Effects of Chronic Endurance Exercise on Doxorubicin-Induced Thymic Damage.

Integr Cancer Ther. 2016 Dec;15(4):535-541

Authors: Quinn CJ, Burns PD, Gibson NM, Bashore A, Hayward R, Hydock DS

Abstract
The use of prior exercise training has shown promise in minimizing doxorubicin (DOX)-induced physical impairments. The purpose of this study was to compare changes in thymus mass, thymocyte (T-cell) number, and tissue peroxidation following chronic endurance exercise and DOX treatment in the rat. The thymus mass, number of viable T-cells, and levels of malondialdehyde and 4-hydroxyalkenals (MDA+4-HAE) were compared 3 days post-injection between rats assigned to the following treatment conditions: (a) 10 weeks of endurance training, followed by a saline injection 24 hours after the last training session (TM+SAL); (b) treadmill training as above, followed by a single, bolus 10-mg/kg injection of DOX (TM+10); (c) treadmill training with 12.5 mg/kg of DOX (TM+12.5); (d) sedentary (without exercise) and a saline injection (SED+SAL); (e) sedentary with 10 mg/kg of DOX (SED+10); and (f) sedentary with 12.5 mg/kg (SED+12.5). Thymic mass and T-cell numbers significantly decreased following DOX injections. TM rats exhibited significantly less lipid peroxidation compared with paired-dose SED groups. TM+10 did not significantly differ from SED+SAL in thymic levels of lipid peroxidation. We conclude that chronic endurance exercise decreases levels of lipid peroxidation in the thymus seen with acute DOX treatment.

PMID: 26590123 [PubMed - indexed for MEDLINE]

Relationship between phase I study duration and symptom burden.

Support Care Cancer. 2017 Oct 05;:

Authors: Treasure M, Daly B, Fu P, Kerpedjieva S, Dowlati A, Meropol NJ

Abstract
PURPOSE: Phase I clinical trials are critical to development of cancer therapeutics. Adverse events (AEs) and symptom burden contribute to early treatment withdrawal, and it is often difficult to ascertain whether these events are disease- or treatment-related. Regardless, early withdrawal may delay determination of the effectiveness of potential new therapies. We sought to characterize the reasons for early treatment termination to identify potential modifiable events.
METHODS: A retrospective chart review was conducted on solid tumor patients enrolled in institutional phase I clinical trials from 2003 to 2013 through the Case Comprehensive Cancer Center.
RESULTS: Two hundred fifty-five patients were included in the analysis. The mean duration on study was 78.4 days (SD 63.4 days), and 23% of the patients were on study ≤ 30 days. Patients experienced an average of 25.1 AEs, of which 46.9% were non-laboratory. Constitutional symptoms (29.3%), gastrointestinal symptoms (24%), and pain (12.8%) were the most common non-laboratory AEs. Disease progression (57.6%) was the most common reason for study discontinuation, followed by adverse events (16.5%). Approximately 13% of the patients discontinued treatment for other reasons, of which 41.7% were identified as related to symptom burden on further review. Increased rates of AEs negatively correlated with duration on study (r = - 0.331; p < 0.01).
CONCLUSIONS: AEs may lead to early termination of trial participation and confound clinical assessment of investigational treatments. Designing interventions to reduce AE burden may extend duration on trial, affect the recommended phase II dose, and benefit the quality of life of participants on phase I trials.

PMID: 28980072 [PubMed - as supplied by publisher]

Ephedrine-induced mitophagy via oxidative stress in human hepatic stellate cells.

