Thalidomide is effective in the treatment of newly diagnosed and relapsed/refractory multiple myeloma (MM). However, the role of thalidomide in the post-autologous stem cell transplantation (ASCT) ...context remains unclear. This study assessed whether the addition of thalidomide consolidation following ASCT would improve the durability of responses achieved and overall survival.
Between January 2002 and March 2005, 269 patients with newly diagnosed MM who achieved disease stabilization or better with conventional induction chemotherapy received a single high-dose melphalan conditioned ASCT. Post-ASCT, 129 patients were randomly assigned to receive indefinite prednisolone maintenance therapy (control group) and 114 to receive the same in addition to 12 months of thalidomide consolidation (thalidomide group). The primary study end points were progression-free survival (PFS) and overall survival (OS). The secondary end point was tolerability.
After a median follow-up of 3 years, the postrandomization 3-year PFS rates were 42% and 23% (P < .001; hazard ratio HR, 0.5; 95% CI, 0.35 to 0.71) and the OS rates were 86% and 75% (P = .004; HR, 0.41; 95% CI, 0.22 to 0.76) in the thalidomide and control groups, respectively. There was no difference in survival between groups 12 months after disease progression (79% v 77%; P = .237). Neurological toxicities were more common in the thalidomide arm but there were no differences between arms for thromboembolic events.
Consolidation therapy with 12 months of thalidomide combined with prednisolone prolongs survival when used after a single high-dose therapy supported ASCT in patients with newly diagnosed MM. Furthermore, thalidomide consolidation therapy did not adversely impact on survival in the subsequent salvage setting.
Human induced pluripotent stem cell-derived cardiomyocytes (hiPS-CMs) are capable of detecting drug-induced clinical arrhythmia, Torsade de Pointes (TdP), and QT prolongation. Efforts herein employ a ...broad set of structurally diverse drugs to optimize the predictive algorithm for applications in discovery toxicology and cardiac safety screening. The changes in the beat rhythm and rate of a confluent monolayer of hiPS-CMs by 88 marketed and 30 internal discovery compounds were detected with real-time cellular impedance measurement and quantified by measures of arrhythmic beating (IB20, lowest concentration inducing ≥ 20% arrhythmic irregular, atypical beats in 3 consecutive 20-s sweeps, and predicted proarrhythmic score PPS-IB20) or changes in beat rate (BR20, the lowest concentration inducing a reduction in beat rate of ≥ 20% at 3 consecutive sweeps compared with the time-matched vehicle control group, and PPS-BR20). Drug-induced arrhythmic beats and reductions in beat rates are predictive of clinical arrhythmia and QT prolongation, respectively. A threshold of ≤ 10 μM for class determination results in 82% in vitro-in vivo concordance for TdP prediction and 91% sensitivity for non-TdP arrhythmia detection, or 83% and 91% if clinically efficacious plasma (effective serum therapeutic concentration C eff) values are incorporated. This human cardiomyocyte arrhythmic risk (hCAR) model provides greater predictivity for torsadogenicity in humans compared with either human ether-a-go-go-related gene (hERG) inhibition (75%) or QT prolongation (81%). The concordance of beat rate reductions to predict clinical QT prolongation is 86%, or 87% when C eff is considered, which is greater than a hERG signal (80%). Further, arrhythmic beats resulting from cytotoxicity were identified by a distinct arrhythmic beating pattern, which occurred after the onset of cytolethality. This hCAR assay showed increased performance over existing preclinical tools in predicting clinical QT prolongation, arrhythmia, and TdP. Thus, hiPS-CMs are a relevant cell system to improve evaluating cardiac safety liabilities of drug candidates.
