Suspected adverse effects after human papillomavirus vaccination: a temporal relationship.

Immunol Res. 2018 12;66(6):723-725

Authors: Ikeda SI, Hineno A, Ozawa K, Kinoshita T

Abstract
In Japan, a significant number of adolescent girls complained unusual symptoms after human papillomavirus (HPV) vaccination, and the vast majority of them were initially diagnosed as having psychiatric illness because of the absence of pathologic findings, radiological images and specific abnormalities in laboratory test results. Later, these symptoms were supposed to be adverse effects after HPV vaccination, and the recommendation for HPV vaccination was withdrawn by Japanese Ministry of Public Health, Labour and Welfare 4 years and 9 months ago. However, a causal link has not been demonstrated between HPV vaccination and the development of these symptoms. Our study has shown that the period of HPV vaccination considerably overlapped with that of unique postvaccination symptom development, adding that new patients with possible HPV vaccine-related symptoms have not appeared during our recent 28-month follow-up period. This social episode has now subsided in Japan.

PMID: 30719604 [PubMed - indexed for MEDLINE]

Adverse Drug Reactions in Palliative Care.

J Pain Palliat Care Pharmacother. 2018 Jun - Sep;32(2-3):98-105

Authors: O'Leary J, Pawasauskas J, Brothers T

Abstract
Adverse drug reactions (ADRs) have an impact on patient morbidity and mortality. Palliative care patients constitute a vulnerable population due to the complexity of their care and treatments. This study sought to identify ADRs in palliative care, assess their severity and preventability, and identify specific medications most commonly involved. This retrospective cohort study included patients who received a consult by the hospital's palliative care service over a 1-year period. Records were reviewed to identify ADR occurrences, causative and resulting events, and variables used to determine preventability and severity. Of the 430 patients who met inclusion criteria, 247 patients experienced an ADR (57.4%). In total, 440 ADRs were documented, with 45.7% of patients experiencing more than one. Patients with repeated hospitalizations, increased medication usage, documented drug allergies, and cancer diagnoses were more likely to experience an ADR. No associations were found between occurrences of ADR with gender or Charlson comorbidity scores. The majority of ADRs were of moderate severity (64.6%) and considered potentially preventable (81.5%). Organ systems most commonly affected by ADRs were gastrointestinal (32.7%) and neurological (15.9%). Antimicrobials, opioids, and anticoagulants were the most common causative agents. ADRs are commonly experienced in palliative care patients and are often preventable. Identification of risk factors for ADRs may prevent occurrences in the complex palliative care patient.

PMID: 30676174 [PubMed - indexed for MEDLINE]

Autonomic dysfunction and HPV immunization: an overview.

Immunol Res. 2018 12;66(6):744-754

Authors: Blitshteyn S, Brinth L, Hendrickson JE, Martinez-Lavin M

Abstract
This article reviews the case series reported from several countries describing patients with suspected severe side effects to the HPV vaccines. The described symptom clusters are remarkably similar and include disabling fatigue, headache, widespread pain, fainting, gastrointestinal dysmotility, limb weakness, memory impairment episodes of altered awareness, and abnormal movements. This constellation of symptoms and signs has been labeled with different diagnoses such as complex regional pain syndrome (CRPS), postural orthostatic tachycardia syndrome (POTS), small fiber neuropathy (SFN), myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), or fibromyalgia. It is known that autoimmunity and autoantibodies are present in a subset of patients with CRPS, POTS, SFN, ME/CFS, and fibromyalgia. This article proposes that vaccine-triggered, immune-mediated autonomic dysfunction could lead to the development of de novo post-HPV vaccination syndrome possibly in genetically susceptible individuals. Being cognizant that a temporal relationship between vaccination and symptom onset does not necessarily equate to causality, mounting evidence of case series calls for well-designed case-control studies to determine the prevalence and possible causation between these symptom clusters and HPV vaccines. Since personalized medicine is gaining momentum, the use of adversomics and pharmacogenetics may eventually help identify individuals who are predisposed to HPV vaccine adverse events.