J Toxicol Sci. 2017;42(4):461-473

Authors: Lee AY, Jang Y, Hong SH, Chang SH, Park S, Kim S, Kang KS, Kim JE, Cho MH

Abstract
The herb Ephedra sinica (also known as Chinese ephedra or Ma Huang), used in traditional Chinese medicine, contains alkaloids identical to ephedrine and pseudoephedrine as its principal active constituents. Recent studies have reported that ephedrine has various side effects in the cardiovascular and nervous systems. In addition, herbal Ephedra, a plant containing many pharmacologically active alkaloids, principally ephedrine, has been reported to cause acute hepatitis. Many studies reported clinical cases, however, the cellular mechanism of liver toxicity by ephedrine remains unknown. In this study, we investigated hepatotoxicity and key regulation of mitophagy in ephedrine-treated LX-2 cells. Ephedrine triggered mitochondrial oxidative stress and depolarization. Mitochondrial swelling and autolysosome were observed in ephedrine-treated cells. Ephedrine also inhibited mitochondrial biogenesis, and the mitochondrial copy number was decreased. Parkin siRNA recovered the ephedrine-induced mitochondrial damage. Excessive mitophagy lead to cell death through imbalance of autophagic flux. Moreover, antioxidants and reducing Parkin level could serve as therapeutic targets for ephedrine-induced hepatotoxicity.

PMID: 28717105 [PubMed - indexed for MEDLINE]

Effectiveness of pharmacovigilance: multifaceted educational intervention related to the knowledge, skills and attitudes of multidisciplinary hospital staff.

Clinics (Sao Paulo). 2017 Jan 01;72(1):51-57

Authors: Varallo FR, Planeta CS, Mastroianni PC

Abstract
OBJECTIVES:: Most educational interventions in pharmacovigilance are designed to encourage physicians to report adverse drug reactions. However, multidisciplinary teams may play an important role in reporting drug-related problems. This study assessed the impact of a multifaceted educational intervention in pharmacovigilance on the knowledge, skills and attitudes of hospital professionals.
METHOD:: This prospective, open-label, non-randomized study was performed in a medium-complexity hospital in São Paulo, Brazil. The intervention involved four activities: 1) an interactive lecture, 2) a practical class, 3) a pre-post questionnaire administered to professionals on a multidisciplinary team, and 4) educational material. The intervention's impact on the professionals' knowledge and skills was assessed using the World Health Organization's definitions. The intervention's effect on the professionals' attitudes was analysed by the prevalence of adverse drug event reports (adverse drug reactions, medication errors, therapeutic failure and drug quality deviations) and the relevance (seriousness and expectancy) of the events.
RESULTS:: One hundred seventy-three professionals were enrolled. A 70-fold increase in the number of adverse drug event reports was observed during the 12 months post-intervention. The intervention improved the professionals' form-completion skills (p<0.0001) and their knowledge of pharmacovigilance (p<0.0001). The intervention also contributed to detecting serious drug-induced events. The nursing staff reported medication errors, and pharmacists and physiotherapists recognized serious adverse drug reactions. Physicians communicated suspicions of therapeutic failure.
CONCLUSIONS:: A multidisciplinary approach to drug-safety assessments contributes to identifying new, relevant drug-related problems and improving the rate of adverse drug event reporting. This strategy may therefore be applied to improve risk communication in hospitals.

PMID: 28226033 [PubMed - indexed for MEDLINE]

Comparing rat and rabbit embryo-fetal developmental toxicity data for 379 pharmaceuticals: on systemic dose and developmental effects.

Crit Rev Toxicol. 2017 May;47(5):402-414

Authors: Theunissen PT, Beken S, Beyer B, Breslin WJ, Cappon GD, Chen CL, Chmielewski G, de Schaepdrijver L, Enright B, Foreman JE, Harrouk W, Hew KW, Hoberman AM, Y Hui J, Knudsen TB, Laffan SB, Makris SL, Martin M, McNerney ME, Siezen CL, Stanislaus DJ, Stewart J, Thompson KE, Tornesi B, Van der Laan JW, Weinbauer GF, Wood S, Piersma AH

