Research Protocol for an Observational Health Data Analysis on the Adverse Events of Systemic Treatment in Patients with Metastatic Hormone-sensitive Prostate Cancer: Big Data Analytics Using the PIONEER Platform.

Combination therapies in metastatic hormone-sensitive prostate cancer (mHSPC), which include the addition of an androgen receptor signaling inhibitor and/or docetaxel to androgen deprivation therapy, have been a game changer in the management of this disease stage. However, these therapies come with their fair share of toxicities and side effects. The goal of this observational study is to report drug-related adverse events (AEs), which are correlated with systemic combination therapies for mHSPC. Determining the optimal treatment option requires large cohorts to estimate the tolerability and AEs of these combination therapies in "real-life" patients with mHSPC, as provided in this study. We use a network of databases that includes population-based registries, electronic health records, and insurance claims, containing the overall target population and subgroups of patients defined by unique certain characteristics, demographics, and comorbidities, to compute the incidence of common AEs associated with systemic therapies in the setting of mHSPC. These data sources are standardised using the Observational Medical Outcomes Partnership Common Data Model. We perform the descriptive statistics as well as calculate the AE incidence rate separately for each treatment group, stratified by age groups and index year. The time until the first event is estimated using the Kaplan-Meier method within each age group. In the case of episodic events, the anticipated mean cumulative counts of events are calculated. Our study will allow clinicians to tailor optimal therapies for mHSPC patients, and they will serve as a basis for comparative method studies.

Cystatin C or creatinine for pre-operative assessment of kidney function and risk of post-operative acute kidney injury: a secondary analysis of the METS cohort study.

Background: Post-operative acute kidney injury (PO-AKI) is a common surgical complication consistently associated with subsequent morbidity and mortality. Prior kidney dysfunction is a major risk factor for PO-AKI, however it is unclear whether serum creatinine, the conventional kidney function marker, is optimal in this population. Serum cystatin C is a kidney function marker less affected by body composition and might provide better prognostic information in surgical patients. Methods: This was a pre-defined, secondary analysis of a multi-centre prospective cohort study of pre-operative functional capacity. Participants were aged ≥40 years, undergoing non-cardiac surgery. We assessed the association of pre-operative estimated glomerular filtration rate (eGFR) calculated using both serum creatinine and serum cystatin C with PO-AKI within 3 days after surgery, defined by KDIGO creatinine changes. The adjusted analysis accounted for established AKI risk factors. Results: A total of 1347 participants were included (median age 65 years, interquartile range 56-71), of whom 775 (58%) were male. A total of 82/1347 (6%) patients developed PO-AKI. These patients were older, had higher prevalence of cardiovascular disease and related medication, were more likely to have intra-abdominal procedures, had more intraoperative transfusion, and were more likely to be dead at 1 year after surgery 6/82 (7.3%) vs 33/1265 (2.7%) (P = .038). Pre-operative eGFR was lower in AKI than non-AKI patients using both creatinine and cystatin C. When both measurements were considered in a single age- and sex-adjusted model, eGFR-Cysc was strongly associated with PO-AKI, with increasing risk of AKI as eGFR-Cysc decreased below 90, while eGFR-Cr was no longer significantly associated. Conclusions: Data from over 1000 prospectively recruited surgical patients confirms pre-operative kidney function as major risk factor for PO-AKI. Of the kidney function markers available, compared with creatinine, cystatin C had greater strength of association with PO-AKI and merits further assessment in pre-operative assessment of surgical risk.

Clinical Characterization of Patients Diagnosed with Prostate Cancer and Undergoing Conservative Management: A PIONEER Analysis Based on Big Data.

