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The Cochrane Database of Systematic... Apr 2017The treatment of multiple sclerosis has changed over the last 20 years. The advent of disease-modifying drugs in the mid-1990s heralded a period of rapid progress in the... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
The treatment of multiple sclerosis has changed over the last 20 years. The advent of disease-modifying drugs in the mid-1990s heralded a period of rapid progress in the understanding and management of multiple sclerosis. With the support of magnetic resonance imaging early diagnosis is possible, enabling treatment initiation at the time of the first clinical attack. As most of the disease-modifying drugs are associated with adverse events, patients and clinicians need to weigh the benefit and safety of the various early treatment options before taking informed decisions.
OBJECTIVES
1. to estimate the benefit and safety of disease-modifying drugs that have been evaluated in all studies (randomised or non-randomised) for the treatment of a first clinical attack suggestive of MS compared either with placebo or no treatment;2. to assess the relative efficacy and safety of disease-modifying drugs according to their benefit and safety;3. to estimate the benefit and safety of disease-modifying drugs that have been evaluated in all studies (randomised or non-randomised) for treatment started after a first attack ('early treatment') compared with treatment started after a second attack or at another later time point ('delayed treatment').
SEARCH METHODS
We searched the Cochrane Multiple Sclerosis and Rare Diseases of the CNS Group Trials Register, MEDLINE, Embase, CINAHL, LILACS, clinicaltrials.gov, the WHO trials registry, and US Food and Drug Administration (FDA) reports, and searched for unpublished studies (until December 2016).
SELECTION CRITERIA
We included randomised and observational studies that evaluated one or more drugs as monotherapy in adult participants with a first clinical attack suggestive of MS. We considered evidence on alemtuzumab, azathioprine, cladribine, daclizumab, dimethyl fumarate, fingolimod, glatiramer acetate, immunoglobulins, interferon beta-1b, interferon beta-1a (Rebif®, Avonex®), laquinimod, mitoxantrone, natalizumab, ocrelizumab, pegylated interferon beta-1a, rituximab and teriflunomide.
DATA COLLECTION AND ANALYSIS
Two teams of three authors each independently selected studies and extracted data. The primary outcomes were disability-worsening, relapses, occurrence of at least one serious adverse event (AE) and withdrawing from the study or discontinuing the drug because of AEs. Time to conversion to clinically definite MS (CDMS) defined by Poser diagnostic criteria, and probability to discontinue the treatment or dropout for any reason were recorded as secondary outcomes. We synthesized study data using random-effects meta-analyses and performed indirect comparisons between drugs. We calculated odds ratios (OR) and hazard ratios (HR) along with relative 95% confidence intervals (CI) for all outcomes. We estimated the absolute effects only for primary outcomes. We evaluated the credibility of the evidence using the GRADE system.
MAIN RESULTS
We included 10 randomised trials, eight open-label extension studies (OLEs) and four cohort studies published between 2010 and 2016. The overall risk of bias was high and the reporting of AEs was scarce. The quality of the evidence associated with the results ranges from low to very low. Early treatment versus placebo during the first 24 months' follow-upThere was a small, non-significant advantage of early treatment compared with placebo in disability-worsening (6.4% fewer (13.9 fewer to 3 more) participants with disability-worsening with interferon beta-1a (Rebif®) or teriflunomide) and in relapses (10% fewer (20.3 fewer to 2.8 more) participants with relapses with teriflunomide). Early treatment was associated with 1.6% fewer participants with at least one serious AE (3 fewer to 0.2 more). Participants on early treatment were on average 4.6% times (0.3 fewer to 15.4 more) more likely to withdraw from the study due to AEs. This result was mostly driven by studies on interferon beta 1-b, glatiramer acetate and cladribine that were associated with significantly more withdrawals for AEs. Early treatment decreased the hazard of conversion to CDMS (HR 0.53, 95% CI 0.47 to 0.60). Comparing active interventions during the first 24 months' follow-upIndirect comparison of interferon beta-1a (Rebif®) with teriflunomide did not show any difference on reducing disability-worsening (OR 0.84, 95% CI 0.43 to 1.66). We found no differences between the included drugs with respect to the hazard of conversion to CDMS. Interferon beta-1a (Rebif®) and teriflunomide were associated with fewer dropouts because of AEs compared with interferon beta-1b, cladribine and glatiramer acetate (ORs range between 0.03 and 0.29, with substantial uncertainty). Early versus delayed treatmentWe did not find evidence of differences between early and delayed treatments for disability-worsening at a maximum of five years' follow-up (3% fewer participants with early treatment (15 fewer to 11.1 more)). There was important variability across interventions; early treatment with interferon beta-1b considerably reduced the odds of participants with disability-worsening during three and five years' follow-up (OR 0.52, 95% CI 0.32 to 0.84 and OR 0.57, 95% CI 0.36 to 0.89). The early treatment group had 19.6% fewer participants with relapses (26.7 fewer to 12.7 fewer) compared to late treatment at a maximum of five years' follow-up and early treatment decreased the hazard of conversion to CDMS at any follow-up up to 10 years (i.e. over five years' follow-up HR 0.62, 95% CI 0.53 to 0.73). We did not draw any conclusions on long-term serious AEs or discontinuation due to AEs because of inadequacies in the available data both in the included OLEs and cohort studies.