PMID: 30478703 [PubMed - indexed for MEDLINE]

Meta-analysis of Interventions to Reduce Adverse Drug Reactions in Older Adults.

J Am Geriatr Soc. 2018 02;66(2):282-288

Authors: Gray SL, Hart LA, Perera S, Semla TP, Schmader KE, Hanlon JT

Abstract
OBJECTIVES: To examine the effect of interventions to optimize medication use on adverse drug reactions (ADRs) in older adults.
DESIGN: Systematic review and meta-analysis. EMBASE, PubMed, OVID, Cochrane Library, Clinicaltrials.gov, and Google Scholar were searched through April 30, 2017.
SETTING: Randomized controlled trials.
PARTICIPANTS: Older adults (mean age ≥65) taking medications.
MEASUREMENTS: Two authors independently extracted relevant information and assessed studies for risk of bias. Discrepancies were resolved in consensus meetings. The outcomes were any and serious ADRs. Random-effects models were used to combine the results of multiple studies and create summary estimates.
RESULTS: Thirteen randomized controlled trials involving 6,198 older adults were included. The studies employed a number of different interventions that were categorized as pharmacist-led interventions (8 studies), other health professional-led interventions (3 studies), a brief educational session (1 study), and a technology intervention (1 study). The intervention group was 21% less likely than the control group to experience any ADR (odds ratio (OR) = 0.79, 95% confidence interval (CI) = 0.62-0.99). In the six studies that examined serious ADRs, the intervention group was 36% less likely than the control group to experience a serious ADR (OR = 0.64, 95% CI = 0.42-0.98).
CONCLUSION: Interventions designed to optimize medication use reduced the risk of any and serious ADRs in older adults. Implementation of these successful interventions in healthcare systems may improve medication safety in older adults.

PMID: 29265170 [PubMed - indexed for MEDLINE]

Hydroxychloroquine-Induced Reversible Hypomnesis in Systemic Lupus Erythematosus.

J Clin Rheumatol. 2018 Aug;24(5):291-293

Authors: Feng SW, Luo ZY, He XQ, Liu JH, Luo DQ

PMID: 29239937 [PubMed - indexed for MEDLINE]

A phase I trial of MK-2206 and hydroxychloroquine in patients with advanced solid tumors.

Cancer Chemother Pharmacol. 2019 Aug 28;:

Authors: Mehnert JM, Kaveney AD, Malhotra J, Spencer K, Portal D, Goodin S, Tan AR, Aisner J, Moss RA, Lin H, Bertino JR, Gibbon D, Doyle LA, White EP, Stein MN

Abstract
PURPOSE: Given the evidence that coordinate inhibition of AKT induces autophagy, we studied the combination of the AKT inhibitor, MK-2206 with hydroxychloroquine (HCQ) in patients with advanced solid tumors.
METHODS: Patients were treated with weekly MK-2206 (135 mg or 200 mg) plus HCQ (200 mg, 400 mg or 600 mg BID).
RESULTS: Thirty-five patients were enrolled across 5 dose levels. Two DLTs of grade 3 maculo-papular rash were observed at dose level 2 (MK-2206 200 mg weekly plus HCQ at 400 mg BID) and 1 DLT of grade 3 fatigue at dose level 2B (MK-2206 135 mg weekly plus HCQ 600 mg BID). The maximum tolerated dose (MTD) was declared as dose level 2B. The most common adverse events attributed to MK-2206 were hyperglycemia (N = 18; 51%), fatigue (N = 17; 49%), maculo-papular rash (N = 16; 46%), diarrhea (N = 12; 34%), anorexia (N = 11; 31%), and nausea (N = 11; 31%). Patients experiencing adverse events attributed to HCQ were small in number (N = 13) and primarily included fatigue (N = 5; 14%) and maculo-papular rashes (N = 3; 9%). Statistically significant effects on the pharmacokinetic properties of MK-2206 were observed in combination with HCQ. In addition, the plasma concentrations of HCQ in the combination with MK-2206 were significantly higher than the plasma levels of HCQ as monotherapy in prior studies. The best overall response of stable disease was observed in 5/34 (15%) patients.
CONCLUSION: The combination of MK-2206 and hydroxychloroquine was tolerable, but with substantial number of drug-related AEs and minimal evidence of antitumor activity.

