Prevalence of renal impairment and use of nephrotoxic agents among patients with bone metastases from solid tumors in the United States

The renal status of patients with bone metastases secondary to solid tumors and their treatment with nephrotoxic agents is not well characterized. This retrospective study analyzed electronic medical records data from US‐based oncology clinics to identify adult (age ≥18) solid tumor patients with first bone metastasis diagnosis and ≥1 serum creatinine recorded between January 1, 2009 and December 31, 2013. Patients with multiple myeloma, multiple primary tumor types, acute renal failure, and/or end‐stage renal disease were excluded. Using the Chronic Kidney Disease Epidemiology Collaboration formula, we determined the prevalence of renal impairment (RI: single estimated glomerular filtration rate [eGFR] value <60 mL/min per 1.73 m2) and chronic kidney disease (CKD: ≥2 eGFR values <60, at least 90 days apart). We also examined the use of intravenous bisphosphonates (IV BP) and other nephrotoxic agents. Approximately half of the 11,809 patients were female. Breast (34%) and lung (28%) tumors were the most common. At bone metastasis diagnosis, mean age was 67 years and 24% of patients exhibited RI. The 5‐year prevalence was 43% for RI and 71% for CKD among RI patients. Nearly half (46%) of CKD patients received IV BP in the 12 months following their confirming eGFR and 13% of these patients received at least one other nephrotoxic agent during that period. This is the first US‐based study to examine the prevalence of RI among patients with bone metastases from solid tumors. RI is common at bone metastases diagnosis, and a substantial proportion of patients develop RI or CKD as their disease progresses. Whenever possible, treatments that are potentially less damaging for the kidney should be considered for patients with or predisposed to RI.In patients with bone metastases secondary to solid tumors, the 5‐year prevalence was 43% for renal impairment (RI) and 71% for chronic kidney disease among evaluable RI patients. Whenever possible, treatments that are potentially less damaging for the kidney should be considered for patients with or predisposed to RI.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/111794/1/cam4403.pd

Impact of prior biologic use on persistence of treatment in patients with psoriatic arthritis enrolled in the US Corrona registry

Psoriatic arthritis (PsA) is a chronic condition characterized by a diverse set of symptoms, from swollen joints to nail disease to skin disease. A variety of treatment options are available, including tumor necrosis factor inhibitors (TNFis). Little is known about treatment persistence in patients with PsA who initiate TNFi therapy, with and without prior biologic use. This study assessed persistence in these subgroups of patients with PsA and identified factors associated with persistence. This retrospective study utilized data from the Corrona registry of patients with PsA-with or without prior biologic experience-who initiated TNFi therapy between October 1, 2002, and March 21, 2013. Kaplan-Meier curves estimated median time to nonpersistence (discontinuation or switch to another biologic). Cox proportional hazards models identified factors associated with TNFi nonpersistence. A total of 1241 TNFi initiations were identified: 549 by biologic-naive and 692 by biologic-experienced patients. Through 4 years of follow-up, more biologic-naive than biologic-experienced patients remained persistent. Biologic-naive patients had a greater mean time to nonpersistence compared with biologic-experienced patients: 32 vs 23 months (p = 0.0002). Moderate and high disease activities based on clinical disease activity index and disease duration were associated with persistence in both biologic-naive and biologic-experienced patients. Additionally, in the biologic-experienced patients, the number of prior medications and skin disease were associated with persistence. The majority of patients with PsA in this study were persistent with their TNFi therapy; biologic-naive patients had greater persistence compared with biologic-experienced patients. Predictors of persistence differed slightly between biologic-naive and biologic-experienced patients

Treatment patterns and outcomes in relapsed/refractory follicular lymphoma: results from the international SCHOLAR-5 study