BACKGROUND: Conservative management is an option for prostate cancer (PCa) patients either with the objective of delaying or even avoiding curative therapy, or to wait until palliative treatment is needed. PIONEER, funded by the European Commission Innovative Medicines Initiative, aims at improving PCa care across Europe through the application of big data analytics. OBJECTIVE: To describe the clinical characteristics and long-term outcomes of PCa patients on conservative management by using an international large network of real-world data. DESIGN, SETTING, AND PARTICIPANTS: From an initial cohort of >100 000 000 adult individuals included in eight databases evaluated during a virtual study-a-thon hosted by PIONEER, we identified newly diagnosed PCa cases (n = 527 311). Among those, we selected patients who did not receive curative or palliative treatment within 6 mo from diagnosis (n = 123 146). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Patient and disease characteristics were reported. The number of patients who experienced the main study outcomes was quantified for each stratum and the overall cohort. Kaplan-Meier analyses were used to estimate the distribution of time to event data. RESULTS AND LIMITATIONS: The most common comorbidities were hypertension (35-73%), obesity (9.2-54%), and type 2 diabetes (11-28%). The rate of PCa-related symptomatic progression ranged between 2.6% and 6.2%. Hospitalization (12-25%) and emergency department visits (10-14%) were common events during the 1st year of follow-up. The probability of being free from both palliative and curative treatments decreased during follow-up. Limitations include a lack of information on patients and disease characteristics and on treatment intent. CONCLUSIONS: Our results allow us to better understand the current landscape of patients with PCa managed with conservative treatment. PIONEER offers a unique opportunity to characterize the baseline features and outcomes of PCa patients managed conservatively using real-world data. PATIENT SUMMARY: Up to 25% of men with prostate cancer (PCa) managed conservatively experienced hospitalization and emergency department visits within the 1st year after diagnosis; 6% experienced PCa-related symptoms. The probability of receiving therapies for PCa decreased according to time elapsed after the diagnosis.

Unanswered questions in prostate cancer - findings of an international multi-stakeholder consensus by the PIONEER consortium.

PIONEER is a European network of excellence for big data in prostate cancer consisting of 37 private and public stakeholders from 9 countries across Europe. Many progresses have been done in prostate cancer management, but unanswered questions in the field still exist, and big data could help to answer these questions. The PIONEER consortium conducted a two-round modified Delphi survey aiming at building consensus between two stakeholder groups - health-care professionals and patients with prostate cancer - about the most important questions in the field of prostate cancer to be answered using big data. Respondents were asked to consider what would be the effect of answering the proposed questions on improving diagnosis and treatment outcomes for patients with prostate cancer and to score these questions on a scale of 1 (not important) to 9 (critically important). The mean percentage of participants who scored each of the proposed questions as critically important was calculated across the two stakeholder groups and used to rank the questions and identify the highest scoring questions in the critically important category. The identification of questions in prostate cancer that are important to various stakeholders will help the PIONEER consortium to provide answers to these questions to improve the clinical care of patients with prostate cancer.

The cost impact of disease progression to metastatic castration-sensitive prostate cancer.

BACKGROUND: Metastatic prostate cancer (PC) is associated with declining survival rates and increased health care expenditure. However, there are few studies quantifying these increased costs. OBJECTIVE: To estimate overall health care resource utilization and costs associated with progression to metastatic disease in Medicare or commercially insured patients with nonmetastatic castration-sensitive PC (nmCSPC) or previously undiagnosed PC. METHODS: In this retrospective, observational cohort study, we used data from the IBM MarketScan Commercial and MarketScan Medicare Supplemental Databases. Included patients were aged 18 years or older, had 2 or more health care claims associated with a diagnosis of PC, and had a diagnosis of metastatic disease (index date) between January 1, 2014, and December 31, 2016. Patients with PC were identified at index as either progressing from a localized disease state (nmCSPC) without evidence of castration resistance (progressors) or de novo metastatic without a prior PC diagnosis. Unadjusted all-cause direct health care costs for the 2-year pre-index period and up to 2 years post-index were summarized. Metastasis-related incremental all-cause direct health care costs were estimated using regression modeling to adjust for patient baseline characteristics, follow-up duration, and possible selection bias. RESULTS: We identified 3,854 patients who met the criteria for CSPC at metastasis: 2,766 Medicare patients (mean age 78.8 ± 7.6 years) and 1,088 commercial patients (mean age 57.6 ± 4.3 years), with de novo patients accounting for 28.9% and 34.5% of the 2 analysis populations, respectively. Mean unadjusted total all-cause health care costs over the 24-month pre-index period among progressors were $52,661 (Medicare) and $43,111 (commercial); those among de novo patients were $39,756 (Medicare) and $22,090 (commercial). Mean unadjusted post-index costs for progressors were $100,331 (Medicare) and $127,374 (commercial) over a mean follow-up duration of 14.63 and 18.41 months, respectively, and $124,538 (Medicare) and $173,408 (commercial) over a mean follow-up duration of 14.14 and 17.29 months for patients with de novo disease. After multivariate adjustment, incremental cost increases due to metastasis in patients with CSPC pre-index were estimated at $104,051 (Medicare) and $93,334 (commercial), assuming data are available for 24 months post-index. Allowing for variation in the postindex observation period, estimates were $71,308 (Medicare) and $82,336 (commercial). Among de novo patients, cost increases due to metastasis were estimated at $180,932 (Medicare) and $215,397 (commercial), assuming all patients have data for 24 months postindex. Allowing for variable follow-up, estimates were $113,253 (Medicare) and $161,714 (commercial). CONCLUSIONS: Development of metastatic CSPC is associated with considerable costs over a 24-month follow-up period. Cost increases are greater for de novo patients than for those who progressed from localized disease. DISCLOSURES: Q.-D. Trinh received personal fees from Astellas, Bayer, and Janssen and grants from Intuitive Surgical. L. Passos Chaves, Q. Feng, J. Zhu, and T. Abbott are employees of Astellas Pharma Global Development, Inc. R. Sandin is an employee of, and holds stock in, Pfizer AB. This study was funded by Astellas Pharma Inc. (Northbrook, IL) and Pfizer Inc., the codevelopers of enzalutamide. Astellas Pharma Inc. was involved in the study design, data collection, analysis, interpretation of data, and decision to present these results.