Abstract
A database of embryo-fetal developmental toxicity (EFDT) studies of 379 pharmaceutical compounds in rat and rabbit was analyzed for species differences based on toxicokinetic parameters of area under the curve (AUC) and maximum concentration (Cmax) at the developmental lowest adverse effect level (dLOAEL). For the vast majority of cases (83% based on AUC of n = 283), dLOAELs in rats and rabbits were within the same order of magnitude (less than 10-fold different) when compared based on available data on AUC and Cmax exposures. For 13.5% of the compounds the rabbit was more sensitive and for 3.5% of compounds the rat was more sensitive when compared based on AUC exposures. For 12% of the compounds the rabbit was more sensitive and for 1.3% of compounds the rat was more sensitive based on Cmax exposures. When evaluated based on human equivalent dose (HED) conversion using standard factors, the rat and rabbit were equally sensitive. The relative extent of embryo-fetal toxicity in the presence of maternal toxicity was not different between species. Overall effect severity incidences were distributed similarly in rat and rabbit studies. Individual rat and rabbit strains did not show a different general distribution of systemic exposure LOAELs as compared to all strains combined for each species. There were no apparent species differences in the occurrence of embryo-fetal variations. Based on power of detection and given differences in the nature of developmental effects between rat and rabbit study outcomes for individual compounds, EFDT studies in two species have added value over single studies.

PMID: 27766926 [PubMed - indexed for MEDLINE]

24 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

("drug-induced" OR "drug-related") AND ("adverse events" OR "side effects" OR "side-effects")

These pubmed results were generated on 2017/10/05

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

24 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

("drug-induced" OR "drug-related") AND ("adverse events" OR "side effects" OR "side-effects")

These pubmed results were generated on 2017/10/05

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

Itraconazole induced congestive heart failure, a case study.

Curr Drug Saf. 2017 Oct 03;:

Authors: Abraham AO, Panda PK

Abstract
Only few cases have been reported with cardiovascular side effects, especially congestive heart failure (HF), of intraconazole therapy after black box warning by US-FDA (2001). It is unknown which category of patients should avoid this important antifungal treatment. A middle-aged man having past history of treated pulmonary tuberculosis and obstructive uropathy presented with 2-weeks of progressive cough with scanty purulent sputum and breathlessness without any fever, chest pain, or pedal edema. Chest examination demonstrated bilateral crackles in upper thorax. Kidney function tests were deranged. Imagings revealed both upper lobe fibrosis with an aspergilloma. He received tablet itraconazole (200mg BD) and on 3rd day, he developed signs and symptoms of congestive HF. With diuretics and stopping of itraconazole, he recovered. With WHO-UMC criteria, probable drug-induced HF was diagnosed. Hence, this case re-affirms a causal relationship between itraconazole and HF. Although previous case studies have characterised cardiac risk factors as relative contraindication to the use itraconazole; this case outlines a caution (or relative contraindication) for systemic use of the drug with non-cardiac risk factors like lungs pathology in form of old koch's fibrotic chest and/or chronic kidney disease; where posaconazole may be a better treatment of choice considering availability and cost issue.

PMID: 28971777 [PubMed - as supplied by publisher]

A systematic review of adverse drug events associated with administration of common asthma medications in children.

PLoS One. 2017;12(8):e0182738

Authors: Leung JS, Johnson DW, Sperou AJ, Crotts J, Saude E, Hartling L, Stang A

Abstract
OBJECTIVE: To systematically review the literature and determine frequencies of adverse drug events (ADE) associated with pediatric asthma medications.
METHODS: Following PRISMA guidelines, we systematically searched six bibliographic databases between January 1991 and January 2017. Study eligibility, data extraction and quality assessment were independently completed and verified by two reviewers. We included randomized control trials (RCT), case-control, cohort, or quasi-experimental studies where the primary objective was identifying ADE in children 1 month- 18 years old exposed to commercial asthma medications. The primary outcome was ADE frequency.
FINDINGS: Our search identified 14,540 citations. 46 studies were included: 24 RCT, 15 cohort, 4 RCT pooled analyses, 1 case-control, 1 open-label trial and 1 quasi-experimental study. Studies examined the following drug classes: inhaled corticosteroids (ICS) (n = 24), short-acting beta-agonists (n = 10), long-acting beta-agonists (LABA) (n = 3), ICS + LABA (n = 3), Leukotriene Receptor Antagonists (n = 3) and others (n = 3). 29 studies occurred in North America, and 29 were industry funded. We report a detailed index of 406 ADE descriptions and frequencies organized by drug class. The majority of data focuses on ICS, with 174 ADE affecting 13 organ systems including adrenal and growth suppression. We observed serious ADE, although they were rare, with frequency ranging between 0.9-6% per drug. There were no confirmed deaths, except for 13 potential deaths in a LABA study including combined adult and pediatric participants. We identified substantial methodological concerns, particularly with identifying ADE and determining severity. No studies utilized available standardized causality, severity or preventability assessments.
CONCLUSION: The majority of studies focus on ICS, with adrenal and growth suppression described. Serious ADE are relatively uncommon, with no confirmed pediatric deaths. We identify substantial methodological concerns, highlighting need for standardization with future research examining pediatric asthma medication safety.