PMID: 31463691 [PubMed - as supplied by publisher]

Comparative efficacy and tolerability of front-line treatments for newly diagnosed chronic-phase chronic myeloid leukemia: an update network meta-analysis.

BMC Cancer. 2019 Aug 28;19(1):849

Authors: Tang L, Zhang H, Peng YZ, Li CG, Jiang HW, Xu M, Mei H, Hu Y

Abstract
BACKGROUND: Recent years have witnessed the rapid evolution of therapies in chronic-phase chronic myeloid leukemia (CP-CML). To assess the efficacy and tolerability of all reported front-line treatments for patients with newly diagnosed CML, a multiple-treatments meta-analysis was performed, which accounted for both direct and indirect comparisons among those treatments.
METHODS: Primary outcomes were the percentage of patients achieving major molecular response (MMR) and complete cytogenetic response (CCyR) within 12 months. Secondary outcomes included the percentage of progression to accelerated phase (AP), serious adverse effects (AEs), overall discontinuation and discontinuation for drug-related AEs. Direct pairwise meta-analysis and indirect multi-comparison meta-analysis among those treatments in each outcome were both conducted. The surface under the cumulative ranking curve (SUCRA) was calculated for all treatments in each outcome. Cluster analysis demonstrated the division of treatments into distinct groupings according to efficacy and tolerability profiles.
RESULTS: A total of 21 randomized controlled trials (RCTs, including 10,187 patients) comparing 15 different interventions for CP-CML patients were included in this study. SUCRA analysis suggested that all tyrosine kinase inhibitors (TKIs) are highly effective in newly diagnosed CP-CML when compared to traditional drugs. Newer TKIs and higher-dose imatinib generally resulted in faster cytogenetic and molecular responses when compared with standard-dose imatinib and traditional drugs. Furthermore, traditional drugs, higher-dose imatinib and newer TKIs demonstrated lower acceptability than standard-dose imatinib. One cluster of interventions, which included nilotinib (300/400 mg BID), dasatinib (100 mg QD) and radotinib (300 mg BID), demonstrated higher efficacy and tolerability than other treatments.
CONCLUSIONS: Nilotinib (300/400 mg BID), dasatinib (100 mg QD) and radotinib (300 mg BID) prove to be the most recommended front-line treatments of the greatest efficacy and tolerability for CP-CML patients. High-dose therapies are recommended only for patients in accelerated phase/blast phase or with suboptimal CML-CP response, and management of adverse events should be carried out to avoid compromising the clinical efficacy.

PMID: 31462241 [PubMed - in process]

Modeling Keyword Search Strategy: Analysis of Pharmacovigilance Specialists' Search of MedDRA Terms.

Stud Health Technol Inform. 2019;257:298-302

Authors: Marcilly R, Douze L, Bousquet C, Pelayo S

Abstract
In the information retrieval task, searching and choosing keywords to form the query is crucial. The present study analyzes and describes the keywords' search strategy into a thesaurus in the field of pharmacovigilance. Two ergonomics experts shadowed 22 pharmacovigilance specialists during their daily work. They focus on the strategies for searching and choosing MedDRA terms to build pharmacovigilance queries. Interviews of four pharmacovigilance specialists completed the observations. Results highlight that, for unusual or complex searches, pharmacovigilance specialists proceed iteratively in three main phases: (i) preparation of a list of terms and of evaluation criteria, (ii) exploration of the MedDRA hierarchy and choice of a term, and (iii) evaluation of the results against the criteria. Overall, the search and the choice of keywords within a thesaurus shares similarity with the information retrieval task and is closely interwoven with the query building process. Based on the results, the paper proposes design specifications for new interfaces supporting the identification of MedDRA terms so that pharmacovigilance reports searches achieve a good level of expressiveness.