The SCHOLAR-5 study examines treatment patterns and outcomes of real-world follicular lymphoma (FL) patients on 3rd line of treatment (LoT) or higher, for whom existing data are limited. SCHOLAR-5 is a retrospective cohort study using data from adults (≥ 18 years) with grade 1-3a FL, initiating ≥3rd LoT after June 2014 at major lymphoma centers in the United States (US) and Europe. Objective response rate (ORR), complete response (CR), progression free survival (PFS) and overall survival (OS) were analyzed by LoT. Time-to-event outcomes were assessed using Kaplan-Meier methods. Of 128 patients, 87 initiated 3rd LoT, 63 initiated 4th LoT, and 47 initiated 5th LoT. At 1st eligible LoT, 31% progressed within 24-months of 1st LoT anti-CD20 combination therapy, 28% had prior autologous stem-cell transplantation, and 31% were refractory to the previous LoT. The most common regimen in each LoT was chemoimmunotherapy; however, experimental drugs were increasingly used at later LoTs. In the US, anti-CD20 monotherapy was more common at ≥3rd LoT compared to Europe, where stem cell transplants were more common. ORR at 3rd LoT was 68% (CR 44%), but decreased after each LoT to 37% (CR 22%) in ≥5 LoT. Median OS and PFS at 3rd LoT were 68 and 11 months, respectively, and reduced to 43 and 4 months at ≥5 LoT. Treatments were heterogenous at each LoT in both the US and Europe. Few FL patients achieved complete response in later LoT, and duration of response and survival diminished with each subsequent line

Will Aging Baby Boomers Bust the Federal Budget?

The authors analyze in three steps the influence of the projected mortality decline on the long-run finances of the Social Security System. First, mortality decline adds person years of life which are distributed across the life cycle. The interaction of this distribution with the age distribution of taxes minus benefits determines the steady state financial consequences of mortality decline. Second, examination of past mortality trends in the United State and of international trends in low mortality populations, suggests that mortality will decline much faster than foreseen by the SSA\u27s forecasts. Third, based on work on stochastic demographic forecasting, stochastic forecasts of the system\u27s actuarial balance are derived, indicating a broader range of demographic uncertainty than in the latest SSA forecasts, and a relatively greater contribution to uncertainty from fertility than mortality

Killer whales and marine mammal trends in the North Pacific : a re-examination of evidence for sequential megafauna collapse and the prey-switching hypothesis

This paper is not subject to U.S. copyright. The definitive version was published in Marine Mammal Science 23 (2007): 766–802, doi:10.1111/j.1748-7692.2006.00093.x.Springer et al. (2003) contend that sequential declines occurred in North Pacific populations of harbor and fur seals, Steller sea lions, and sea otters. They hypothesize that these were due to increased predation by killer whales, when industrial whaling's removal of large whales as a supposed primary food source precipitated a prey switch. Using a regional approach, we reexamined whale catch data, killer whale predation observations, and the current biomass and trends of potential prey, and found little support for the prey-switching hypothesis. Large whale biomass in the Bering Sea did not decline as much as suggested by Springer et al., and much of the reduction occurred 50–100 yr ago, well before the declines of pinnipeds and sea otters began; thus, the need to switch prey starting in the 1970s is doubtful. With the sole exception that the sea otter decline followed the decline of pinnipeds, the reported declines were not in fact sequential. Given this, it is unlikely that a sequential megafaunal collapse from whales to sea otters occurred. The spatial and temporal patterns of pinniped and sea otter population trends are more complex than Springer et al. suggest, and are often inconsistent with their hypothesis. Populations remained stable or increased in many areas, despite extensive historical whaling and high killer whale abundance. Furthermore, observed killer whale predation has largely involved pinnipeds and small cetaceans; there is little evidence that large whales were ever a major prey item in high latitudes. Small cetaceans (ignored by Springer et al.) were likely abundant throughout the period. Overall, we suggest that the Springer et al. hypothesis represents a misleading and simplistic view of events and trophic relationships within this complex marine ecosystem