PMID: 28793336 [PubMed - indexed for MEDLINE]

Improving medication safety and diabetes management in Hong Kong: a multidisciplinary approach.

Hong Kong Med J. 2017 Apr;23(2):158-67

Authors: Chung AY, Anand S, Wong IC, Tan KC, Wong CF, Chui WC, Chan EW

Abstract
INTRODUCTION: Patients with diabetes often require complex medication regimens. The positive impact of pharmacists on improving diabetes management or its co-morbidities has been recognised worldwide. This study aimed to characterise drug-related problems among diabetic patients in Hong Kong and their clinical significance, and to explore the role of pharmacists in the multidisciplinary diabetes management team by evaluating the outcome of their clinical interventions.
METHODS: An observational study was conducted at the Diabetes Clinic of a public hospital in Hong Kong from October 2012 to March 2014. Following weekly screening, and prior to the doctor's consultation, selected high-risk patients were interviewed by a pharmacist for medication reconciliation and review. Drug-related problems were identified and documented by the pharmacist who presented clinical recommendations to doctors to optimise a patient's drug regimen and resolve or prevent potential drug-related problems.
RESULTS: A total of 522 patients were analysed and 417 drug-related problems were identified. The incidence of patients with drug-related problems was 62.8% with a mean of 0.9 (standard deviation, 0.6) drug-related problems per patient. The most common categories of drug-related problems were associated with dosing (43.9%), drug choice (17.3%), and non-allergic adverse reactions (15.6%). Drugs most frequently involved targeted the endocrine or cardiovascular system. The majority (71.9%) of drug-related problems were of moderate clinical significance and 28.1% were considered minor problems. Drug-related problems were totally solved (50.1%) and partially solved (11.0%) by doctors' acceptance of pharmacist recommendations, or received acknowledgement from doctors (5.5%).
CONCLUSIONS: Pharmacists, in collaboration with the multidisciplinary team, demonstrated a positive impact by identifying, resolving, and preventing drug-related problems in patients with diabetes. Further plans for sustaining pharmacy service in the Diabetes Clinic would enable further studies to explore the long-term impact of pharmacists in improving patients' clinical outcomes in diabetes management.

PMID: 28302923 [PubMed - indexed for MEDLINE]

National Action Plan for Adverse Drug Event Prevention: Recommendations for Safer Outpatient Opioid Use.

Pain Med. 2016 Dec;17(12):2291-2304

Authors: Ducoffe AR, York A, Hu DJ, Perfetto D, Kerns RD

Abstract
INTRODUCTION: Adverse drug events (ADEs) have been highlighted as a major patient safety and public health challenge by the National Action Plan for Adverse Drug Event Prevention (ADE Action Plan), which was released by the Office of Disease Prevention and Health Promotion (ODPHP) in August 2014. The ADE Action Plan focuses on surveillance, evidence-based prevention, incentives, and oversights, additional research needs as well as possible measures and metrics to track progress of ADE prevention within three drug classes: anticoagulants, diabetes agents, and opioids.Objectives and Recommendations. With outpatient opioid prescriptions being a great concern among many healthcare providers, this article focuses on recommendations from the ADE Action Plan to help guide safer opioid use in healthcare delivery settings. Its aim is to discuss current federal methods in place to prevent opioid ADEs while also providing evidence to encourage providers and hospitals to innovate new systems and practices to increase prevention.

