Introduction.
Most clinical reports on methadone rotation describe outcomes in hospitalized patients. The few studies that have included outpatients are retrospective. The aim of this study was to ...assess the efficacy and safety of methadone as a second‐line opioid in adult patients with advanced cancer after rotation in routine clinical practice at a palliative care outpatient clinic.
Patients and Methods.
This was a prospective, open‐label study of 145 patients whose treatment was rotated from other opioids to methadone. Informed consent was obtained in all cases. The main outcome measure was change in the variable “worst pain” at day 28. Pain and pain interference were assessed with the Brief Pain Inventory, with side effects evaluated according to the Common Terminology Criteria for Adverse Events version 3.0. Pain levels were evaluated at study entry and at days 3, 7, 9, 14, 21, and 28.
Results.
Rotation to methadone was performed for the following reasons: poor pain control (77.9%), opioid side effects (2.1%), or both (20%). The mean daily oral morphine equivalent dose before rotation was 193.7 mg. The median worst and average pain scores decreased significantly (p < .0001) from baseline to day 28: The median worst pain score decreased from 9 (interquartile range IQR: 8–10) to 6 (IQR: 3–8), and the median average pain score decreased from 6 (IQR: 5–7) to 4 (IQR: 2–5). The proportions of patients with moderate to severe worst and average pain decreased by 30.3% and 47.5%, respectively, by day 28. No increase in opioid toxicity was observed during the study.
Conclusion.
In outpatients with advanced cancer, rotation to methadone as a second‐line opioid was efficacious and safe when using a tiered scheme with close follow‐up by experienced health professionals.
Implications for Practice:
The results of this study, conducted prospectively under real clinical conditions, support the efficacy and safety of oral methadone as a second‐line opioid in ambulatory patients with cancer. Moreover, these findings corroborate previously reported outcomes in retrospective outpatient studies and prospective studies that evaluated inpatient populations. Although more research into methadone rotation strategies is still needed, this study describes a successful tiered scheme of oral methadone rotation that was proven safe and effective during follow‐up.
This prospective, open‐label study of 145 patients with advanced cancer assessed the efficacy and safety of methadone as a second‐line opioid after rotation from other opioids. The main outcome measure, assessed with the Brief Pain Inventory and the CTCAE, was change in the variable “worst pain” at day 28. The median worst pain and average pain scores decreased significantly (30.3% and 47.5%, respectively) at day 28.
The precise effects of HIV-1 on the gut microbiome are unclear. Initial cross-sectional studies provided contradictory associations between microbial richness and HIV serostatus and suggested shifts ...from Bacteroides to Prevotella predominance following HIV-1 infection, which have not been found in animal models or in studies matched for HIV-1 transmission groups. In two independent cohorts of HIV-1-infected subjects and HIV-1-negative controls in Barcelona (n=156) and Stockholm (n=84), men who have sex with men (MSM) predominantly belonged to the Prevotella-rich enterotype whereas most non-MSM subjects were enriched in Bacteroides, independently of HIV-1 status, and with only a limited contribution of diet effects. Moreover, MSM had a significantly richer and more diverse fecal microbiota than non-MSM individuals. After stratifying for sexual orientation, there was no solid evidence of an HIV-specific dysbiosis. However, HIV-1 infection remained consistently associated with reduced bacterial richness, the lowest bacterial richness being observed in subjects with a virological-immune discordant response to antiretroviral therapy. Our findings indicate that HIV gut microbiome studies must control for HIV risk factors and suggest interventions on gut bacterial richness as possible novel avenues to improve HIV-1-associated immune dysfunction.
•The fecal microbiota of gay men in Europe is systematically richer and has a distinct composition.•HIV-1 infection is independently associated with reduced gut bacterial richness, more so in immune discordant subjects.•Interventions to increase gut bacterial richness might offer novel avenues to improve HIV-1-associated immune dysfunction.
The human intestinal microbiota is essential for human health and well-being and is driven by genetic, lifestyle and environmental factors. Here, we show in two independent cohorts of HIV-1-infected subjects and HIV-1-negative controls in Europe that gay men often have a distinct composition of the human fecal microbiota, with increased microbial richness and diversity and enrichment in the Prevotella enterotype. This is independent of HIV-1 status, and with only a limited contribution of diet effects. After accounting for sexual orientation, however, HIV-1 infection remains associated to reduced bacterial richness, more so in subjects with suboptimal CD4+ T-cell count recovery under antiretroviral therapy. Future studies should evaluate if interventions to increase gut bacterial richness could improve HIV-associated immune dysfunction.