PMID: 30741213 [PubMed - indexed for MEDLINE]

Adjuvant carboplatin therapy in patients with clinical stage 1 testicular seminoma: is long-term morbidity increased?

J Cancer Res Clin Oncol. 2019 Sep;145(9):2335-2342

Authors: Ruf CG, Borck S, Anheuser P, Matthies C, Nestler T, Zecha H, Isbarn H, Dieckmann KP

Abstract
PURPOSE: Clinical stage (CS) 1 testicular seminoma is cured in almost 100% of cases following either retroperitoneal radiotherapy, carboplatin monotherapy, or surveillance strategies. Little is known about potential long-term effects of carboplatin. We, therefore, examined late sequelae of this drug in seminoma patients.
PATIENTS AND METHODS: We retrospectively identified 451 patients with CS1 testicular seminoma treated between 1994 and 2014, of whom 243 underwent carboplatin therapy [median follow-up (F/U) 96 months], 81 received radiotherapy (median F/U 142 months), and 127 underwent surveillance (median F/U 40 months). Satisfaction regarding management, as well as the following events during F/U, were analysed by questionnaire: subsequent malignant neoplasms (SMNs), cardiovascular events, arterial hypertension, peptic ulcer, tinnitus, peripheral neuropathy, hypogonadism, and infertility. The relative frequencies of the events were analysed using descriptive statistics. The frequency of observed SMNs was compared with the expected number.
RESULTS: Patients receiving carboplatin tolerated the treatment less well (71.2%) than those under surveillance (81.9%). After carboplatin, 12 SMNs (5.0%) were noted vis-a-vis 5.0 expected. There were three cases of prostatic cancer and 3 melanomas among the SMNs. Half of these SMNs occurred early after treatment. Among the other health events, only reported hypogonadism (13.2%) appeared to be marginally increased in frequency.
CONCLUSIONS: This study found a 2.4-fold higher than expected rate of SMN-and a slightly increased rate of hypogonadism-in the long-term period following carboplatin treatment. Although further studies are needed to confirm these preliminary findings, these results are probably informative for clinicians caring for seminoma patients.

PMID: 31286241 [PubMed - indexed for MEDLINE]

Safety of trifluridine/tipiracil in an open-label expanded-access program in elderly and younger patients with metastatic colorectal cancer.

Cancer Chemother Pharmacol. 2018 12;82(6):961-969

Authors: Mayer RJ, Hochster HS, Cohen SJ, Winkler R, Makris L, Grothey A

Abstract
PURPOSE: Trifluridine/tipiracil (FTD/TPI; TAS-102, Lonsurf®), a novel form of chemotherapy for metastatic colorectal cancer (mCRC), has shown clinical benefit in the global, phase III RECOURSE trial, regardless of patient age. Here, we report the safety and tolerability profile of FTD/TPI from an expanded-access program (EAP) in the US patients with mCRC whose disease has progressed on the standard therapies.
METHODS: A total of 549 patients (≥ 18 years) with histologically confirmed mCRC following two or more regimens of standard therapy and an Eastern Cooperative Oncology Group performance status of 0 or 1 participated in this open-label EAP. During the 28-day treatment cycle, patients took FTD/TPI 35 mg/m2 twice daily for 5 days followed by 2 days of rest for 2 weeks, with a 14-day rest period. Data were collected for therapy duration, treatment discontinuation, and adverse events. Age-based post hoc analysis was performed to determine the safety of FTD/TPI in elderly (≥ 65 years) versus younger (< 65 years) patients.
RESULTS: FTD/TPI-treated patients in this EAP had a similar therapy duration and time to treatment discontinuation to those in the RECOURSE trial. The safety profile in elderly patients was consistent with that in younger patients, with no unexpected safety concerns.
CONCLUSIONS: This USA-based, open-label EAP has confirmed a similar safety and tolerability profile for FTD/TPI to that observed in the RECOURSE trial. Furthermore, FTD/TPI is well tolerated and can be considered as a treatment option in elderly patients with mCRC.
TRIAL REGISTRATION: NCT02286492.