PMID: 28025363 [PubMed - indexed for MEDLINE]

Unusual side effect of acyclovir: bradycardia.

Am J Emerg Med. 2017 03;35(3):525.e3-525.e4

Authors: Gill D, Glidden M, Dean R

PMID: 27810252 [PubMed - indexed for MEDLINE]

Prescribe medication…Withdraw medication.

Turk J Gastroenterol. 2016 09;27(5):476

Authors: Cerezo Ruiz A

PMID: 27782901 [PubMed - indexed for MEDLINE]

Big Data Mining and Adverse Event Pattern Analysis in Clinical Drug Trials.

Assay Drug Dev Technol. 2016 Dec;14(10):557-566

Authors: Federer C, Yoo M, Tan AC

Abstract
Drug adverse events (AEs) are a major health threat to patients seeking medical treatment and a significant barrier in drug discovery and development. AEs are now required to be submitted during clinical trials and can be extracted from ClinicalTrials.gov ( https://clinicaltrials.gov/ ), a database of clinical studies around the world. By extracting drug and AE information from ClinicalTrials.gov and structuring it into a database, drug-AEs could be established for future drug development and repositioning. To our knowledge, current AE databases contain mainly U.S. Food and Drug Administration (FDA)-approved drugs. However, our database contains both FDA-approved and experimental compounds extracted from ClinicalTrials.gov . Our database contains 8,161 clinical trials of 3,102,675 patients and 713,103 reported AEs. We extracted the information from ClinicalTrials.gov using a set of python scripts, and then used regular expressions and a drug dictionary to process and structure relevant information into a relational database. We performed data mining and pattern analysis of drug-AEs in our database. Our database can serve as a tool to assist researchers to discover drug-AE relationships for developing, repositioning, and repurposing drugs.

PMID: 27631620 [PubMed - indexed for MEDLINE]

Contrast Utilization During Chronic Total Occlusion Percutaneous Coronary Intervention: Insights From a Contemporary Multicenter Registry.

J Invasive Cardiol. 2016 Jul;28(7):288-94

Authors: Christakopoulos GE, Karmpaliotis D, Alaswad K, Yeh RW, Jaffer FA, Wyman RM, Lombardi W, Grantham JA, Kandzari DA, Lembo N, Moses JW, Kirtane A, Parikh M, Green P, Finn M, Garcia S, Doing A, Patel M, Bahadorani J, Christopoulos G, Karatasakis A, Thompson CA, Banerjee S, Brilakis ES

Abstract
BACKGROUND: Administration of a large amount of contrast volume during chronic total occlusion (CTO) percutaneous coronary intervention (PCI) may lead to contrast-induced nephropathy.
METHODS: We examined the association of clinical, angiographic and procedural variables with contrast volume administered during 1330 CTO-PCI procedures performed at 12 experienced United States centers.
RESULTS: Technical and procedural success was 90% and 88%, respectively, and mean contrast volume was 289 ± 138 mL. Approximately 33% of patients received >320 mL of contrast (high contrast utilization group). On univariable analysis, male gender (P=.01), smoking (P=.01), prior coronary artery bypass graft surgery (P=.04), moderate or severe calcification (P=.01), moderate or severe tortuosity (P=.04), proximal cap ambiguity (P=.01), distal cap at a bifurcation (P<.001), side branch at the proximal cap (P<.001), blunt/no stump (P=.01), occlusion length (P<.001), higher J-CTO score (P=.02), use of antegrade dissection and reentry or retrograde approach (P<.001), ad hoc CTO-PCI (P=.04), dual arterial access (P<.001), and 8 Fr guide catheters (P<.001) were associated with higher contrast volume; conversely, diabetes mellitus (P=.01) and in-stent restenosis (P=.01) were associated with lower contrast volume. On multivariable analysis, moderate/severe calcification (P=.04), distal cap at a bifurcation (P<.001), ad hoc CTO-PCI (P<.001), dual arterial access (P=.01), 8 Fr guide catheters (P=.02), and use of antegrade dissection/reentry or the retrograde approach (P<.001) were independently associated with higher contrast use, whereas diabetes (P=.02), larger target vessel diameter (P=.03), and presence of "interventional" collaterals (P<.001) were associated with lower contrast utilization.
CONCLUSIONS: Several baseline clinical, angiographic, and procedural characteristics are associated with higher contrast volume administration during CTO-PCI.