AUTHORS' CONCLUSIONS
Very low-quality evidence suggests a small and uncertain benefit with early treatment compared with placebo in reducing disability-worsening and relapses. The advantage of early treatment compared with delayed on disability-worsening was heterogeneous depending on the actual drug used and based on very low-quality evidence. Low-quality evidence suggests that the chances of relapse are less with early treatment compared with delayed. Early treatment reduced the hazard of conversion to CDMS compared either with placebo, no treatment or delayed treatment, both in short- and long-term follow-up. Low-quality evidence suggests that early treatment is associated with fewer participants with at least one serious AE compared with placebo. Very low-quality evidence suggests that, compared with placebo, early treatment leads to more withdrawals or treatment discontinuation due to AEs. Difference between drugs on short-term benefit and safety was uncertain because few studies and only indirect comparisons were available. Long-term safety of early treatment is uncertain because of inadequately reported or unavailable data.
Topics: Adjuvants, Immunologic; Cladribine; Cohort Studies; Crotonates; Disease Progression; Glatiramer Acetate; Humans; Hydroxybutyrates; Immunosuppressive Agents; Interferon beta-1a; Multiple Sclerosis; Nitriles; Publication Bias; Randomized Controlled Trials as Topic; Recurrence; Time Factors; Toluidines
PubMed: 28440858
DOI: 10.1002/14651858.CD012200.pub2 -
Journal of Neuroimmunology Apr 2021NK/T-cell ratios predict disease activity in relapsing remitting multiple sclerosis (RRMS). We investigated in 50 RRMS patients whether interleukin-2 receptor...
NK/T-cell ratios predict disease activity in relapsing remitting multiple sclerosis (RRMS). We investigated in 50 RRMS patients whether interleukin-2 receptor alpha-chain (IL-2Rα) expression and shedding associates with NK/T-cell balance, as suggested by daclizumab-trials in RRMS. A subsample (N = 31) was genotyped for IL2RA-associated MS risk SNPs. CD56 NK-cell/IL-17ACD4 T-cell ratios correlated negatively with plasma and PBMC-culture supernatant sIL-2Rα-levels [R = -0.209; p = 0.038 and R = -0.254; p = 0.012, resp.], and with CD4 T-cell CD25 MFI [R = -0.341; p = 0.001]. Carriers of the rs3118470 risk-allele showed higher sIL-2Rα-levels (P = 0.031) and a lower CD56 NK-cell/IL-17ACD4 T-cell ratio (P = 0.038). Therefore, IL-2Rα may be involved in the interplay between NK-cells and T-cells.
Topics: Adult; CD4-Positive T-Lymphocytes; Female; Genetic Predisposition to Disease; Genotype; Humans; Interleukin-2 Receptor alpha Subunit; Killer Cells, Natural; Lymphocyte Count; Middle Aged; Multiple Sclerosis, Relapsing-Remitting; Polymorphism, Single Nucleotide
PubMed: 33529846
DOI: 10.1016/j.jneuroim.2021.577499 -
Pediatric Transplantation Nov 2019End-organ disease caused by CMV is a significant cause of morbidity and mortality in pediatric SOT recipients. Pediatric transplant centers have adopted various...
