Purpose
First‐in‐class (FIC) drugs with novel modes of action pose concerns regarding important postmarketing safety issues. The purpose of this study was to analyze the factors related to the ...occurrence of postmarketing safety‐related regulatory actions (PSRAs) for drugs approved in the United States (US), with a focus on FIC drugs.
Methods
New molecular entities and new therapeutic biologics approved in the United States between 1 January 2003 and 31 December 2013 were included in the analysis. Important drug‐specific PSRAs were defined as market withdrawal or the addition of new black box warnings or warnings due to adverse drug reactions. The relationship between baseline characteristics and the occurrence of important drug‐specific PSRAs was investigated using a multivariate logistic regression model. We also defined the event as the first important PSRA and estimated the time‐to‐event for each factor.
Results
ATC category L (antineoplastic and immunomodulating agents) and FIC drug classification were shown to be statistically significant factors, with odds ratios of 2.15 (95% CI: 1.12‐4.11; P = 0.0203) and 1.87 (95% CI: 1.06‐3.31; P = 0.0309), respectively. ATC category L and FIC drugs were also significant factors for time to occurrence of the first event.
Conclusion
FIC designation and ATC category L were identified as factors related to important drug‐specific PSRAs. These factors were also associated with the time to occurrence of the first important drug‐specific PSRAs.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Objective
Hypertrophic pachymeningitis (HP) related to anti-neutrophil cytoplasmic antibody (ANCA) is the most frequently seen immune-mediated HP. We investigated cerebrospinal fluid (CSF) biomarkers ...related to the pathogenesis of ANCA-related HP (ANCA-HP).
Methods
The levels of B cell activation factor of the tumor necrosis factor family (BAFF), a proliferation-inducing ligand (APRIL), and transforming growth factor beta 1 (TGF-β1) in the CSF were compared between patients with ANCA-HP (
n
= 12), other types of immune-mediated HP (other HP;
n
= 12), multiple sclerosis (MS;
n
= 14), and non-inflammatory neurological disorders (NIND;
n
= 10). In addition, we evaluated whether ANCA would be detected in CSF.
Results
CSF levels of BAFF, APRIL, and TGF-β1 were significantly increased in ANCA-HP and other HP. In particular, BAFF and APRIL levels were significantly correlated with the IgG index in ANCA-HP. In other HP, BAFF and APRIL levels were significantly correlated with cell counts and protein levels in CSF. Of 12 patients with ANCA-HP, the CSF of 7 patients (58%) tested positive for myeloperoxidase (MPO)- or proteinase 3 (PR3)-ANCA, while none of the CSF samples from other HP, MS, or NIND patients tested positive.
Conclusion
The levels of BAFF, APRIL, and TGF-β1 may serve as useful CSF biomarkers for assessing the disease activity of immune-mediated HP. Moreover, BAFF and APRIL in the CSF may be implicated in the pathogenesis of ANCA-HP via promoting autoreactive B cells, while detecting MPO- or PR3-ANCA in the CSF may be found in some patients with ANCA-HP.
Key Points
•
CSF BAFF, APRIL, and TGF-β1 levels increase significantly in immune-mediated HP.
•
CSF BAFF and APRIL levels are significantly correlated with IgG index in ANCA-HP.
•
Detection of MPO- or PR3-ANCA in the CSF is found in some patients with ANCA-HP.
•
BAFF, APRIL, and ANCA in the CSF may be implicated in the pathogenesis of ANCA-HP.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
We encountered a 27-year-old Japanese woman with sensorineural deafness progressing to motor and sensory neuropathy. At 16 years old, she had developed weakness in her lower extremities and hearing ...impairment, which gradually deteriorated. At 22 years old, combined audiological, electrophysiological, and radiological examination results were consistent with auditory neuropathy spectrum disorder (ANSD). Genetic analyses identified a previously reported missense variant in the ATP1A1 gene (NM_000701.8:c.1799C>G, p.Pro600Arg). Although sensorineural deafness has been reported as a clinical manifestation of ATP1A1-related disorders, our case suggested that ANSD may underlie the pathogenesis of deafness in ATP1A1-related disorders. This case report broadens the genotype-phenotype spectrum of ATP1A1-related disorders.
The current standard diagnostic approach for progressive multifocal leukoencephalopathy (PML) is to perform a DNA test to identify the presence of the JC virus in cerebrospinal fluid (CSF). A ...32-year-old woman with a 5-year history of systemic lupus erythematosus developed right hemiplegia and motor aphasia. MRI revealed a large white matter lesion in the left frontal lobe. JC virus DNA was undetectable in the CSF, but a brain biopsy showed typical histopathology and a high DNA load of the JC virus. The patient was treated with mefloquine and mirtazapine, and is currently alive at 24 months after onset. An early brain biopsy may therefore be important for making a timely diagnosis of PML.