Author Correction: Introducing PIONEER: a project to harness big data in prostate cancer research.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Introducing PIONEER: a project to harness big data in prostate cancer research.

Prostate Cancer Diagnosis and Treatment Enhancement Through the Power of Big Data in Europe (PIONEER) is a European network of excellence for big data in prostate cancer, consisting of 32 private and public stakeholders from 9 countries across Europe. Launched by the Innovative Medicines Initiative 2 and part of the Big Data for Better Outcomes Programme (BD4BO), the overarching goal of PIONEER is to provide high-quality evidence on prostate cancer management by unlocking the potential of big data. The project has identified critical evidence gaps in prostate cancer care, via a detailed prioritization exercise including all key stakeholders. By standardizing and integrating existing high-quality and multidisciplinary data sources from patients with prostate cancer across different stages of the disease, the resulting big data will be assembled into a single innovative data platform for research. Based on a unique set of methodologies, PIONEER aims to advance the field of prostate cancer care with a particular focus on improving prostate-cancer-related outcomes, health system efficiency by streamlining patient management, and the quality of health and social care delivered to all men with prostate cancer and their families worldwide.

Association between Hyaluronic Acid Injections and Time-to-Total Knee Replacement Surgery.

This study assessed the association between hyaluronic acid (HA) injections and time-to-total knee replacement (TKR) surgery for patients with knee osteoarthritis (OA). Patients 18 to 64 years of age who had TKR surgery between January 1, 2006 and December 31, 2011 were identified from the MarketScan Commercial claims database. All patients had 6 years or more of continuous enrollment prior to TKR surgery. There were two cohorts (1) patients with HA injections prior to TKR surgery and (2) patients who did not have HA injections prior to TKR surgery. Time-to-TKR was defined as the total days from the date of diagnosis of knee OA on the patient's first visit to an orthopedic surgeon to the date of TKR surgery. Results included 22,555 patients who had TKR surgery: 14,132 in the non-HA and 8,423 in the HA cohort. In this retrospective analysis of patients undergoing TKR, the median Time-to-TKR surgery was 326 days for the non-HA and 908 days for the HA cohort, a difference of 582 days. Those receiving HA injections had a median 1.6-year longer Time-to-TKR surgery versus those who did not receive HA injections. These results have both clinical and economic implications.

Threonine 149 phosphorylation enhances ΔFosB transcriptional activity to control psychomotor responses to cocaine.

