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1.
Consensus opinion on diagnosis and management of thrombotic microangiopathy in Australia and New Zealand.
Fox, LC, Cohney, SJ, Kausman, JY, Shortt, J, Hughes, PD, Wood, EM, Isbel, NM, de Malmanche, T, Durkan, A, Hissaria, P, et al
Nephrology (Carlton, Vic.). 2018;(6):507-517
Abstract
Thrombotic microangiopathy (TMA) arises in a variety of clinical circumstances with the potential to cause significant dysfunction of the kidneys, brain, gastrointestinal tract and heart. TMA should be considered in all patients with thrombocytopenia and anaemia, with an immediate request to the haematology laboratory to look for red cell fragments on a blood film. While TMA of any aetiology generally demands prompt treatment, this is especially so in thrombotic thrombocytopenic purpura (TTP) and atypical haemolytic uraemic syndrome (aHUS), where organ failure may be precipitous, irreversible and fatal. In all adults, urgent, empirical plasma exchange (PE) should be started within 4-8 h of presentation for a possible diagnosis of TTP, pending a result for ADAMTS13 activity (a disintegrin and metalloprotease thrombospondin, number 13). A sodium citrate plasma sample should be collected for ADAMTS13 testing prior to any plasma therapy. In children, Shiga toxin-associated haemolytic uraemic syndrome due to infection with Escherichia coli (STEC-HUS) is the commonest cause of TMA, and is managed supportively. If TTP and STEC-HUS have been excluded, a diagnosis of aHUS should be considered, for which treatment is with the monoclonal complement C5 inhibitor, eculizumab. While early confirmation of aHUS is often not possible, except in the minority of patients in whom autoantibodies against factor H are identified, genetic testing ultimately reveals a complement-related mutation in a significant proportion of aHUS cases. The presence of other TMA-associated conditions (e.g. infection, pregnancy/postpartum and malignant hypertension) does not exclude TTP or aHUS as the underlying cause of TMA.
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2.
Novel Approaches for the Management of AL Amyloidosis.
Joseph, NS, Kaufman, JL
Current hematologic malignancy reports. 2018;(3):212-219
Abstract
PURPOSE OF REVIEW Light-chain-associated (AL) amyloidosis is a rare disease with a poor prognosis. However, we have made recent strides in more accurate diagnosis and effective treatment. Here, we discuss the most recent updates and advancements during the past year in the diagnosis, prognostication, and management of AL amyloidosis both in the upfront and relapsed setting. RECENT FINDINGS New imaging modalities, such as cardiac magnetic resonance (CMR) and use of fluorine-labeled radiotracers, are emerging as an important diagnostic tool in conjunction with biomarkers in the diagnosis, prognosis, and monitoring of the effects of therapy. In addition, ongoing evaluation of plasma cell-directed therapeutics, including daratumumab, pomalidomide, and ixazomib, as well as promising targeted novel therapies, such as the monoclonal antibody NEOD001, are in development. In conclusion, incorporating the use of plasma cell-directed therapy and novel agents targeting the amyloid deposits itself hold enormous potential in achieving improved outcomes in AL amyloidosis.
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3.
Baseline metabolic profiles of early rheumatoid arthritis patients achieving sustained drug-free remission after initiating treat-to-target tocilizumab, methotrexate, or the combination: insights from systems biology.
Teitsma, XM, Yang, W, Jacobs, JWG, Pethö-Schramm, A, Borm, MEA, Harms, AC, Hankemeier, T, van Laar, JM, Bijlsma, JWJ, Lafeber, FPJG
Arthritis research & therapy. 2018;(1):230
Abstract
BACKGROUND We previously identified, in newly diagnosed rheumatoid arthritis (RA) patients, networks of co-expressed genes and proteomic biomarkers associated with achieving sustained drug-free remission (sDFR) after treatment with tocilizumab- or methotrexate-based strategies. The aim of this study was to identify, within the same patients, metabolic pathways important for achieving sDFR and to subsequently study the complex interactions between different components of the biological system and how these interactions might affect the therapeutic response in early RA. METHODS Serum samples were analyzed of 60 patients who participated in the U-Act-Early trial (ClinicalTrials.gov number NCT01034137) and initiated treatment with methotrexate, tocilizumab, or the combination and who were thereafter able to achieve sDFR (n = 37); as controls, patients were selected who never achieved a drug-free status (n = 23). Metabolomic measurements were performed using mass spectrometry on oxidative stress, amine, and oxylipin platforms covering various compounds. Partial least square discriminant analyses (PLSDA) were performed to identify, per strategy arm, relevant metabolites of which the biological pathways were studied. In addition, integrative analyses were performed correlating the previously identified transcripts and proteins with the relevant metabolites. RESULTS In the tocilizumab plus methotrexate, tocilizumab, and methotrexate strategy, respectively, 19, 13, and 12 relevant metabolites were found, which were subsequently used for pathway analyses. The most significant pathway in the tocilizumab plus methotrexate strategy was "histidine metabolism" (p < 0.001); in the tocilizumab strategy it was "arachidonic acid metabolism" (p = 0.018); and in the methotrexate strategy it was "arginine and proline metabolism" (p = 0.022). These pathways have treatment-specific drug interactions with metabolites affecting either the signaling of interleukin-6, which is inhibited by tocilizumab, or affecting protein synthesis from amino acids, which is inhibited by methotrexate. CONCLUSION In early RA patients treated-to-target with a tocilizumab- or methotrexate-based strategy, several metabolites were found to be associated with achieving sDFR. In line with our previous observations, by analyzing relevant transcripts and proteins within the same patients, the metabolic profiles were found to be different between the strategy arms. Our metabolic analysis further supports the hypothesis that achieving sDFR is not only dependent on predisposing biomarkers, but also on the specific treatment that has been initiated. TRIAL REGISTRATION ClinicalTrials.gov, NCT01034137 . Registered on January 2010.