We describe a 24-year-old woman with anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis that developed 3 weeks after normal delivery. She was treated with methylprednisolone, intravenous ...immunoglobulin, and plasmapheresis, in addition to teratoma excision. However, her recovery was slow, and dysmnesia and mental juvenility persisted even two years after onset. To date, five patients with postpartum anti-NMDAR encephalitis have been reported. All of those patients showed psychotic symptoms and were suspected of having postpartum psychosis in the early period of the encephalitis. Changes in hormonal factors, modification of immune tolerance, or retrograde infection of the ovary may be contributing factors for postpartum anti-NMDAR encephalitis.
In the revised World Health Organization classification 2016, anaplastic pleomorphic xanthoastrocytoma (PXA) has been newly defined as a variant of the PXA entity. Furthermore, some anaplastic PXA ...were reported to have extremely poor prognosis which showed a type of pediatric glioblastoma (GBM) molecular profile. Recent integrated molecular classification for primary central nervous system tumors proposed some differences between histological and molecular features. Herein, in a genome‐wide molecular analysis, we show an extreme aggressive anaplastic PXA that resulted in a pediatric GBM molecular profile. A full implementation of the molecular approach is the key to predict prognosis and decide the treatment strategy for anaplastic PXA.
This report suggests that anaplastic PXA consists of clinically and biologically distinct multiple entities, and genome‐wide molecular profiling may help to identify them. This new approach will be useful for predicting prognosis and choosing treatment for anaplastic PXA patients.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
•CSF levels of BAFF and APRIL increase in PCNSBL.•CSF levels of BAFF and APRIL could decrease after clinical remission in PCNSBL.•CNS levels of BAFF could vary depending on the therapeutic effect in ...PCNSBL.
We evaluated the cerebrospinal fluid (CSF) levels of the B-cell activating factor of the tumor necrosis factor family (BAFF) and A proliferation-inducing ligand (APRIL) in two cases of primary central nervous system B-cell lymphoma (PCNSBL) before and after treatment. One patient achieved clinical remission, and demonstrated decrease in the CSF levels of both BAFF and APRIL after treatment. Meanwhile, the other patient with insufficient therapeutic response showed increase in the BAFF levels despite decrease in APRIL levels. This report suggests that the combination of BAFF and APRIL levels could be useful in estimating the therapeutic efficacy in treating PCNSBL as reliable CSF markers.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Rotigotine, a non-ergot dopamine receptor agonist, offers potential for continuous dopaminergic stimulation that could avoid the fluctuations observed with traditional treatments. We conducted a ...randomized, double-blind, placebo-controlled trial in Japanese patients with advanced Parkinson’s disease (PD) to investigate the efficacy and safety of rotigotine. Inclusion criteria included the presence of motor complications, such as wearing off, on–off, delayed-on/no-on, any circumstances that could interfere with levodopa dose escalation because of side effects, or declining levodopa efficacy. The enrolled patients received once-daily applications of rotigotine transdermal patches or matched placebo patches. A total of 174 patients were randomly assigned to rotigotine (87 patients) or placebo (87 patients). The full analysis set included 172 patients (86 for the rotigotine group and 86 for the placebo group). The maximum maintenance dose of rotigotine was set at 16 mg/24 h. The changes in unified PD rating scale Part III scores from baseline to the end of the trial were −10.1 ± 9.0 (mean ± standard deviation) in the rotigotine group and −4.4 ± 7.4 in the placebo group (
p
< 0.001). There was a significantly greater reduction in the off-time (
p
= 0.014) in the rotigotine group. Rotigotine was well tolerated, with serious adverse events being reported in only three patients in each group. Rotigotine at doses of up to 16 mg/24 h is efficacious and safe in Japanese patients with advanced PD.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Infant acute lymphoblastic leukemia with lysine (K)‐specific methyltransferase 2A (KMT2A) rearrangements usually has a poor prognosis regardless of the fusion partners of KMT2A. However, the ...prognosis of pediatric acute myeloid leukemia (AML) with KMT2A rearrangements depends on its translocation partners. We herein report the case of a 9‐month‐old boy with a KMT2A‐USP2 fusion, which required diagnosis by whole transcriptome sequencing after the failure of detection of known translocation partners by conventional screening approaches. As this first report of a patient with AML with a KMT2A‐USP2 fusion illustrates, identification of the partners in all patients with KMT2A‐rearranged AML is critical to elucidate the outcomes associated with specific rearrangements and to develop appropriate treatment strategies. Moreover, development of additional methods to detect specific translocation partners of KMT2A and leukemia‐specific targeting drugs is important to improve further the outcomes of KMT2A‐rearranged AML.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
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