Short-term androgen suppression and radiotherapy versus intermediate-term androgen suppression and radiotherapy, with or without zoledronic acid, in men with locally advanced prostate cancer (TROG 03.04 RADAR): 10-year results from a randomised, phase 3, factorial trial.

Lancet Oncol. 2018 Dec 19;:

Authors: Denham JW, Joseph D, Lamb DS, Spry NA, Duchesne G, Matthews J, Atkinson C, Tai KH, Christie D, Kenny L, Turner S, Gogna NK, Diamond T, Delahunt B, Oldmeadow C, Attia J, Steigler A

Abstract
BACKGROUND: The optimal duration of androgen suppression for men with locally advanced prostate cancer receiving radiotherapy with curative intent is yet to be defined. Zoledronic acid is effective in preventing androgen suppression-induced bone loss, but its role in preventing castration-sensitive bone metastases in locally advanced prostate cancer is unclear. The RADAR trial assessed whether the addition of 12 months of adjuvant androgen suppression, 18 months of zoledronic acid, or both, can improve outcomes in men with locally advanced prostate cancer who receive 6 months of androgen suppression and prostatic radiotherapy. This report presents 10-year outcomes from this trial.
METHODS: For this randomised, phase 3, 2 × 2 factorial trial, eligible men were 18 years or older with locally advanced prostate cancer (either T2b-4, N0 M0 tumours or T2a, N0 M0 tumours provided Gleason score was ≥7 and baseline prostate-specific antigen [PSA] concentration was ≥10 μg/L). We randomly allocated participants in a 2 × 2 factorial design by computer-generated randomisation (using the minimisation technique, and stratified by centre, baseline PSA concentration, clinical tumour stage, Gleason score, and use of a brachytherapy boost) in a 1:1:1:1 ratio to four treatment groups. Patients in the control group received 6 months of neoadjuvant androgen suppression with leuprorelin (22·5 mg every 3 months, intramuscularly) and radiotherapy alone (short-term androgen suppression [STAS]); this treatment was either followed by another 12 months of adjuvant androgen suppression with leuprorelin (22·5 mg every 3 months, intramuscularly; intermediate-term androgen suppression [ITAS]), or accompanied by 18 months of zoledronic acid (4 mg every 3 months, intravenously) starting at randomisation (STAS plus zoledronic acid), or both (ITAS plus zoledronic acid). All patients received radiotherapy to the prostate and seminal vesicles, starting from the end of the fifth month of androgen suppression; dosing options were 66, 70, and 74 Gy in 2-Gy fractions per day, or 46 Gy in 2-Gy fractions followed by a high-dose-rate brachytherapy boost dose of 19·5 Gy in 6·5-Gy fractions. Treatment allocation was open label. The primary endpoint was prostate cancer-specific mortality and was analysed according to intention-to-treat using competing-risks methods. The trial is closed to follow-up and this is the final report of the main endpoints. This trial is registered with ClinicalTrials.gov, number NCT00193856.
FINDINGS: Between Oct 20, 2003, and Aug 15, 2007, 1071 men were enrolled and randomly assigned to STAS (n=268), ITAS (n=268), STAS plus zoledronic acid (n=268), and ITAS plus zoledronic acid (n=267). Median follow-up was 10·4 years (IQR 7·9-11·7). At this 10-year follow-up, no interactions were observed between androgen suppression and zoledronic acid so the treatment groups were collapsed to compare treatments according to duration of androgen suppression: 6 months of androgen suppression plus radiotherapy (6AS+RT) versus 18 months of androgen suppression plus radiotherapy (18AS+RT) and to compare treatments according to whether or not patients received zoledronic acid. The total number of deaths was 375 (200 men receiving 6AS+RT and 175 men receiving 18AS+RT), of which 143 (38%) were attributable to prostate cancer (81 men receiving 6AS+RT and 62 men receiving 18AS+RT). When analysed by duration of androgen suppression, the adjusted cumulative incidence of prostate cancer-specific mortality was 13·3% (95% CI 10·3-16·0) for 6AS+RT versus 9·7% (7·3-12·0) for 18AS+RT, representing an absolute difference of 3·7% (95% CI 0·3-7·1; sub-hazard ratio [sHR] 0·70 [95% CI 0·50-0·98], adjusted p=0·035). The addition of zoledronic acid did not affect prostate cancer-specific mortality; the adjusted cumulative incidence of prostate cancer-specific mortality was 11·2% (95% CI 8·7-13·7) with zoledronic acid vs 11·7% (9·2-14·1) without, representing an absolute difference of -0·5% (95% CI -3·8 to 2·9; sHR 0·95 [95% CI 0·69-1·32], adjusted p=0·78). Although safety analysis was not prespecified for this 10-year analysis, one new serious adverse event (osteonecrosis of the mandible, in a patient who received 18 months of androgen suppression plus zoledronic acid) occurred since our previous report, bringing the total number of cases of this serious adverse event to three (<1% out of 530 patients who received zoledronic acid evaluated for safety) and the total number of drug-related serious adverse events to 12 (1% out of all 1065 patients evaluable for safety). No treatment-related deaths occurred during the study.
INTERPRETATION: 18 months of androgen suppression plus radiotherapy is a more effective treatment option for locally advanced prostate cancer than 6 months of androgen suppression plus radiotherapy, but the addition of zoledronic acid to this treatment regimen is not beneficial. Evidence from the RADAR and French Canadian Prostate Cancer Study IV trials suggests that 18 months of androgen suppression with moderate radiation dose escalation is an effective but more tolerable option than longer durations of androgen suppression for men with locally advanced prostate cancer including intermediate and high risk elements.
FUNDING: National Health and Medical Research Council of Australia, Novartis Pharmaceuticals Australia, AbbVie Pharmaceuticals Australia, New Zealand Health Research Council, New Zealand Cancer Society, Cancer Standards Institute New Zealand, University of Newcastle (Australia), Hunter Medical Research Institute, Calvary Mater Newcastle Radiation Oncology Fund, and Maitland Cancer Appeal.