End-organ disease caused by CMV is a significant cause of morbidity and mortality in pediatric SOT recipients. Pediatric transplant centers have adopted various approaches for CMV disease prevention in this patient population. We observed significant practice variation in CMV testing, prophylaxis, and surveillance across SOT groups in our center. To address this, we implemented evidence-based standardized protocols and measured outcomes pre- and post-implementation of these protocols. We performed retrospective chart review for SOT recipients from 2009 to 2014 at Boston Children's Hospital. Using descriptive statistics, we measured practice improvement in provision of appropriate prophylaxis, occurrence of neutropenia and associated complications, and occurrence of CMV DNAemia and CMV disease pre- and post-intervention. The pre- and post-intervention periods included 141 and 109 patients, respectively. With the exception of kidney transplant recipients, provision of appropriate valganciclovir prophylaxis improved across SOT groups post-intervention (P < .01). Occurrence of >1 episode of neutropenia was greater in the preintervention period (30% vs 10%, P < .001). In both periods, neutropenia was associated with few episodes of invasive infections. The occurrence of CMV disease did not differ and was overall low. However, due to routine surveillance a significantly greater number of asymptomatic CMV DNAemia episodes were identified and treated in the post-intervention period. Implementation of standardized prevention protocols helped to improve the provision of appropriate prophylaxis to patients at risk for CMV acquisition, increased the diagnosis and treatment of asymptomatic CMV DNAemia, and decreased episodes of recurrent neutropenia in patients receiving prophylaxis.
Topics: Adolescent; Alemtuzumab; Antiviral Agents; Basiliximab; Boston; Child; Child, Preschool; Cytomegalovirus; Cytomegalovirus Infections; DNA, Viral; Daclizumab; Female; Humans; Infant; Male; Organ Transplantation; Retrospective Studies; Risk; Steroids; Transplant Recipients; Valganciclovir
PubMed: 31515909
DOI: 10.1111/petr.13568 -
Cytotherapy Jan 2021Certain therapies (e.g., daclizumab) that promote expansion of natural killer (NK) cells are associated with clinical amelioration of disease in the context of multiple...
BACKGROUND AIMS
Certain therapies (e.g., daclizumab) that promote expansion of natural killer (NK) cells are associated with clinical amelioration of disease in the context of multiple sclerosis and associated mouse models. The clinical benefits are putatively attributable to an enhanced capacity of NK cells to kill activated pathogenic T cells. Whether a parallel approach will also be effective in systemic lupus erythematosus (lupus), a multi-organ autoimmune disease driven by aberrant responses of self-reactive T and B cells, is unclear.
METHODS
In the present study, the authors assess the therapeutic impact of IL-2- and IL-15-based strategies for expanding NK cells on measures of lupus-like disease in a mouse model.
RESULTS
Unexpectedly, cytokine-mediated expansion of cytotoxic lymphocytes aggravated immunological measures of lupus-like disease. Depletion studies revealed that the negative effects of these cytokine-based regimens can largely be attributed to expansion of CD8 T cells rather than NK cells.
CONCLUSIONS
These results provoke caution in the use of cytokine-based therapeutics to treat co-morbid cancers in patients with lupus and highlight the need for new methods to selectively expand NK cells to further assess their clinical value in autoimmune disease.
Topics: Animals; CD8-Positive T-Lymphocytes; Humans; Immunomodulation; Interleukin-15; Interleukin-2; Killer Cells, Natural; Lupus Erythematosus, Systemic; Lymphocyte Activation; Male; Mice
PubMed: 33092988
DOI: 10.1016/j.jcyt.2020.09.003 -
Experimental and Clinical... Aug 2019Immunosuppressive therapy in kidney transplant recipients with hepatitis B virus infection may increase the risk of disease progression. Here, we compared outcomes of... (Comparative Study)
Comparative Study
OBJECTIVES
Immunosuppressive therapy in kidney transplant recipients with hepatitis B virus infection may increase the risk of disease progression. Here, we compared outcomes of depleting (antithymocyte globulin/alemtuzumab) versus nondepleting (basiliximab/daclizumab) antibody induction in kidney transplant recipients at different serologic phases of hepatitis B virus infection.