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4.
Reslizumab in the treatment of severe eosinophilic asthma: an update.
Walsh, GM
Immunotherapy. 2018;(8):695-698
Abstract
A marked heterogeneity is exhibited by asthma both clinically and at the molecular level with different phenotypes driven by diverse mechanistic pathways that require specifically targeted treatments. Biologics aimed at IL-4/13, IL-5 or IgE are proven or potentially effective treatments for patients with difficult to treat eosinophilic asthma. Importantly, it is now widely accepted that biologic-based therapies give significant clinical improvements in those patient populations where asthma phenotypes are taken into account. Such asthma phenotypes have been identified by reproducible and straightforward discriminatory biomarkers. This short review discusses recent studies of the effectiveness of the anti-IL-5 reslizumab in relation to the use of simple reproducible biomarkers in eosinophilic asthma.
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5.
Pembrolizumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib (KEYNOTE-224): a non-randomised, open-label phase 2 trial.
Zhu, AX, Finn, RS, Edeline, J, Cattan, S, Ogasawara, S, Palmer, D, Verslype, C, Zagonel, V, Fartoux, L, Vogel, A, et al
The Lancet. Oncology. 2018;(7):940-952
Abstract
BACKGROUND Immune checkpoint blockade therapy has shown promising results in patients with advanced hepatocellular carcinoma. We aimed to assess the efficacy and safety of pembrolizumab in this patient population. METHODS KEYNOTE-224 is a non-randomised, multicentre, open-label, phase 2 trial that is set in 47 medical centres and hospitals across ten countries. Eligible patients had pathologically confirmed hepatocellular carcinoma; had previously been treated with sorafenib and were either intolerant to this treatment or showed radiographic progression of their disease after treatment; an Eastern Cooperative Oncology Group performance status of 0-1; adequate organ function, and were Child-Pugh class A. Participants received 200 mg pembrolizumab intravenously every 3 weeks for about 2 years or until disease progression, unacceptable toxicity, patient withdrawal, or investigator decision. The primary endpoint was objective response, defined as the proportion of patients with complete or partial response in all patients who received at least one dose of pembrolizumab, which was radiologically confirmed by use of the Response Evaluation Criteria in Solid Tumors version 1.1 by central review. Safety was also assessed in all treated patients. This trial is ongoing but closed to enrolment and is registered with ClinicalTrials.gov number NCT02702414. FINDINGS Between June 7, 2016, and Feb 9, 2017, we screened 169 patients with advanced hepatocellular carcinoma, of whom 104 eligible patients were enrolled and treated. As of data cutoff on Feb 13, 2018, 17 (16%) patients were still receiving pembrolizumab. We recorded an objective response in 18 (17%; 95% CI 11-26) of 104 patients. The best overall responses were one (1%) complete and 17 (16%) partial responses; meanwhile, 46 (44%) patients had stable disease, 34 (33%) had progressive disease, and six (6%) patients who did not have a post-baseline assessment on the cutoff date were considered not to be assessable. Treatment-related adverse events occurred in 76 (73%) of 104 patients, which were serious in 16 (15%) patients. Grade 3 treatment-related events were reported in 25 (24%) of the 104 patients; the most common were increased aspartate aminotransferase concentration in seven (7%) patients, increased alanine aminotransferase concentration in four (4%) patients, and fatigue in four (4%) patients. One (1%) grade 4 treatment-related event of hyperbilirubinaemia occurred. One death associated with ulcerative oesophagitis was attributed to treatment. Immune-mediated hepatitis occurred in three (3%) patients, but there were no reported cases of viral flares. INTERPRETATION Pembrolizumab was effective and tolerable in patients with advanced hepatocellular carcinoma who had previously been treated with sorafenib. These results indicate that pembrolizumab might be a treatment option for these patients. This drug is undergoing further assessment in two phase 3, randomised trials as a second-line treatment in patients with hepatocellular carcinoma. FUNDING Merck & Co, Inc.