Stable changes in neuronal gene expression have been studied as mediators of addicted states. Of particular interest is the transcription factor ΔFosB, a truncated and stable FosB gene product whose expression in nucleus accumbens (NAc), a key reward region, is induced by chronic exposure to virtually all drugs of abuse and regulates their psychomotor and rewarding effects. Phosphorylation at Ser(27) contributes to ΔFosB's stability and accumulation following repeated exposure to drugs, and our recent work demonstrates that the protein kinase CaMKIIα phosphorylates ΔFosB at Ser(27) and regulates its stability in vivo. Here, we identify two additional sites on ΔFosB that are phosphorylated in vitro by CaMKIIα, Thr(149) and Thr(180), and demonstrate their regulation in vivo by chronic cocaine. We show that phosphomimetic mutation of Thr(149) (T149D) dramatically increases AP-1 transcriptional activity while alanine mutation does not affect transcriptional activity when compared with wild-type (WT) ΔFosB. Using in vivo viral-mediated gene transfer of ΔFosB-T149D or ΔFosB-T149A in mouse NAc, we determined that overexpression of ΔFosB-T149D in NAc leads to greater locomotor activity in response to an initial low dose of cocaine than does WT ΔFosB, while overexpression of ΔFosB-T149A does not produce the psychomotor sensitization to chronic low-dose cocaine seen after overexpression of WT ΔFosB and abrogates the sensitization seen in control animals at higher cocaine doses. We further demonstrate that mutation of Thr(149) does not affect the stability of ΔFosB overexpressed in mouse NAc, suggesting that the behavioral effects of these mutations are driven by their altered transcriptional properties.

Nonenzymatic domains of Kalirin7 contribute to spine morphogenesis through interactions with phosphoinositides and Abl.

Like several Rho GDP/GTP exchange factors (GEFs), Kalirin7 (Kal7) contains an N-terminal Sec14 domain and multiple spectrin repeats. A natural splice variant of Kalrn lacking the Sec14 domain and four spectrin repeats is unable to increase spine formation; our goal was to understand the function of the Sec14 and spectrin repeat domains. Kal7 lacking its Sec14 domain still increased spine formation, but the spines were short. Strikingly, Kal7 truncation mutants containing only the Sec14 domain and several spectrin repeats increased spine formation. The Sec14 domain bound phosphoinositides, a minor but crucial component of cellular membranes, and binding was increased by a phosphomimetic mutation. Expression of KalSec14-GFP in nonneuronal cells impaired receptor-mediated endocytosis, linking Kal7 to membrane trafficking. Consistent with genetic studies placing Abl, a non-receptor tyrosine kinase, and the Drosophila orthologue of Kalrn into the same signaling pathway, Abl1 phosphorylated two sites in the fourth spectrin repeat of Kalirin, increasing its sensitivity to calpain-mediated degradation. Treating cortical neurons of the wild-type mouse, but not the Kal7(KO) mouse, with an Abl inhibitor caused an increase in linear spine density. Phosphorylation of multiple sites in the N-terminal Sec14/spectrin region of Kal7 may allow coordination of the many signaling pathways contributing to spine morphogenesis.

Gorham disease of the mandible: radiographic findings and radiotherapy response.

Gorham disease, a rare condition of unknown etiology, is characterized histologically by bone disintegration and endothelial proliferation. We describe serial imaging findings, the treatment course, and radiotherapy response in a patient with pathologically confirmed Gorham disease involving the right mandible. Progressive mandibular resorption was managed initially with multiple surgical resections and reconstruction, followed by external-beam radiotherapy, which was an effective treatment method in this case. The patient's reconstructed mandible is functional and he is asymptomatic. Our literature review provides further insights regarding the clinical, radiologic, and pathologic behavior of this entity and examines the available treatment strategies.

Nasopharyngeal carcinoma with axillary node involvement as a component of failure following chemoradiotherapy.

We describe the treatment course and imaging correlations in a patient with a unique case of undifferentiated nasopharyngeal carcinoma with axillary lymph node involvement as a component of failure following chemoradiotherapy. To our knowledge, this is the only such case reported in the literature. A preliminary diagnosis ofaxillary node involvement was based on both positron-emission tomography and computed tomography; these findings were subsequently confirmed by pathologic review following dissection of the node. This case represents a rare presentation of a recurrent nasopharyngeal carcinoma and illustrates the importance of a comprehensive physical examination and correlation with imaging modalities when following these patients over time.

Evaluation of three population-based strategies for fracture prevention: results of the osteoporosis population-based risk assessment (OPRA) trial.