PMID: 30350179 [PubMed - indexed for MEDLINE]

Exposure-response analysis and simulation of lenvatinib safety and efficacy in patients with radioiodine-refractory differentiated thyroid cancer.

Cancer Chemother Pharmacol. 2018 12;82(6):971-978

Authors: Hayato S, Shumaker R, Ferry J, Binder T, Dutcus CE, Hussein Z

Abstract
PURPOSE: Once-daily lenvatinib 24 mg is the approved dose for radioiodine-refractory differentiated thyroid cancer. In a phase 3 trial with lenvatinib, the starting dose of 24 mg was associated with a relatively high incidence of adverse events that required dose reductions. We used an exposure-response model to investigate the risk-benefit of different dosing regimens for lenvatinib.
METHODS: A population pharmacokinetics/pharmacodynamics modeling analysis was used to simulate the potential benefit of lower starting doses to retain efficacy with improved safety. The seven lenvatinib regimens tested were: 24 mg; and 20 mg, 18 mg, and 14 mg, all with or without up-titration to 24 mg. Exposure-response models for efficacy and safety were created using a 24-week time course.
RESULTS: The approved dose of lenvatinib at 24 mg, predicted the best efficacy. However, the lenvatinib dosing regimens of 14 mg with up-titration or 18 mg without up-titration potentially provides comparable efficacy (objective response rate at 24 weeks) and a better safety profile.
CONCLUSIONS: Treatment with lenvatinib at starting doses lower than the approved once-daily 24 mg dose could provide comparable antitumor efficacy and a similar or better safety profile. Based on the results from this modeling and simulation study, a comparator dose of lenvatinib 18 mg without up-titration was selected for evaluation in a clinical trial.

PMID: 30244318 [PubMed - indexed for MEDLINE]

[List-based concepts in pharmacotherapy of older and geriatric patients].

Z Gerontol Geriatr. 2018 Jun;51(4):394-398

Authors: Thiem U

Abstract
Pharmacotherapy for older and geriatric patients is a challenge, especially because older and geriatric patients are particularly prone to adverse drug reactions and the evidence for drug use is limited for this patient group; therefore, several list-based recommendations have recently been developed in order to improve appropriate pharmacotherapy. These lists of recommendations differ in their criteria and the compilation of drugs, for example in terms of potentially inappropriate medication, drugs increasing the risk of falling and anticholinergic effects. This review highlights the characteristics of selected recently published lists, describes the concepts behind them and discusses the advantages and disadvantages of the individual approaches.

PMID: 29725752 [PubMed - indexed for MEDLINE]

The Mixed Opioid Receptor Antagonist Naltrexone Mitigates Stimulant-Induced Euphoria: A Double-Blind, Placebo-Controlled Trial of Naltrexone.

J Clin Psychiatry. 2018 Mar/Apr;79(2):

Authors: Spencer TJ, Bhide P, Zhu J, Faraone SV, Fitzgerald M, Yule AM, Uchida M, Spencer AE, Hall AM, Koster AJ, Feinberg L, Kassabian S, Storch B, Biederman J