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6.
Harnessing the Immune System in Pancreatic Cancer.
Das, S, Berlin, J, Cardin, D
Current treatment options in oncology. 2018;(10):48
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Abstract
Managing patients with metastatic pancreatic adenocarcinoma (mPDA) is a challenging proposition for any treating oncologist. Although the potency of first-line therapies has improved with the approvals of FOLFIRINOX and gemcitabine plus nab-paclitaxel, many patients are unable to derive significant benefit from later lines of therapy upon progression. Enrollment on clinical trials remains among the best options for patients with mPDA in all lines of therapy. At our institution, we routinely check for microsatellite instability (MSI-H) and perform next-generation sequencing (NGS) at the time of diagnosis in all good performance status mPDA patients. Although MSI-H status is only found in 1% of patients with mPDA, given pembrolizumab's tissue-agnostic approval for MSI-H tumors in later-line settings, it is a viable option when deciding on subsequent lines of therapy. Any use of immune therapy in mPDA is investigational outside the MSI-H setting. NGS can identify BRCA or other DNA damage response (DDR) defects in patients which can predict sensitivity to platinum-based therapies and influence choice of both initial and later lines of therapy. It can also identify rare actionable genomic alterations such as HER2 (2%) and TRK fusions (0.1%) and offer patients the option of enrollment on clinical trials with agents targeting these or other identified alterations. We believe enrolling mPDA patients on clinical trials with immune-modulating agents is critical to determine if there are other patient subsets, outside of the MSI-H setting, who would benefit from these approaches. Immunotherapy's general tolerability and potential to generate durable responses make it particularly appealing for mPDA patients. Although single-modality immunotherapy such as checkpoint inhibitors or vaccines have not demonstrated efficacy in this disease, combinatorial strategies targeting unique aspects of PDA including the tumor microenvironment and desmoplastic stroma have shown preclinical or early-phase success. Validating these treatments with later-phase prospective studies is essential to making immunotherapy a routine component of the treatment armamentarium for mPDA patients.
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Ixekizumab treatment shows a neutral impact on cardiovascular parameters in patients with moderate-to-severe plaque psoriasis: Results from UNCOVER-1, UNCOVER-2, and UNCOVER-3.
Egeberg, A, Wu, JJ, Korman, N, Solomon, JA, Goldblum, O, Zhao, F, Mallbris, L
Journal of the American Academy of Dermatology. 2018;(1):104-109.e8
Abstract
BACKGROUND The impact of ixekizumab treatment for psoriasis on cardiovascular-related parameters in patients is unknown. OBJECTIVE To investigate cardiovascular-related parameters in patients with psoriasis treated with ixekizumab. METHODS In phase 3 trials, patients with moderate-to-severe psoriasis were randomized and treated with placebo, ixekizumab, or etanercept during the induction period (weeks 0-12; UNCOVER-1, UNCOVER-2, and UNCOVER-3). At week 12, responders were rerandomized to receive placebo or ixekizumab through the maintenance period (weeks 12-60; UNCOVER-1 and UNCOVER-2). Laboratory measures (fasting lipid profiles, glucose level, or high-sensitivity C-reactive protein [hsCRP] level), weight, blood pressure, and electrocardiograms were obtained through 60 weeks. RESULTS Baseline parameters were within normal ranges with the exception of elevated triglyceride and hsCRP levels. After maintenance dosing, no significant changes were observed versus placebo for total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, very-low-density lipoprotein cholesterol, triglyceride, apolipoprotein A1, apolipoprotein B, or fasting glucose levels or for systolic/diastolic blood pressure at 60 weeks. Importantly, low-density lipoprotein-to-high-density lipoprotein ratios remained stable during the induction and maintenance periods. HsCRP concentrations were significantly reduced versus placebo at 12 weeks and remained reduced at 60 weeks, although not significantly. Although transient changes were observed for some parameters during the induction period, these changes did not persist into the maintenance period. LIMITATIONS A lack of echocardiogram evaluations. CONCLUSIONS Ixekizumab had a neutral impact on cardiovascular-related parameters in patients with psoriasis.
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Safety and Efficacy of Reslizumab for Children and Adolescents With Eosinophilic Esophagitis Treated for 9 Years.