Hospital deaths carry a significant healthcare cost that has been confirmed to be lower when palliative care units (PCUs) are available.
To compare the last admission hospital health care cost of ...dying in a first-level hospital between the PCU and the rest of the hospital services.
A retrospective, comparative, observational study evaluating costs from the payer perspective on treatments and diagnostic-therapeutic tests performed on patients who die in first-level hospital, comparing whether they were treated by the PCU or another unit (Non-PCU). Patients with a mortality risk >2 were included according to the Severity of Illness Index (SOI) and Risk of Mortality (MOR). All cost express in €, median per patient and interquartile range (IQR).
From 1,833 patients who died, 1,389 were included, 442 (31.1%) treated by PCU and 928 (68.9%) Non-PCU. Statistical differences were found for the last admission total cost (€262.8 (€470.1) for PCU versus €515.3 (€980.48) in Non-PCU), daily total cost (€74.27 (€127.4) vs €115.8 (€142.4) Non-PCU). Savings were maintained when the sample was broken down by diagnosis-related group (DRG) and a multivariate analysis was performed to determine how the different patients baseline characteristics between PCU and Non-PCU patients influenced the results obtained.
Data from this study show that cost is significantly lower when the patients are treated by a PCU during their last hospital stay when they pass away.
The mammalian target of rapamycin (mTOR) pathway inhibitors are key drugs for the treatment of many tumor types, however, there are no predictive biomarkers in clinical use. Here, we performed a ...molecular and immunohistochemical characterization of key mTOR pathway components in a series of 105 renal cell carcinoma patients treated with rapalogs, aimed at identifying markers of treatment response. Mutational analysis in MTOR, TSC1 and TSC2 was performed through targeted next‐generation sequencing (NGS), and immunohistochemistry (IHC) was performed for PTEN, pAKT, pS6K1, pS6 and p21. Among patients with NGS data, 11 of 87 (13%) had mTOR pathway mutations (8 in MTOR, 1 in TSC1 and 2 in TSC2). When comparing the molecular data to the response of the patients, we found that partial response was more frequent in cases with mTOR pathway mutations than in those without mutations (odds ratio OR = 0.08, 95% confidence interval CI = 0.008–0.79, p = 0.030 univariate; p = 0.038 multivariable). Regarding IHC, negative PTEN staining was detected in 58% of the tumors, and it was more frequent in rapalog responder patients (OR = 0.24, 95% CI = 0.065–0.86, p = 0.029 univariate; p = 0.029 multivariable). Mutations and PTEN IHC were not mutually exclusive events and its combination improved response prediction (OR = 0.16, 95% CI = 0.04–0.62, p = 0.008 univariate; p = 0.013 multivariable). The staining of other proteins did not show and association with response and no association with PFS was observed in unselected patients. In conclusion, our findings suggest that mTOR pathway mutations, negative PTEN IHC and their combination are potential markers of rapalog response.
What's new?
Inhibitors of the mammalian Target of Rapamycin (mTOR) are key drugs for the treatment of renal cell carcinoma. However, only a subset of patients benefits clinically, and it is unclear why. Here the authors identified mutations in mTOR pathway, as well as loss of expression of the tumor suppressor PTEN, as markers of favorable outcome, underscoring the potential of these markers– either alone or in combination – to serve as clinical tools for patient stratification.
The President and Immigration Law Cox, Adam B.; Rodríguez, Cristina M.
The Yale law journal,
12/2009, Letnik:
119, Številka:
3
Journal Article
The plenary power doctrine sharply limits the judiciary's power to police immigration regulation—a fact that has preoccupied immigration law scholars for decades. But scholars' persistent focus on ...the distribution of power between the courts and the political branches has obscured a second important separation-of-powers question: how is immigration authority distributed between the political branches themselves? The Court's jurisprudence has shed little light on this question. In this Article, we explore how the allocation of regulatory power between the President and Congress has evolved as a matter of political and constitutional practice. A long-overlooked history hints that the Executive has at times asserted inherent authority to regulate immigration. At the same time, the expansion of the administrative state has assimilated most executive policymaking into a model of delegated authority. The intricate immigration code associated with this delegation framework may appear at first glance to limit the President's policymaking discretion. In practice, however, the modern structure of immigration law actually has enabled the President to exert considerable control over immigration law's core question: which types of noncitizens, and how many, should be permitted to enter and reside in the United States? Whether Congress intended for the President to have such freedom is less important than understanding that the Executive's power is asymmetric. The President has considerable authority to screen immigrants at the back end of the system through enforcement decisions, but minimal control over screening at the front end, before immigrants enter the United States. We argue that this asymmetry, in certain circumstances, has pathological consequences that Congress could address by formally delegating power to the President to adjust the quotas and admissions criteria at the heart of immigration law.
