data prognostic model of overall survival in patients with advanced NSCLC receiving anti-PD-1/PD-L1 immune checkpoint inhibitors as second-line monotherapy.

BACKGROUND AND AIM: The objective of this retrospective, observational, noninterventional cohort study was to investigate prognostic factors of overall survival (OS) in patients with advanced non-small cell lung cancer (aNSCLC) and to develop a novel prognostic model. METHODS: A total of 4049 patients with aNSCLC diagnosed between January 2011 and February 2020 who received atezolizumab, nivolumab, or pembrolizumab as second-line monotherapy were selected from a real-world deidentified database to build the cohort. Patients could not have received first-line treatment with clinical study drug(s) nor immune checkpoint inhibitors including anti-programmed cell death 1 (PD-1)/programmed death-ligand 1 (PD-L1), and anti-cytotoxic T-lymphocyte-associated protein 4 therapies. RESULTS: Patients had a median age of 69 years; 45% were female, 75% White, 70% had stage IV at initial diagnosis, and 70% had nonsquamous histology. A Cox proportional hazards model with lasso regularization was used to build a prognostic model for OS using 18 baseline demographic and clinical factors based on the real-world data cohort. The risk-increasing prognostic factors were abnormally low albumin and chloride levels, Eastern Cooperative Oncology Group performance status score ≥ 2, and abnormally high levels of alkaline phosphatase and white blood cells. The risk-decreasing prognostic factors were PD-L1 positivity, longer time from advanced diagnosis to start of first-line therapy, and higher systolic blood pressure. The performance of the model was validated using data from the OAK trial, and the c-index for the OAK trial validation cohort was 0.65 and 0.67 for the real-world data cohort. CONCLUSIONS: Based on baseline demographic and clinical factors from a real-world setting, this prognostic model was developed to discriminate the risk of death in patients with aNSCLC treated with checkpoint inhibitors as second-line monotherapy, and it performed well in the real-world data and clinical trial cohorts.

Sanitizer efficacy in reducing microbial load on commercially grown hydroponic lettuce.

BACKGROUND: Most hydroponic lettuce growers harvest and package their marketable-size lettuces with an intact root ball. With a high microbial load on the peat moss substrate, there is a risk of microbial transfer onto the edible portion during packaging and throughout the product's shelf life. Since the produce is believed to have no contact with the substrate, no sanitizer wash is performed before packaging and storage. RESULTS: Aerobic plate count (APC) results suggested that reduction in count was influenced by both sanitizer application and storage time. Peroxyacetic acid significantly reduced APC count on leaves, roots, and substrate, with a 1.8 log CFU g-1 initial reduction on the leaf. Fungi and APC levels increased with storage time, with the greatest APC increase in the roots. Leaves had the lowest coliform bacteria (CB), with chlorine slightly reducing CB count. Unlike APC, CB levels decreased during storage on the substrate and root samples. No Listeria positive was confirmed by agglutination test. Further evaluation of different commercial substrates reveals that Com4, a drier-compacted plug, had the least ability to support growth/survival of all microbial populations enumerated relative to the spongy, wet black plugs. CONCLUSION: The ability of peat moss substrates to host microorganisms is influenced by the physical properties of the product. Sanitizer wash efficacy is dependent on the initial microbial load and the length of storage. Chlorine and peroxyacetic acid are effective in reducing microbial populations on the leaves of hydroponically grown lettuce without affecting visual quality during shelf life. © 2020 Society of Chemical Industry.

Transitions across cognitive states and death among older adults in relation to education: A multistate survival model using data from six longitudinal studies.

INTRODUCTION: This study examines the role of educational attainment, an indicator of cognitive reserve, on transitions in later life between cognitive states (normal Mini-Mental State Examination (MMSE), mild MMSE impairment, and severe MMSE impairment) and death. METHODS: Analysis of six international longitudinal studies was performed using a coordinated approach. Multistate survival models were used to estimate the transition patterns via different cognitive states. Life expectancies were estimated. RESULTS: Across most studies, a higher level of education was associated with a lower risk of transitioning from normal MMSE to mild MMSE impairment but was not associated with other transitions. Those with higher levels of education and socioeconomic status had longer nonimpaired life expectancies. DISCUSSION: This study highlights the importance of education in later life and that early life experiences can delay later compromised cognitive health. This study also demonstrates the feasibility and benefit in conducting coordinated analysis across multiple studies to validate findings.

Flexible multistate models for interval-censored data: Specification, estimation, and an application to ageing research.

Continuous-time multistate survival models can be used to describe health-related processes over time. In the presence of interval-censored times for transitions between the living states, the likelihood is constructed using transition probabilities. Models can be specified using parametric or semiparametric shapes for the hazards. Semiparametric hazards can be fitted using P-splines and penalised maximum likelihood estimation. This paper presents a method to estimate flexible multistate models that allow for parametric and semiparametric hazard specifications. The estimation is based on a scoring algorithm. The method is illustrated with data from the English Longitudinal Study of Ageing.

Tratamento da hidradenite supurativa por excisão em monobloco / Treatment of hidradenitis suppurativa en bloc excision

A hidradenite supurativa é definida como doença crônica, supurativa, bacteriana, que compromete as glândulas sudoríparas. Em sua grande maioria esta presente no períneo, região glútea e escrotal. Este trabalho vem relatar um caso de hidradenite supurativa com tratamento cirúrgico proposto de excisão em monobloco, e tem por objetivo nortear uma possível conduta atualizada para pacientes com esta afecção.

The hidradenitis suppurativa is defined as chronic, suppurative bacterial infection, which affects the sweat glands. The vast majority is present in the perineum, buttocks and scrotum. This work has been reporting a caseof hidradenitis suppurativa with surgical treatment of en bloc excision, and aims to guide conduct a possible date for patients with this disease.

Uso de matérias primas da agroindústria: garapa e extrato de levedura: na produção de asparaginase por Zymomonas mobilis CP4 / Utilization of raw materials from agroindustry: sugar cane juice and yeast extract: for asparaginase production by Zymomonas mobilis CP4

Garapa e extrato de levedura foram usados na produção de asparaginase por Zymomonas mobilis CP4. Na otimização utilizou metodologia de superfície de resposta com 2 variáveis (extrato de levedura e asparagina) em 3 níveis (1,0; 5,5 e 10,0 g/L) e uma repetição do ponto central. A fermentação em batelada utilizou garapa diluída a 8 % (P/V) de Açúcares Totais e inóculo de Zymomonas mobilis CP4 na concentração de 2 mg/mL. Após a fermentação de 18 horas, a maior produção obtida de asparaginase foi de 9,75 U/L em extrato de levedura em 5,5 g/L e asparagina em 1,0 g/L.

Sugar cane juice and yeast extract have been used for asparaginase production by Z. mobilis CP4. A complete factorial design of two variables (yeast extract and asparagin) at three levels (1.0; 5.5 and 10.0 g/L) with one replication at the central point was used. Batch fermentation utilised sugar cane juice diluted at 8 % (W/V) of Total Sugars and an inoculum of 2 mg of cells/mL. After fermentation time of 18 hours, the highest production of asparaginase was 9.75 U/L using both yeast extract (5.5 g/L) and asparagin (1.0 g/l).