MATERIALS AND METHODS
We used the Organ Procurement and Transplantation Network/United Network for Organ Sharing database to identify adult kidney transplant recipients at different serologic phases of hepatitis B virus infection (transplants received from 2001-2011 after patients received perioperative induction with discharge on calcineurin inhibitors/mycophenolate mofetil with/without steroids). We used a Cox model to compare outcomes among patient groups.
RESULTS
Median follow-up was 50.7 months (range, 28.6 to 82.6 mo). Serologic phase for the 7681 study patients were as follows: 1098 at HBsAg+/anti-HBc- (depleting = 652, nondepleting = 446), 446 at HBsAg+/anti-HBc+ (depleting = 250, nondepleting = 216), and 6117 at HBsAg-/anti-HBc+ (depleting = 3562, nondepleting = 2555) (where anti-HBc denotes hepatitis B core antibody, HBsAg denotes hepatitis B surface antigen, and +/- denote positive/negative). When we compared those with depleting versus nondepleting agents, hazard ratios (95% confidence intervals) for adjusted overall graft, death-censored graft, and patient survival were 0.97 (0.78-1.26; P = .86), 1.20 (0.83-1.60; P = .44), and 0.92 (0.66-1.30; P = .51) in the HBsAg+/anti-HBc-; 0.81 (0.55-1.18; P = .27), 0.59 (0.32-1.12; P = .11), and 0.95 (0.60-1.49; P = .83) in the HBsAg+/anti-HBc+; and 0.96 (0.86-1.05; P = .37), 0.95 (0.60-1.49; P = .97), and 0.92 (0.80-1.05; P = 0.22) in the HBsAg-/anti-HBc+ groups.
CONCLUSIONS
Our study did not show adverse graft and patient outcomes associated with depleting versus nondepleting antibody induction in kidney transplant recipients at different phases of hepatitis B virus infection. This supports the selection and use of induction agents based on immunologic risk in such patients.
Topics: Adult; Alemtuzumab; Antilymphocyte Serum; Basiliximab; Clinical Decision-Making; Daclizumab; Databases, Factual; Disease Progression; Drug Therapy, Combination; Female; Graft Rejection; Graft Survival; Hepatitis B; Hepatitis B Antibodies; Hepatitis B Surface Antigens; Hepatitis B virus; Humans; Immunocompromised Host; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Retrospective Studies; Risk Assessment; Risk Factors; Time Factors; Treatment Outcome; Young Adult
PubMed: 30066624
DOI: 10.6002/ect.2017.0286 -
BMJ Neurology Open 2021Daclizumab is an anti-CD25 monoclonal antibody developed for the treatment of relapsing remitting multiple sclerosis, which was withdrawn worldwide in March 2018, due to...
BACKGROUND
Daclizumab is an anti-CD25 monoclonal antibody developed for the treatment of relapsing remitting multiple sclerosis, which was withdrawn worldwide in March 2018, due to emerging serious immune-mediated systemic andcentral nervous system adverse events. We report a case of anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis occurring 14 weeks after stopping daclizumab, which responded to the proteasome inhibitor bortezomib.
METHODS
Following lack of effective clinical response to first line (corticosteroid, plasma exchange, intravenous immunoglobulin) and second line (rituximab) treatments, bortezomib therapy was commenced. The patient received six cycles of bortezomib treatment.
RESULTS
Clinical improvement was noted 4 weeks after the first of six cycles of bortezomib and the patient experienced sustained clinical improvement.
CONCLUSION
Our case provides further class IV evidence of the use of bortezomib therapy for treatment refractory anti-NMDAR encephalitis.
PubMed: 34079936
DOI: 10.1136/bmjno-2020-000096 -
Advances in Therapy Jul 2016Cutaneous adverse events (AEs) have been observed in clinical studies of daclizumab high-yield process (HYP) in relapsing-remitting multiple sclerosis (RRMS). Here, we... (Randomized Controlled Trial)
Randomized Controlled Trial
Cutaneous Adverse Events in the Randomized, Double-Blind, Active-Comparator DECIDE Study of Daclizumab High-Yield Process Versus Intramuscular Interferon Beta-1a in Relapsing-Remitting Multiple Sclerosis.
INTRODUCTION
Cutaneous adverse events (AEs) have been observed in clinical studies of daclizumab high-yield process (HYP) in relapsing-remitting multiple sclerosis (RRMS). Here, we report cutaneous AEs observed in the randomized, double-blind, active-comparator DECIDE study (ClinicalTrials.gov identifier, NCT01064401).