Methotrexate Is a JAK/STAT Pathway Inhibitor

Background: The JAK/STAT pathway transduces signals from multiple cytokines and controls haematopoiesis, immunity and inflammation. In addition, pathological activation is seen in multiple malignancies including the myeloproliferative neoplasms (MPNs). Given this, drug development efforts have targeted the pathway with JAK inhibitors such as ruxolitinib. Although effective, high costs and side effects have limited its adoption. Thus, a need for effective low cost treatments remains. Methods & Findings: We used the low-complexity Drosophila melanogaster pathway to screen for small molecules that modulate JAK/STAT signalling. This screen identified methotrexate and the closely related aminopterin as potent suppressors of STAT activation. We show that methotrexate suppresses human JAK/STAT signalling without affecting other phosphorylation-dependent pathways. Furthermore, methotrexate significantly reduces STAT5 phosphorylation in cells expressing JAK2 V617F, a mutation associated with most human MPNs. Methotrexate acts independently of dihydrofolate reductase (DHFR) and is comparable to the JAK1/2 inhibitor ruxolitinib. However, cells treated with methotrexate still retain their ability to respond to physiological levels of the ligand erythropoietin. Conclusions: Aminopterin and methotrexate represent the first chemotherapy agents developed and act as competitive inhibitors of DHFR. Methotrexate is also widely used at low doses to treat inflammatory and immune-mediated conditions including rheumatoid arthritis. In this low-dose regime, folate supplements are given to mitigate side effects by bypassing the biochemical requirement for DHFR. Although independent of DHFR, the mechanism-of-action underlying the low-dose effects of methotrexate is unknown. Given that multiple pro-inflammatory cytokines signal through the pathway, we suggest that suppression of the JAK/STAT pathway is likely to be the principal anti-inflammatory and immunosuppressive mechanism-of-action of low-dose methotrexate. In addition, we suggest that patients with JAK/STAT-associated haematological malignancies may benefit from low-dose methotrexate treatments. While the JAK1/2 inhibitor ruxolitinib is effective, a £43,200 annual cost precludes widespread adoption. With an annual methotrexate cost of around £32, our findings represent an important development with significant future potential

Dissecting the Shared Genetic Architecture of Suicide Attempt, Psychiatric Disorders, and Known Risk Factors

Background Suicide is a leading cause of death worldwide, and nonfatal suicide attempts, which occur far more frequently, are a major source of disability and social and economic burden. Both have substantial genetic etiology, which is partially shared and partially distinct from that of related psychiatric disorders. Methods We conducted a genome-wide association study (GWAS) of 29,782 suicide attempt (SA) cases and 519,961 controls in the International Suicide Genetics Consortium (ISGC). The GWAS of SA was conditioned on psychiatric disorders using GWAS summary statistics via multitrait-based conditional and joint analysis, to remove genetic effects on SA mediated by psychiatric disorders. We investigated the shared and divergent genetic architectures of SA, psychiatric disorders, and other known risk factors. Results Two loci reached genome-wide significance for SA: the major histocompatibility complex and an intergenic locus on chromosome 7, the latter of which remained associated with SA after conditioning on psychiatric disorders and replicated in an independent cohort from the Million Veteran Program. This locus has been implicated in risk-taking behavior, smoking, and insomnia. SA showed strong genetic correlation with psychiatric disorders, particularly major depression, and also with smoking, pain, risk-taking behavior, sleep disturbances, lower educational attainment, reproductive traits, lower socioeconomic status, and poorer general health. After conditioning on psychiatric disorders, the genetic correlations between SA and psychiatric disorders decreased, whereas those with nonpsychiatric traits remained largely unchanged. Conclusions Our results identify a risk locus that contributes more strongly to SA than other phenotypes and suggest a shared underlying biology between SA and known risk factors that is not mediated by psychiatric disorders.Peer reviewe

Global Retinoblastoma Presentation and Analysis by National Income Level.

Importance: Early diagnosis of retinoblastoma, the most common intraocular cancer, can save both a child's life and vision. However, anecdotal evidence suggests that many children across the world are diagnosed late. To our knowledge, the clinical presentation of retinoblastoma has never been assessed on a global scale. Objectives: To report the retinoblastoma stage at diagnosis in patients across the world during a single year, to investigate associations between clinical variables and national income level, and to investigate risk factors for advanced disease at diagnosis. Design, Setting, and Participants: A total of 278 retinoblastoma treatment centers were recruited from June 2017 through December 2018 to participate in a cross-sectional analysis of treatment-naive patients with retinoblastoma who were diagnosed in 2017. Main Outcomes and Measures: Age at presentation, proportion of familial history of retinoblastoma, and tumor stage and metastasis. Results: The cohort included 4351 new patients from 153 countries; the median age at diagnosis was 30.5 (interquartile range, 18.3-45.9) months, and 1976 patients (45.4%) were female. Most patients (n = 3685 [84.7%]) were from low- and middle-income countries (LMICs). Globally, the most common indication for referral was leukocoria (n = 2638 [62.8%]), followed by strabismus (n = 429 [10.2%]) and proptosis (n = 309 [7.4%]). Patients from high-income countries (HICs) were diagnosed at a median age of 14.1 months, with 656 of 666 (98.5%) patients having intraocular retinoblastoma and 2 (0.3%) having metastasis. Patients from low-income countries were diagnosed at a median age of 30.5 months, with 256 of 521 (49.1%) having extraocular retinoblastoma and 94 of 498 (18.9%) having metastasis. Lower national income level was associated with older presentation age, higher proportion of locally advanced disease and distant metastasis, and smaller proportion of familial history of retinoblastoma. Advanced disease at diagnosis was more common in LMICs even after adjusting for age (odds ratio for low-income countries vs upper-middle-income countries and HICs, 17.92 [95% CI, 12.94-24.80], and for lower-middle-income countries vs upper-middle-income countries and HICs, 5.74 [95% CI, 4.30-7.68]). Conclusions and Relevance: This study is estimated to have included more than half of all new retinoblastoma cases worldwide in 2017. Children from LMICs, where the main global retinoblastoma burden lies, presented at an older age with more advanced disease and demonstrated a smaller proportion of familial history of retinoblastoma, likely because many do not reach a childbearing age. Given that retinoblastoma is curable, these data are concerning and mandate intervention at national and international levels. Further studies are needed to investigate factors, other than age at presentation, that may be associated with advanced disease in LMICs