Abstract
OBJECTIVE: Supratherapeutic doses of methylphenidate activate μ-opioid receptors, which are linked to euphoria. This study assessed whether naltrexone, a mixed μ-opioid antagonist, may attenuate the euphoric effects of stimulants, thereby minimizing their abuse potential in subjects with attention-deficit/hyperactivity disorder (ADHD).
METHODS: We conducted a 6-week, double-blind, placebo-controlled, randomized clinical trial of naltrexone in adults with DSM-IV ADHD receiving open treatment with a long-acting formulation of methylphenidate (January 2013 to June 2015). Spheroidal Oral Drug Absorption System methylphenidate (SODAS-MPH) was administered twice daily, was titrated to ~1 mg/kg/d over 3 weeks, and was continued for 3 additional weeks depending on response and adverse effects. Subjects were adults with ADHD preselected for having experienced euphoria with an oral test dose of 60 mg of immediate-release methylphenidate (IR-MPH). The primary outcome measure was Question 2 (Liking a Drug Effect) on the Drug Rating Questionnaire, Subject version, which was assessed after oral test doses of 60 mg of IR-MPH were administered after the third and sixth weeks of treatment with SODAS-MPH.
RESULTS: Thirty-seven subjects who experienced stimulant-induced (mild) euphoria at a baseline visit were started in the open trial of SODAS-MPH and randomized to naltrexone 50 mg/d or placebo. Thirty-one subjects completed through week 3, and 25 completed through week 6. Naltrexone significantly diminished the euphoric effect of IR-MPH during the heightened-risk titration phase (primary outcome; first 3 weeks) (χ² = 5.07, P = .02) but not the maintenance phase (weeks 4-6) (χ² = 0.22, P = .64) of SODAS-MPH treatment.
CONCLUSIONS: Preclinical findings are extended to humans showing that naltrexone may mitigate stimulant-associated euphoria. Our findings provide support for further studies combining opioid receptor antagonists with stimulants to reduce abuse potential.
TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01673594.

PMID: 29617066 [PubMed - indexed for MEDLINE]

Prediction of Central Nervous System Side Effects Through Drug Permeability to Blood-Brain Barrier and Recommendation Algorithm.

J Comput Biol. 2018 04;25(4):435-443

Authors: Fan J, Yang J, Jiang Z

Abstract
Drug side effects are one of the public health concerns. Using powerful machine-learning methods to predict potential side effects before the drugs reach the clinical stages is of great importance to reduce time consumption and protect the security of patients. Recently, researchers have proved that the central nervous system (CNS) side effects of a drug are closely related to its permeability to the blood-brain barrier (BBB). Inspired by this, we proposed an extended neighborhood-based recommendation method to predict CNS side effects using drug permeability to the BBB and other known features of drug. To the best of our knowledge, this is the first attempt to predict CNS side effects considering drug permeability to the BBB. Computational experiments demonstrated that drug permeability to the BBB is an important factor in CNS side effects prediction. Moreover, we built an ensemble recommendation model and obtained higher AUC score (area under the receiver operating characteristic curve) and AUPR score (area under the precision-recall curve) on the data set of CNS side effects by integrating various features of drug.

PMID: 29058464 [PubMed - indexed for MEDLINE]

The efficacy and safety of luseogliflozin and sitagliptin depending on the sequence of administration in patients with type 2 diabetes mellitus: a randomized controlled pilot study.

Expert Opin Pharmacother. 2019 Aug 26;:1-10

Authors: Takihata M, Terauchi Y

Abstract
Background: The efficacy and safety of SGLT-2 and DPP-4 inhibitor monotherapies in T2DM is well established; however, data on the effect of combination therapies and sequence of administration are lacking. We investigated the efficacy and safety of the sequence of SGLT-2 and DPP-4 inhibitor administration in Japanese T2DM patients. Research design and methods: In this single-institution, open-label, randomized controlled study, T2DM patients inadequately controlled (HbA1c ≥6.5%) with conventional therapy were randomized to receive luseogliflozin-sitagliptin (LS; luseogliflozin 2.5 mg for 0-12 weeks, then luseogliflozin plus sitagliptin 50 mg for 12-24 weeks) or sitagliptin-luseogliflozin (SL; sitagliptin 50 mg for 0-12 weeks, then sitagliptin plus luseogliflozin 2.5 mg for 12-24 weeks). The main outcome was the difference in mean change in HbA1c at 24 weeks relative to baseline between both groups. Results: Of the 41 enrolled and randomized patients, 34 completed the study. Mean ± SD HbA1c at baseline was 10.35 ± 1.04% and 10.02 ± 1.40% in the LS and SL groups, respectively, and mean ± SD change in HbA1c at 24 weeks from baseline was -3.81 ± 1.21% vs -2.46 ± 1.42% (P < 0.01), respectively. No drug-related adverse events were reported. Conclusion: Over the 24-week period, LS was more effective in reducing HbA1c levels than SL in Japanese T2DM patients.