Doxorubicin is widely used in the treatment of different cancers, and its side effects can be severe in many tissues, including the intestines. Symptoms such as diarrhoea and abdominal pain caused by ...intestinal inflammation lead to the interruption of chemotherapy. Nevertheless, the molecular mechanisms associated with doxorubicin intestinal toxicity have been poorly explored. This study aims to investigate such mechanisms by exposing 3D small intestine and colon organoids to doxorubicin and to evaluate transcriptomic responses in relation to viability and apoptosis as physiological endpoints. The in vitro concentrations and dosing regimens of doxorubicin were selected based on physiologically based pharmacokinetic model simulations of treatment regimens recommended for cancer patients. Cytotoxicity and cell morphology were evaluated as well as gene expression and biological pathways affected by doxorubicin. In both types of organoids, cell cycle, the p53 signalling pathway, and oxidative stress were the most affected pathways. However, significant differences between colon and SI organoids were evident, particularly in essential metabolic pathways. Short time-series expression miner was used to further explore temporal changes in gene profiles, which identified distinct tissue responses. Finally, in silico proteomics revealed important proteins involved in doxorubicin metabolism and cellular processes that were in line with the transcriptomic responses, including cell cycle and senescence, transport of molecules, and mitochondria impairment. This study provides new insight into doxorubicin-induced effects on the gene expression levels in the intestines. Currently, we are exploring the potential use of these data in establishing quantitative systems toxicology models for the prediction of drug-induced gastrointestinal toxicity.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Late-onset combined immunodeficiency (LOCID), considered now a subset of common variable immunodeficiency (CVID) disorders, is characterized by a predominantly T-cell immune defect. LOCID has a ...distinct phenotype from CVID with a greater risk of lymphoproliferative complications. As compared to the CVID cohort, LOCID patients also have increased rates of splenomegaly and granulomatous disease. We report a case of central nervous system (CNS) T-cell lymphoma in a 67-year-old male as the presenting manifestation of LOCID. The patient achieved a complete response to therapy after 4 cycles of MATRix (methotrexate, cytarabine, and thiotepa) and 2 cycles of ICE (etoposide, carboplatin, and ifosfamide) chemotherapy followed by CNS-directed autologous stem cell transplantation. Intravenous immunoglobulin replacement was commenced to address the underlying immunodeficiency. Pulmonary lesions consistent with a diagnosis of granulomatous and lymphocytic interstitial lung disease (GLILD) were identified as a second noninfectious complication of LOCID. The pulmonary lesions resolved after chemotherapy and immunoglobulin replacement. The patient remains well with no evidence of disease recurrence now more than 18 months after completion of therapy. This is the first reported case of T-cell lymphoma in an adult patient with LOCID. Further study is needed to elucidate the mechanisms of transformation of B- or T-cells to lymphoproliferation in primary immunodeficiency patients as well as research to inform evidence-based therapeutic strategies for this challenging cohort of patients.
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FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UL, UM, UPUK
Current in vitro approaches to cardiac safety testing typically focus on mechanistic ion channel testing to predict in vivo proarrhythmic potential. Outside of the Comprehensive in vitro ...Proarrhythmia Assay (CiPA) initiative, structural and functional cardiotoxicity related to chronic dosing effects are of great concern as these effects can impact compound attrition. Development and implementation of an in vitro cardiotoxicity screening platform that effectively identifies these liabilities early in the discovery process should reduce costly attrition and decrease preclinical development time. Impedence platforms have the potential to accurately identify structural and functional cardiotoxicity and have sufficient throughput to be included in a multi-parametric optimization approach. Human induced pluripotent stem cell cardiomyocytes (hIPSC-CMs) have demonstrated utility in cardiac safety and toxicity screening. The work described here leverages these advantages to assess the predictive value of data generated by two impedance platforms. The response of hIPSC-CMs to compounds with known or predicted cardiac functional or structural toxicity was determined. The compounds elicited cardiac activities and/or effects on “macro” impedance often associated with overt structural or cellular toxicity, detachment, or hypertrophy. These assays correctly predicted in vivo cardiotox findings for 81% of the compounds tested and did not identify false positives. In addition, internal or literature Cmax values from in vivo studies correlated within 4 fold of the in vitro observations. The work presented here demonstrates the predictive power of impedance platforms with hIPSC-CMs and provides a means toward accelerating lead candidate selection by assessing preclinical cardiac safety earlier in the drug discovery process.