Markowitz, JE, Jobe, L, Miller, M, Frost, C, Laney, Z, Eke, R
Journal of pediatric gastroenterology and nutrition. 2018;(6):893-897
Abstract
BACKGROUND Eosinophilic esophagitis (EoE) is a chronic disease characterized by infiltration of eosinophils in the esophageal epithelium. There are limited treatment options for EoE. The rationale of the study was to evaluate the long-term safety and efficacy of reslizumab (RSZ) in pediatric patients who received RSZ in a randomized controlled trial (RCT) and expanded access program. METHODS Records of patients who received RSZ in our center were reviewed. Patients received RSZ 2 mg/kg (or placebo) every 4 weeks as part of the RCT, open-label extension (OLE), and compassionate use (CU). Data were analyzed as of their most recent evaluation in August 2017. Labwork, history, and examinations were conducted every 12 weeks. Biopsy results were compared from baseline (before RCT) and at the most recent evaluation. Adverse events (AE) were recorded. RESULTS Twelve patients entered the RCT at our center; 6 patients completed the OLE and 4 received RSZ through CU. Between the RCT, OLE, and CU periods, patients received 549 doses of RSZ (median 37, range 2-116). No serious AE were attributed to RSZ. Symptoms improved on treatment: dysphagia (42% vs 0%), abdominal pain (58% vs 0%), heartburn (18% vs 0%), vomiting (67% vs. 17%), reflux (58% vs. 0%). Median esophageal eosinophil count improved (35 eosinophils per high-power field vs 3, P < 0.001). Patients receiving RSZ maintain a relatively unrestricted diet. CONCLUSIONS RSZ appears to be safe in children with EoE over 9 years of treatment experience. Symptoms and eosinophil count improved considerably during treatment with RSZ despite a relatively unrestricted diet.
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FORWARD I: a Phase III study of mirvetuximab soravtansine versus chemotherapy in platinum-resistant ovarian cancer.
Moore, KN, Vergote, I, Oaknin, A, Colombo, N, Banerjee, S, Oza, A, Pautier, P, Malek, K, Birrer, MJ
Future oncology (London, England). 2018;(17):1669-1678
Abstract
Mirvetuximab soravtansine, an antibody-drug conjugate that binds with high affinity to folate receptor-α to provide tumor-directed delivery of the potent microtubule-disrupting agent DM4, has emerged as a promising investigational agent for the treatment of ovarian cancer, particularly in the setting of platinum-resistant disease. Here we describe the rationale and design of FORWARD I (NCT02631876), the first randomized, multicenter Phase III study to compare the safety and efficacy of mirvetuximab soravtansine versus investigator's choice of chemotherapy in women with folate receptor-α-positive, platinum-resistant epithelial ovarian, primary peritoneal or fallopian tube cancer. Patients will be randomized in a 2:1 ratio. The primary end point is progression-free survival, and key secondary objectives include comparison of overall response rates, overall survival and duration of response.
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10.
Monoclonal Antibodies for Treatment of Eosinophilic Esophagitis.
Eskian, M, Khorasanizadeh, M, Assa'ad, AH, Rezaei, N
Clinical reviews in allergy & immunology. 2018;(1):88-98
Abstract
Eosinophilic esophagitis (EoE) is a chronic inflammatory disease of the esophagus affecting both children and adults, with debilitating and progressive symptoms. EoE has shown an explosive epidemiological rise in the past few decades. Many patients experience a poor level of disease control despite maximal use of available guideline-based therapies, which seriously hampers their quality of life. Diet restrictions and systemic and topical corticosteroids are the current mainstays of EoE therapy, but are associated with significant efficacy, treatment compliance, and safety issues such as oral or esophageal candidiasis, growth retardation, osteopenia, osteoporosis, glucose intolerance, and cataract formation. As EoE is a chronic inflammatory disease, immune cells and cytokines are responsible for the inflammatory response and symptoms. Monoclonal antibodies specifically targeting these pathophysiologic effectors offer more potent relief of histologic and clinical disease features while keeping off-target adverse effects to a minimum. Herein, we have reviewed the current evidence regarding efficacy and safety of monoclonal antibodies including mepolizumab (anti-IL-5), reslizumab (anti-IL-5), QAX576 (anti-IL-13), omalizumab (anti-immunoglobulin-E), and infliximab (anti-TNF-α) in treatment of EoE. Our review indicates that although the use of monoclonal antibodies for EoE treatment is safe with limited and reversible adverse events, however, it is not yet possible to reach a final verdict on the efficacy of mAbs in EoE. Future well-designed studies are needed to clarify the exact role of mAbs in EoE.