PMID: 27342206 [PubMed - indexed for MEDLINE]

11 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

("drug-induced" OR "drug-related") AND ("adverse events" OR "side effects" OR "side-effects")

These pubmed results were generated on 2017/10/03

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

Psychiatric Patients with Antipsychotic Drug-Induced Hyperprolactinemia and Menstruation Disorders.

Biol Pharm Bull. 2017;40(10):1775-1778

Authors: Takechi K, Yoshioka Y, Kawazoe H, Tanaka M, Takatori S, Kobayashi M, Matsuoka I, Yanagawa H, Zamami Y, Imanishi M, Ishizawa K, Tanaka A, Araki H

Abstract
Treatment with antipsychotic drugs has been associated with hyperprolactinemia. The same antipsychotic drugs have also been associated with side effects such as menstruation disorders. The aim of this study was to evaluate the prevalence of hyperprolactinemia and menstruation disorders in women undergoing antipsychotic treatment. We performed a retrospective chart review study of psychiatric patients who underwent laboratory testing for serum prolactin (PRL) level between March 2011 and March 2015 in Ehime University Hospital. Patients presenting with and without menstruation disorders were evaluated to determine if they presented concomitant hyperprolactinemia. Patients with menstrual disorders had a significant increase in serum PRL level with a mean of approximately 90 ng/mL. Those with menstrual disorders presented increased PRL levels by 2-fold that of patients without menstrual disorder. However, there was no significant difference in the equivalent dose of chlorpromazine between these two groups. Additionally, about 70% of patients with menstrual disorders received risperidone treatment. The receiver operating characteristic curve showed that the optimal cutoff point of serum PRL level associated with the development of menstrual disorders was 60 ng/mL. Based on these results, we concluded that patients with menstrual disorders presented increased serum PRL, and that most of them underwent treatment with risperidone.

PMID: 28966250 [PubMed - in process]

Post-marketing safety surveillance conducted in Korea (2008-2013) following the introduction of the rotavirus vaccine, RIX4414 (Rotarix™).

Hum Vaccin Immunother. 2016 Oct 02;12(10):2590-2594

Authors: Shin SM, Kim CS, Karkada N, Liu A, Jayadeva G, Han HH

Abstract
PURPOSE: According to regulations from the Ministry of Food and Drug Safety in Korea, additional safety information on the use of Rotarix™ vaccine (RIX4414; GSK, Belgium) in ≥3000 evaluable Korean infants was required following vaccine registration. In order to comply with these regulations, we conducted a 6-year open, non-comparative, multicenter post-marketing surveillance (NCT00750893).
METHODS: During this time, the original lyophilized vaccine formulation of RIX4414 was replaced by a liquid formulation. Healthy infants aged ≥6 weeks were enrolled and given 2 doses of the RIX4414 vaccine, separated by an interval of ≥4 weeks. The overall incidence of adverse events (AEs) (expected and unexpected) was then assessed for up to 30 days along with the incidence of serious adverse events (SAEs). Adverse drug reactions (ADRs: any AE whose causality to the drug could not be ruled out) were identified.
RESULTS: A total of 3040 children (mean age: 9.55 weeks) were analyzed. One or more expected AE was experienced by 30.5% infants and 8.6% had an ADR. The most commonly seen expected AE was irritability (14.0%). One or more unexpected AE was seen in 32.5% infants and 3.1% experienced an ADR. The most commonly seen unexpected AE was upper respiratory tract infection (8.7%). Of 34 SAEs recorded in 24 subjects, none were related to vaccination.
CONCLUSIONS: We conclude that this 6-year surveillance showed both formulations of RIX4414 to have acceptable safety profiles when administered to Korean infants according to local prescribing recommendations and current clinical practice.