PMID: 31450983 [PubMed - as supplied by publisher]

Pattern of adverse events induced by aflibercept and ranibizumab: A nationwide spontaneous adverse event reporting database, 2007-2016.

Medicine (Baltimore). 2019 Aug;98(33):e16785

Authors: Ha D, Choi SR, Kwon Y, Park HH, Shin JY

Abstract
Data regarding the safety of anti-vascular endothelial growth factor (anti-VEGF) treatment is limited.To compare the adverse events (AEs) induced by aflibercept and ranibizumab using a spontaneous reporting system and determine the signals.We used data from the Korea Institute of Drug Safety & Risk Management-Korea Adverse Event Reporting System Database (KIDS-KD), collected between 2007 and 2016. Differences in patient demographics, report type, reporter, causality, and serious-AEs between aflibercept and ranibizumab were compared. Metrics including proportional reporting ratio (PRR), reporting odds ratio (ROR), and information component (IC), were used to compare signals with the AEs on the drug labels in the United States of America and Korea. Logistic regression analysis was performed to identify AEs that are more likely to occur with drug use.A total of 32 aflibercept and 103 ranibizumab cases of AEs were identified. The proportion of AEs that were reported voluntarily was higher with aflibercept (50.5%) use than ranibizumab (4.9%), whereas the AEs reported by post-marketing surveillance were higher with ranibizumab (46.6%) use than aflibercept (31.3%). The percentage of AEs in patients >60 years old, reports by consumers, and the ratio of SAEs to AEs associated with aflibercept (84. %, 9.4%, and 75.0%, respectively) were higher than those of ranibizumab (77.7%, 1.9%, and 19.4%, respectively). The number of newly detected AEs after aflibercept and ranibizumab treatment was 3 and 8, respectively. Among these, conjunctivitis and medicine ineffective were not included on the aflibercept and ranibizumab labels, respectively. Endophthalmitis (OR 6.96, 95% CI 2.74-17.73) was more likely to be reported in patients with aflibercept than in patients without aflibercept, whereas medicine ineffective (OR 18.49, 95% CI 2.39-143.29) and retinal disorder (OR 7.03, 95% CI 1.60-30.96) were more likely to be reported in patients with ranibizumab than in patients without ranibizumab.New signals have been identified for aflibercept and ranibizumab. Further research is necessary to evaluate the causality of AEs that were detected as signals in this study.

PMID: 31415382 [PubMed - indexed for MEDLINE]

Pharmacogenomics.

Lancet. 2019 08 10;394(10197):521-532

Authors: Roden DM, McLeod HL, Relling MV, Williams MS, Mensah GA, Peterson JF, Van Driest SL

Abstract
Genomic medicine, which uses DNA variation to individualise and improve human health, is the subject of this Series of papers. The idea that genetic variation can be used to individualise drug therapy-the topic addressed here-is often viewed as within reach for genomic medicine. We have reviewed general mechanisms underlying variability in drug action, the role of genetic variation in mediating beneficial and adverse effects through variable drug concentrations (pharmacokinetics) and drug actions (pharmacodynamics), available data from clinical trials, and ongoing efforts to implement pharmacogenetics in clinical practice.

PMID: 31395440 [PubMed - indexed for MEDLINE]

Atezolizumab-induced sarcoid-like granulomatous reaction in a patient with urothelial cell carcinoma.