Celotno besedilo
Dostopno za:
BFBNIB, DOBA, IZUM, KILJ, NMLJ, NUK, PILJ, PNG, PRFLJ, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The mechanisms committed in the activation and response of vascular and inflammatory immune cells play a major role in tissue remodeling in cardiovascular diseases (CVDs) such as atherosclerosis, ...pulmonary arterial hypertension, and abdominal aortic aneurysm. Cardiovascular remodeling entails interrelated cellular processes (proliferation, survival/apoptosis, inflammation, extracellular matrix (ECM) synthesis/degradation, redox homeostasis, etc.) coordinately regulated by a reduced number of transcription factors. Nuclear receptors of the subfamily 4 group A (NR4A) have recently emerged as key master genes in multiple cellular processes and vital functions of different organs, and have been involved in a variety of high-incidence human pathologies including atherosclerosis and other CVDs. This paper reviews the major findings involving NR4A3 (Neuron-derived Orphan Receptor 1, NOR-1) in the cardiovascular remodeling operating in these diseases.
T‐cell acute lymphoblastic leukemia (T‐ALL) has a poor prognosis derived from its genetic heterogeneity, which translates to a high chemoresistance. Recently, our workgroup designed ...thrombospondin‐1‐derived CD47 agonist peptides and demonstrated their ability to induce cell death in chronic lymphocytic leukemia. Encouraged by these promising results, we evaluated cell death induced by PKHB1 (the first‐described serum‐stable CD47‐agonist peptide) on CEM and MOLT‐4 human cell lines (T‐ALL) and on one T‐murine tumor lymphoblast cell‐line (L5178Y‐R), also assessing caspase and calcium dependency and mitochondrial membrane potential. Additionally, we evaluated selectivity for cancer cell lines by analyzing cell death and viability of human and murine non‐tumor cells after CD47 activation. In vivo, we determined that PKHB1‐treatment in mice bearing the L5178Y‐R cell line increased leukocyte cell count in peripheral blood and lymphoid organs while recruiting leukocytes to the tumor site. To analyze whether CD47 activation induced immunogenic cell death (ICD), we evaluated damage‐associated molecular patterns (DAMP) exposure (calreticulin, CRT) and release (ATP, heat shock proteins 70 and 90, high‐mobility group box 1, CRT). Furthermore, we gave prophylactic antitumor vaccination, determining immunological memory. Our data indicate that PKHB1 induces caspase‐independent and calcium‐dependent cell death in leukemic cells while sparing non‐tumor murine and human cells. Moreover, our results show that PKHB1 can induce ICD in leukemic cells as it induces CRT exposure and DAMP release in vitro, and prophylactic vaccinations inhibit tumor establishment in vivo. Together, our results improve the knowledge of CD47 agonist peptides potential as therapeutic tools to treat leukemia.
In the present study, we found that the TSP‐1‐mimetic, CD47 agonist peptide, PKHB1, induces fast immunogenic cell death in T‐cell acute lymphoblastic leukemia cells, while sparing noncancerous leukocytes. Giving a prophylactic antitumor vaccine comprising tumor cells previously treated with PKHB1 prevented tumor establishment in vivo in an immunocompetent mouse model.
Type I interferon (IFN-I) provides effective antiviral immunity but can exacerbate harmful inflammatory reactions and cause hematopoietic stem cell (HSC) exhaustion; therefore, IFN-I expression must ...be tightly controlled. While signaling mechanisms that limit IFN-I induction and function have been extensively studied, less is known about transcriptional repressors acting directly on IFN-I regulatory regions. We show that NFAT5, an activator of macrophage pro-inflammatory responses, represses Toll-like receptor 3 and virus-induced expression of IFN-I in macrophages and dendritic cells. Mice lacking NFAT5 exhibit increased IFN-I production and better control of viral burden upon LCMV infection but show exacerbated HSC activation under systemic poly(I:C)-induced inflammation. We identify IFNβ as a primary target repressed by NFAT5, which opposes the master IFN-I inducer IRF3 by binding to an evolutionarily conserved sequence in the IFNB1 enhanceosome that overlaps a key IRF site. These findings illustrate how IFN-I responses are balanced by simultaneously opposing transcription factors.
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