PMID: 27494163 [PubMed - indexed for MEDLINE]

Pembrolizumab (Keytruda).

Hum Vaccin Immunother. 2016 Nov;12(11):2777-2789

Authors: Kwok G, Yau TC, Chiu JW, Tse E, Kwong YL

Abstract
The programmed cell death protein 1 (PD1) is one of the checkpoints that regulates the immune response. Ligation of PD1 with its ligands PDL1 and PDL2 results in transduction of negative signals to T-cells. PD1 expression is an important mechanism contributing to the exhausted effector T-cell phenotype. The expression of PD1 on effector T-cells and PDL1 on neoplastic cells enables tumor cells to evade anti-tumor immunity. Blockade of PD1 is an important immunotherapeutic strategy for cancers. Pembrolizumab (Keytruda) is a humanized monoclonal anti-PD1 antibody that has been extensively investigated in numerous malignancies. In melanoma refractory to targeted therapy, pembrolizumab induced overall response rates (ORRs) of 21-34%. It was superior to another immune checkpoint inhibitor ipilimumab (Yervoy) in stage III/IV unresectable melanoma. In refractory non-small cell lung cancer (NSCLC), pembrolizumab induced ORRs of 19-25%. Based on these results, pembrolizumab was approved by the USA FDA for the treatment of advanced melanoma and NSCLC. Tumor cell PDL1 expression may be a valid response predictor. Molecular analysis also showed that tumors with high gene mutation burdens, which might result in the formation of more tumor-related neo-antigens, had better responses to pembrolizumab. In malignancies including lymphomas and other solid tumors, preliminary data showed that ORRs of around 20-50 % could be achieved. Adverse events occurred in up to 60% of patients, but grade 3/4 toxicities were observed in <10% of cases. Immune-related adverse events including thyroid dysfunction, hepatitis and pneumonitis are more serious and may lead to cessation of treatment.

PMID: 27398650 [PubMed - indexed for MEDLINE]

Post-licensure safety surveillance study of routine use of tetanus toxoid, reduced diphtheria toxoid and 5-component acellular pertussis vaccine.

Hum Vaccin Immunother. 2016 Nov;12(11):2742-2748

Authors: Baxter R, Hansen J, Timbol J, Pool V, Greenberg DP, Johnson DR, Decker MD

Abstract
An observational post-licensure (Phase IV) retrospective large-database safety study was conducted at Kaiser Permanente, a US integrated medical care organization, to assess the safety of Tetanus Toxoid, Reduced Diphtheria Toxoid and 5-Component Acellular Pertussis Vaccine (Tdap5) administered as part of routine healthcare among adolescents and adults. We evaluated incidence rates of various clinical events resulting in outpatient clinic, emergency department (ED), and hospital visits during various time intervals (windows) following Tdap5 vaccination using 2 pharmacoepidemiological methods (risk interval and historic cohort) and several screening thresholds. Plausible outcomes of interest with elevated incidence rate ratios (IRRs) were further evaluated by reviewing individual patient records to confirm the diagnosis, timing (temporal relationship), alternative etiology, and other health record details to discern possible relatedness of the health events to vaccination. Overall, 124,139 people received Tdap5 vaccine from September 2005 through mid-October 2006, and 203,154 in the comparison cohort received a tetanus and diphtheria toxoid adsorbed vaccine (and no live virus vaccine) during the year prior to initiation of this study. In the outpatient, ED and hospital databases, respectively, we identified 11/26, 179/700 and 187/700 unique health outcomes with IRRs significantly >1.0. Among the same unique health outcomes in the outpatient, ED, and hospital databases, 9, 146, and 385, respectively, had IRRs significantly <1.0. Further scrutiny of the outcomes with elevated IRRs did not reveal unexpected signals of adverse outcomes related to vaccination. In conclusion, Tdap5 vaccine was found to be safe among this large population of adolescents and adults.

PMID: 27388557 [PubMed - indexed for MEDLINE]