METHODS
DECIDE was a randomized, double-blind, active-controlled phase 3 study of daclizumab HYP 150 mg subcutaneous every 4 weeks versus interferon (IFN) beta-1a 30 mcg intramuscular (IM) once weekly in RRMS. Treatment-emergent AEs were classified and recorded by investigators. Investigators also assessed the severity of each AE, and whether it met the criteria for a serious AE. Cutaneous AEs were defined as AEs coded to the Medical Dictionary for Regulatory Activities System Organ Class of skin and subcutaneous tissue disorders. The incidence, severity, onset, resolution, and management of AEs were analyzed by treatment group.
RESULTS
Cutaneous AEs were reported in 37% of daclizumab HYP-treated patients and 19% of IFN beta-1a-treated patients. The most common investigator-reported cutaneous AEs with daclizumab HYP were rash (7%) and eczema (4%). Most patients with cutaneous AEs remained on treatment (daclizumab HYP, 81%; IM IFN beta-1a, 90%) and had events that were mild or moderate (94% and 98%) and subsequently resolved (78% and 82%). Most patients with cutaneous AEs did not require treatment with corticosteroids or were treated with topical corticosteroids (daclizumab HYP, 73%; IM IFN beta-1a, 81%). Serious cutaneous AEs were reported in 14 (2%) daclizumab HYP patients and one (<1%) IM IFN beta-1a patient.
CONCLUSION
There was an increased risk of cutaneous AEs with daclizumab HYP. While physicians should be aware of the potential for serious cutaneous AEs, the typical cutaneous AEs were mild-to-moderate in severity, manageable, and resolved over time.
FUNDING
Biogen and AbbVie Biotherapeutics Inc.
TRIAL REGISTRATION
ClinicalTrials.gov identifier, NCT01064401.
Topics: Adult; Antibodies, Monoclonal, Humanized; Daclizumab; Double-Blind Method; Female; Humans; Immunoglobulin G; Incidence; Interferon beta-1a; Male; Middle Aged; Multiple Sclerosis, Relapsing-Remitting; Severity of Illness Index; Skin Diseases; Treatment Outcome
PubMed: 27251051
DOI: 10.1007/s12325-016-0353-2 -
BMC Bioinformatics Dec 2019Multiple Sclerosis (MS) is an immune-mediated inflammatory disease of the Central Nervous System (CNS) which damages the myelin sheath enveloping nerve cells thus...
BACKGROUND
Multiple Sclerosis (MS) is an immune-mediated inflammatory disease of the Central Nervous System (CNS) which damages the myelin sheath enveloping nerve cells thus causing severe physical disability in patients. Relapsing Remitting Multiple Sclerosis (RRMS) is one of the most common form of MS in adults and is characterized by a series of neurologic symptoms, followed by periods of remission. Recently, many treatments were proposed and studied to contrast the RRMS progression. Among these drugs, daclizumab (commercial name Zinbryta), an antibody tailored against the Interleukin-2 receptor of T cells, exhibited promising results, but its efficacy was accompanied by an increased frequency of serious adverse events. Manifested side effects consisted of infections, encephalitis, and liver damages. Therefore daclizumab has been withdrawn from the market worldwide. Another interesting case of RRMS regards its progression in pregnant women where a smaller incidence of relapses until the delivery has been observed.
RESULTS
In this paper we propose a new methodology for studying RRMS, which we implemented in GreatSPN, a state-of-the-art open-source suite for modelling and analyzing complex systems through the Petri Net (PN) formalism. This methodology exploits: (a) an extended Colored PN formalism to provide a compact graphical description of the system and to automatically derive a set of ODEs encoding the system dynamics and (b) the Latin Hypercube Sampling with PRCC index to calibrate ODE parameters for reproducing the real behaviours in healthy and MS subjects.To show the effectiveness of such methodology a model of RRMS has been constructed and studied. Two different scenarios of RRMS were thus considered. In the former scenario the effect of the daclizumab administration is investigated, while in the latter one RRMS was studied in pregnant women.
CONCLUSIONS
We propose a new computational methodology to study RRMS disease. Moreover, we show that model generated and calibrated according to this methodology is able to reproduce the expected behaviours.