A novel formulation of inhaled sodium cromoglicate (PA101) in idiopathic pulmonary fibrosis and chronic cough: a randomised, double-blind, proof-of-concept, phase 2 trial

Background Cough can be a debilitating symptom of idiopathic pulmonary fibrosis (IPF) and is difficult to treat. PA101 is a novel formulation of sodium cromoglicate delivered via a high-efficiency eFlow nebuliser that achieves significantly higher drug deposition in the lung compared with the existing formulations. We aimed to test the efficacy and safety of inhaled PA101 in patients with IPF and chronic cough and, to explore the antitussive mechanism of PA101, patients with chronic idiopathic cough (CIC) were also studied. Methods This pilot, proof-of-concept study consisted of a randomised, double-blind, placebo-controlled trial in patients with IPF and chronic cough and a parallel study of similar design in patients with CIC. Participants with IPF and chronic cough recruited from seven centres in the UK and the Netherlands were randomly assigned (1:1, using a computer-generated randomisation schedule) by site staff to receive PA101 (40 mg) or matching placebo three times a day via oral inhalation for 2 weeks, followed by a 2 week washout, and then crossed over to the other arm. Study participants, investigators, study staff, and the sponsor were masked to group assignment until all participants had completed the study. The primary efficacy endpoint was change from baseline in objective daytime cough frequency (from 24 h acoustic recording, Leicester Cough Monitor). The primary efficacy analysis included all participants who received at least one dose of study drug and had at least one post-baseline efficacy measurement. Safety analysis included all those who took at least one dose of study drug. In the second cohort, participants with CIC were randomly assigned in a study across four centres with similar design and endpoints. The study was registered with ClinicalTrials.gov (NCT02412020) and the EU Clinical Trials Register (EudraCT Number 2014-004025-40) and both cohorts are closed to new participants. Findings Between Feb 13, 2015, and Feb 2, 2016, 24 participants with IPF were randomly assigned to treatment groups. 28 participants with CIC were enrolled during the same period and 27 received study treatment. In patients with IPF, PA101 reduced daytime cough frequency by 31·1% at day 14 compared with placebo; daytime cough frequency decreased from a mean 55 (SD 55) coughs per h at baseline to 39 (29) coughs per h at day 14 following treatment with PA101, versus 51 (37) coughs per h at baseline to 52 (40) cough per h following placebo treatment (ratio of least-squares [LS] means 0·67, 95% CI 0·48–0·94, p=0·0241). By contrast, no treatment benefit for PA101 was observed in the CIC cohort; mean reduction of daytime cough frequency at day 14 for PA101 adjusted for placebo was 6·2% (ratio of LS means 1·27, 0·78–2·06, p=0·31). PA101 was well tolerated in both cohorts. The incidence of adverse events was similar between PA101 and placebo treatments, most adverse events were mild in severity, and no severe adverse events or serious adverse events were reported. Interpretation This study suggests that the mechanism of cough in IPF might be disease specific. Inhaled PA101 could be a treatment option for chronic cough in patients with IPF and warrants further investigation