Immunotherapy. 2018 10;10(14):1189-1192

Authors: Mitchell MA, Hogan K, Amjadi K

Abstract
A 61-year-old woman with locally advanced, high-grade urothelial cell carcinoma was treated with the anti-programmed death-ligand 1 antibody atezolizumab. She initially received neoadjuvant chemotherapy and surgery that led to clinical and radiographic remission at the time of atezolizumab initiation. Within 3 months she developed new mediastinal and hilar lymphadenopathy as well as pulmonary nodules in a pattern characteristic of pulmonary sarcoidosis. Mediastinal lymph node biopsy by endobronchial ultrasound demonstrated noncaseating granulomas without evidence of malignancy or infection. Within 4 weeks of initiation of prednisone and cessation of atezolizumab there was marked reduction in intrathoracic lymphadenopathy and perilymphatic nodules. This is the first reported case of atezolizumab-induced sarcoid-like granulomatous reaction.

PMID: 30326785 [PubMed - indexed for MEDLINE]

Intravenous immunoglobulin 10% in children with primary immunodeficiency diseases.

Immunotherapy. 2018 10;10(14):1193-1202

Authors: Ochs HD, Melamed I, Borte M, Moy JN, Pyringer B, D Kobayashi AL, Knutsen AP, Smits W, Pituch-Noworolska A, Kobayashi RH

Abstract
AIM: To assess the safety and efficacy of an intravenous immunoglobulin (IVIG) 10% preparation (Panzyga®; Octapharma AG, Lachen, Switzerland) in predominantly antibody-deficient children with primary immunodeficiency disease.
METHODS: Data from two prospective, open-label and noncontrolled multicenter Phase III studies of IVIG 10% that included 25 patients <16 years of age were analyzed for efficacy, pharmacokinetics and safety.
RESULTS: The rate of serious bacterial infections was 0.04/patient-year. A maximal infusion rate of 0.14 ml/kg/min was achieved in 82% of pediatric patients (n = 9). Infusions of immunoglobulin G trough levels between infusions remained ≥5-6 g/l; median half-life was 32.79-36.62 days. Abdominal pain, headache and chills were the most common treatment-related adverse events.
CONCLUSION: IVIG 10% is safe and effective for the treatment of predominantly antibody-deficient children.

PMID: 30088423 [PubMed - indexed for MEDLINE]

Efficacy and Safety of CalliSpheres® Drug-Eluting Beads Transarterial Chemoembolization in Barcelona Clinic Liver Cancer Stage C Patients.

Oncol Res. 2019 May 07;27(5):565-573

Authors: Liu Y, Huang W, He M, Lian H, Guo Y, Huang J, Zhou J, Zhu K

Abstract
This study aimed to investigate the efficacy and safety of drug-eluting beads transarterial chemoembolization (DEB-TACE) treatment in Barcelona Clinic Liver Cancer (BCLC) stage C liver cancer patients. In 39 patients with BCLC stage C liver cancer, after the first cycle of DEB-TACE, 2 (5.1%) and 24 (61.5%) patients achieved complete response (CR) and partial response (PR) to give an overall objective response rate (ORR) of 66.7%. With respect to the second cycle of therapy, the ORR was higher in patients receiving DEB-TACE compared with those receiving cTACE (57.1% vs. 11.1%). After the first cycle of DEB-TACE treatment, the percentages of abnormal albumin (ALB), total protein (TP), total bilirubin (TBIL), and alanine aminotransferase (ALT) worsened at 1 week and recovered at 1 month. The number of patients with abnormal aspartate aminotransferase (AST) did not increase at 1 week but elevated at 1 month. After the second cycle of DEB-TACE or cTACE treatment, no difference was observed between cTACE and DEB-TACE in terms of all adverse events (AEs) at all visits, and most of the AEs did not change after the second cycle in both groups. The most common AEs after the first and second treatment cycles were pain, fever, and nausea/vomiting. These results demonstrate that DEB-TACE offers patients with BCLC stage C liver cancer a clinically active short-term treatment that is safe and relatively well tolerated.

PMID: 30005719 [PubMed - indexed for MEDLINE]