•Assessment of the impedance platform to predict both chronic and acute in vivo cardiotoxicity.•Cardiac functional and structural cardiotoxicity was evaluated.•The impedance assay predicted >80% of known in vivo cardiotoxicity.•Data supports utilization of this assay for early drug discovery cardiac safety profiling.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPUK, ZRSKP
Gefitinib is a tyrosine kinase inhibitor (TKI) that selectively inhibits the epidermal growth factor receptor (EGFR), hampering cell growth and proliferation. Due to its action, gefitinib has been ...used in the treatment of cancers that present abnormally increased expression of EGFR. However, side effects from gefitinib therapy may occur, among which diarrhoea is most common, that can lead to interruption of the planned therapy in the more severe cases. The mechanisms underlying intestinal toxicity induced by gefitinib are not well understood. Therefore, this study aims at providing insight into these mechanisms based on transcriptomic responses induced in vitro. A 3D culture of healthy human colon and small intestine (SI) organoids was exposed to 0.1, 1, 10 and 30 µM of gefitinib, for a maximum of three days. These drug concentrations were selected using physiologically-based pharmacokinetic simulation considering patient dosing regimens. Samples were used for the analysis of viability and caspase 3/7 activation, image-based analysis of structural changes, as well as RNA isolation and sequencing via high-throughput techniques. Differential gene expression analysis showed that gefitinib perturbed signal transduction pathways, apoptosis, cell cycle, FOXO-mediated transcription, p53 signalling pathway, and metabolic pathways. Remarkably, opposite expression patterns of genes associated with metabolism of lipids and cholesterol biosynthesis were observed in colon versus SI organoids in response to gefitinib. These differences in the organoids' responses could be linked to increased activated protein kinase (AMPK) activity in colon, which can influence the sensitivity of the colon to the drug. Therefore, this study sheds light on how gefitinib induces toxicity in intestinal organoids and provides an avenue towards the development of a potential tool for drug screening and development.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
ABSTRACT
Introduction: Acquired and hereditary amyloidosis can cause peripheral neuropathy, but the mechanisms by which this occurs have not been established. Threshold tracking techniques allow in ...vivo assessment of the properties of the axonal membrane and may shed light on pathogenetic mechanisms underlying neuropathic disorders. Methods: We studied 10 subjects with primary amyloidosis using conventional nerve conduction studies and quantitative sensory, autonomic, and axonal excitability testing of median motor and sensory fibers. Results: As expected, subjects with amyloidosis had evidence of small‐ and large‐fiber neuropathy on conventional testing. There was no significant difference in axonal excitability between subjects and controls apart from the stimulus required to activate sensory fibers. Conclusions: Amyloid‐related neuropathy does not produce a change in membrane potential as either a primary or secondary event. This suggests that ischemia and axonal compression are unlikely mechanisms for the neuropathy. Muscle Nerve 51: 443–445, 2015
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Objective(s)To describe the spectrum of neurological presentations of chloromas.MethodTwo case reports.ResultsA 72 year-old female presented with a right-sided cavernous sinus syndrome on a ...background of a myeloproliferative disorder. MRI brain demonstrated a FLAIR hyperintense lesion centred on the right cavernous sinus. Cerebrospinal fluid (CSF) was acellular with negative cytology and flow cytometry. FDG PET/CT demonstrated diffuse marrow hypermetabolism, hepatosplenomegaly and focal FDG uptake in the cavernous sinus and a remote paraspinal region, suspicious for chloromas. The patient developed pancytopaenia with blasts, and tumour lysis syndrome (TLS) consistent with transformation to acute myeloid leukaemia (AML). The patient was given pulse methylprednisolone, hydroxyurea and external beam radiotherapy to the cavernous sinus lesion with symptomatic improvement. The second case is of a 76 year-old male who presented with progressive lower limb weakness with acute faecal incontinence. This was on a background of AML treated with induction STIMULus (cytarabine and thioguanine) followed by remission confirmed on a recent bone marrow biopsy. CSF showed a marked lymphocytosis with many undifferentiated cells, and flow cytometry was consistent with AML. An MRI whole spine demonstrated a solitary avidly enhancing intramedullary T11 cord lesion with associated oedema. In the context of AML and CSF pathology this was thought to reflect an intramedullary chloroma. The patient was treated with external beam radiotherapy, pulse intravenous methylprednisolone and intrathecal chemotherapy with symptomatic improvement.ConclusionThese two cases demonstrate the diversity of neurological clinical presentations of chloromas, an unusual collection of leukaemic cells exerting mass-like effect.