Topics: Computational Biology; Computer Simulation; Disease Progression; Female; Humans; Immunosuppressive Agents; Multiple Sclerosis, Relapsing-Remitting; Pregnancy; Recurrence
PubMed: 31822261
DOI: 10.1186/s12859-019-3196-4 -
Scientific Reports Nov 2021Small antibody mimetics that contain high-affinity target-binding peptides can be lower cost alternatives to monoclonal antibodies (mAbs). We have recently developed a...
Small antibody mimetics that contain high-affinity target-binding peptides can be lower cost alternatives to monoclonal antibodies (mAbs). We have recently developed a method to create small antibody mimetics called FLuctuation-regulated Affinity Proteins (FLAPs), which consist of a small protein scaffold with a structurally immobilized target-binding peptide. In this study, to further develop this method, we established a novel screening system for FLAPs called monoclonal antibody-guided peptide identification and engineering (MAGPIE), in which a mAb guides selection in two manners. First, antibody-guided design allows construction of a peptide library that is relatively small in size, but sufficient to identify high-affinity binders in a single selection round. Second, in antibody-guided screening, the fluorescently labeled mAb is used to select mammalian cells that display FLAP candidates with high affinity for the target using fluorescence-activated cell sorting. We demonstrate the reliability and efficacy of MAGPIE using daclizumab, a mAb against human interleukin-2 receptor alpha chain (CD25). Three FLAPs identified by MAGPIE bound CD25 with dissociation constants of approximately 30 nM as measured by biolayer interferometry without undergoing affinity maturation. MAGPIE can be broadly adapted to any mAb to develop small antibody mimetics.
Topics: Amino Acid Sequence; Animals; Antibodies, Monoclonal; Antibody Affinity; Cell Line; Cell Line, Tumor; Cell Surface Display Techniques; Flow Cytometry; HEK293 Cells; HeLa Cells; Humans; Interleukin-2 Receptor alpha Subunit; K562 Cells; Mammals; Peptide Library; Protein Binding
PubMed: 34764369
DOI: 10.1038/s41598-021-01603-w -
Clinical Transplantation Dec 2020Older (≥65) KT recipients differ from their younger counterparts in their immune response to immunosuppression (IS) and may have a different risk of malignancy after...
BACKGROUND
Older (≥65) KT recipients differ from their younger counterparts in their immune response to immunosuppression (IS) and may have a different risk of malignancy after receiving induction.
METHODS
We identified 66 700 adult KT recipients treated with anti-thymocyte globulin (ATG) (n = 40 443) or interleukin-2 receptor antagonist (IL-2RA) (n = 26 327) induction (1/1/1999-12/31/2014) using USRDS/Medicare data. We estimated the risk of first-diagnosed post-KT malignancy associated with induction (ATG vs. IL-2RA) using Cox proportional hazard models. We then tested whether these risks differed between older and younger recipients (Wald test for interaction). Models incorporated inverse probability of treatment weights to adjust for confounders.
RESULTS
The 3-year cumulative incidences of any diagnosed malignancy were 11.5%. ATG was associated with a higher malignancy risk (HR = 1.12, 95%CI:1.06-1.18). This association differed (p = 0.04) between younger (HR = 1.12, 95%CI:1.06-1.18) and older recipients (HR = 1.03, 95%CI:0.96-1.09). ATG was also associated with higher risk of skin (HR = 1.18, 95%CI:1.08-1.29), lung (HR = 1.24, 95%CI:1.05-1.47), and ovary malignancies (HR = 1.94, 95%CI:1.08-3.48). However, only the association of ATG with post-KT skin malignancy differed (p = 0.01) between younger (HR = 1.18; 95%CI:1.08-1.29) and older (HR = 1.01; 95%CI:0.93-1.09) recipients.
CONCLUSIONS
Compared with IL-2RA induction, ATG was associated with elevated post-KT malignancy risk but only among younger recipients. Transplant centers may need to tailor induction IS for younger recipients to mitigate malignancy risk.
Topics: Adult; Aged; Antilymphocyte Serum; Female; Graft Rejection; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Kidney Transplantation; Medicare; Neoplasms; Prospective Studies; United States
PubMed: 33048385
DOI: 10.1111/ctr.14121