BACKGROUND: The integration of bone density testing into well-designed fracture prevention programs that can be applied in populations has not been studied. OBJECTIVES: We sought to compare the outcomes of 3 strategies for allocating bone density testing within an HMO-based fracture prevention program. RESEARCH DESIGN: Women were randomly sampled and allocated to one of 3 groups: (1) a universal group, in which all were offered bone mineral density (BMD) testing (1986 contacted; 415 participated); 2) the SCORE group, in which women scoring > or = 7 on the SCORE questionnaire were invited for BMD testing (1940 contacted; 576 participated); and (3) the Study of Osteoporotic Fracture (SOF)-based group, in which women with > or = 5 hip fracture risk factors were invited for BMD testing (5342 contacted; 2176 participated). SUBJECTS: Women aged 60-80 not taking hormone therapy or osteoporosis medication were included. MEASURES: Outcomes ascertained during 33 months of follow-up in all women contacted included initiation of osteoporosis treatment and hip and total fracture rates. Outcomes evaluated among all participants included changes in fracture risk factors, osteoporosis knowledge, and satisfaction with the program. RESULTS: Osteoporosis treatment rates did not differ among all women contacted but were slightly higher among trial participants in the universal and SCORE groups (21.1% and 20.2%, respectively; versus 16.7% in the SOF-based group (P value versus universal = 0.04). Among all women contacted, fracture rates were lowest in the universal group (74.11/1000) and differed significantly compared with the SCORE (99.44/1000; P = 0.009) and SOF-based groups (91.77/1000;P = 0.02). Knowledge about osteoporosis risk factors was highest in the universal group and lowest in the SOF-based group (P < 0.01). CONCLUSIONS: The degree to which BMD testing was offered to women in a fracture prevention program significantly affected total fracture rates, change in some fracture risk factors, and knowledge about risk factors.

A population-based osteoporosis screening program: who does not participate, and what are the consequences?

OBJECTIVES: To describe differences in osteoporosis risk factors and rates of fracture and antiresorptive therapy use in women who did and did not participate in an osteoporosis screening program. SETTING: Group Health Cooperative, a health maintenance organization in western Washington state. PARTICIPANTS: A total of 9,268 women (aged 60-80) who were not using any antiresorptive therapy were invited to participate in an osteoporosis screening program. This study compares the 35% who participated with the 65% who did not. DESIGN: This observational cohort study of women invited to participate in a randomized, controlled trial of an osteoporosis screening program provided all participants with personalized feedback on their risk of osteoporosis. Some participants also received bone density testing. Automated administrative data were used to examine differences between participants and nonparticipants in fracture outcomes and medication initiation before and after invitation. RESULTS: Baseline fracture rates did not differ between participants and nonparticipants. After age adjustment, nonparticipants had a higher hip fracture rate (14.1 vs 8.3 per 1,000) and a lower rate of initiating any antiresorptive therapy (10.3 vs 17.9 per 100) than participants after an average of 28 to 29 months of follow-up. CONCLUSION: Participants had reduced hip fracture rates and increased initiation of antiresorptive therapy compared with nonparticipants. It was not possible to determine whether participating in the screening program, unmeasured confounding, or selection bias accounted for differences in hip fracture or therapy initiation rates. These results suggest that women who do not participate in osteoporosis screening should be pursued to identify individuals who could benefit from primary and secondary osteoporosis prevention.

Evaluation of decision rules to identify postmenopausal women for intervention related to osteoporosis.

Decision rules for intervention that utilize screening tools for bone mineral density (BMD) testing and incorporating the BMD findings and other risk factors to identify high-risk women to prevent fracture have not been evaluated. We examine the sensitivity and specificity of decision rules for intervention based on two pre-BMD screening tools: Simple Calculated Osteoporosis Risk Estimation (SCORE) and a Study of Osteoporotic Fractures (SOF)-based tool. Women 60 years of age and older without previous osteoporosis diagnosis were randomly selected from a managed care population and invited to receive a BMD test. Four hundred sixteen women had complete information and were included in the study. Women were classified as high risk requiring intervention using three different criteria: World Health Organization (t-score -2.5 or less), National Osteoporosis Foundation (t-score -2.0 or less, or -1.5 or less with one or more risk factors), and the SOF-based criteria (prior fracture; or age 60-64 with t-score less than -2.5 or age 65 or older with z-score less than -0.43 and five or more risk factors). SCORE identified 82% of the women as appropriate for BMD testing, whereas the SOF-based tool identified 26%. Sensitivity and specificity were 89.8%-96.5% and 23.8%-34.8%, respectively, for the decision rule using SCORE as the screening tool and 30.5%-84.9% and 76.0%-95.8%, respectively, for the decision rule based on SOF screening criteria. SCORE correctly identified more women who were at high risk for intervention, whereas the SOF-based tool correctly identified more women who do not meet intervention criteria. The appropriate selection of a screening tool depends upon the objective for intervention and trade-off between not identifying women for BMD testing who are at high risk and identifying more women for BMD testing who are at low risk.