Abstract
We have built a quantitative systems toxicology modeling framework focused on the early prediction of oncotherapeutic‐induced clinical intestinal adverse effects. The model describes stem ...and progenitor cell dynamics in the small intestinal epithelium and integrates heterogeneous epithelial‐related processes, such as transcriptional profiles, citrulline kinetics, and probability of diarrhea. We fitted a mouse‐specific version of the model to quantify doxorubicin and 5‐fluorouracil (5‐FU)‐induced toxicity, which included pharmacokinetics and 5‐FU metabolism and assumed that both drugs led to cell cycle arrest and apoptosis in stem cells and proliferative progenitors. The model successfully recapitulated observations in mice regarding dose‐dependent disruption of proliferation which could lead to villus shortening, decrease of circulating citrulline, increased diarrhea risk, and transcriptional induction of the p53 pathway. Using a human‐specific epithelial model, we translated the cytotoxic activity of doxorubicin and 5‐FU quantified in mice into human intestinal injury and predicted with accuracy clinical diarrhea incidence. However, for gefitinib, a specific‐molecularly targeted therapy, the mice failed to reproduce epithelial toxicity at exposures much higher than those associated with clinical diarrhea. This indicates that, regardless of the translational modeling approach, preclinical experimental settings have to be suitable to quantify drug‐induced clinical toxicity with precision at the structural scale of the model. Our work demonstrates the usefulness of translational models at early stages of the drug development pipeline to predict clinical toxicity and highlights the importance of understanding cross‐settings differences in toxicity when building these approaches.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Viral replication places oncolytic viruses (OVs) in a unique niche in the field of drug pharmacokinetics (PK) as their self-amplification obscures exposure-response relationships. Moreover, standard ...bioanalytical techniques are unable to distinguish the input from replicated drug products. Here, we combine two novel approaches to characterize PK and biodistribution (BD) after systemic administration of vesicular stomatitis virus pseudotyped with lymphocytic choriomeningitis virus glycoprotein (VSV-GP) in healthy mice. First: to decouple input drug PK/BD versus replication PK/BD, we developed and fully characterized a replication-incompetent tool virus that retained all other critical attributes of the drug. We used this approach to quantify replication in blood and tissues and to determine its impact on PK and BD. Second: to discriminate the genomic and antigenomic viral RNA strands contributing to replication dynamics in tissues, we developed an in situ hybridization method using strand-specific probes and assessed their spatiotemporal distribution in tissues. This latter approach demonstrated that distribution, transcription, and replication localized to tissue-resident macrophages, indicating their role in PK and BD. Ultimately, our study results in a refined PK/BD profile for a replicating OV, new proposed PK parameters, and deeper understanding of OV PK/BD using unique approaches that could be applied to other replicating vectors.
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The authors demonstrate novel approaches for assessing oncolytic virus pharmacokinetics and biodistribution (PK/BD) in mice, differentiating input virus from replicated virus, and tracking spatiotemporal dynamics of replication in tissues. A high-resolution pharmacokinetic profile for a replicating vector in non-tumor tissues and tissue-resident macrophages is revealed.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPUK, ZAGLJ, ZRSKP
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