PMID: 30579763 [PubMed - as supplied by publisher]

Drug-related Dysgeusia: A Systematic Review.

Oral Health Prev Dent. 2018;16(6):499-507

Authors: Mortazavi H, Shafiei S, Sadr S, Safiaghdam H

Abstract
PURPOSE: Dysgeusia is an unpleasant alteration in taste. It can affect the nutritional and psychological status and decrease the quality of life of patients. It may be caused by nerve injury, head and neck trauma or surgery, infections, radiotherapy and drugs, but certain aetiological factors have not yet been identified. Understanding dysgeusia as a drug side effect is important for practitioners. The aim of this systematic review was to provide detailed information about dysgeusia in patients receiving different common medications.
MATERIALS AND METHODS: An electronic search was conducted in MEDLINE, Google Scholar and Scopus databases, and studies were selected according to our inclusion criteria. We included studies on human subjects that reported dysgeusia as a drug side effect.
RESULTS: Thirty-four eligible studies were included in the systematic review. Thirty-five drugs were found in the literature to be correlated to dysgeusia. The most commonly reported offending drugs were from keratolytic agents, chemotherapeutic and cancer medication, antihistamine, antibiotics and angiotensin-converting enzyme inhibitors.
CONCLUSION: The quality of evidence was low in most reviewed studies. More studies with standard methodology are needed in this field. However, physicians and dental practitioners must consider the probability of dysgeusia as an adverse side effect when prescribing certain medications.

PMID: 30574604 [PubMed - in process]

Oral manifestation of systemic diseases-a perspective from an oral pathology diagnostic service.

Oral Dis. 2018 03;24(1-2):219-223

Authors: Bradley G, Magalhaes MA

PMID: 29480619 [PubMed - indexed for MEDLINE]

Assessing the safety of new drugs during pregnancy.

Br J Dermatol. 2018 01;178(1):18-19

Authors: Hyrich KL

PMID: 29357613 [PubMed - indexed for MEDLINE]

Favorable adverse effect profile of brivaracetam vs levetiracetam in a preclinical model.

Epilepsy Behav. 2018 02;79:117-125

Authors: Sanon NT, Gagné J, Wolf DC, Aboulamer S, Bosoi CM, Simard A, Messiet E, Desgent S, Carmant L

Abstract
Levetiracetam (LEV), and its newer selective analog brivaracetam (BRV), are two seizure medications that share an innovative mechanism of action targeting the Synaptic Vesicle Protein 2A (SV2A), altering neurotransmitter release and decreasing seizure frequency. Behavioral changes are the most significant adverse effects reported by patients taking LEV. We hypothesize that BRV, the more potent SV2A analog, could exert less behavioral side effects, as it requires lower doses than LEV. Using Kainic Acid (KA)-treated and control rats, we measured adverse behavioral effect profiles of LEV, BRV, or Saline, on social and nonsocial behaviors. Our data indicate that both tested drugs had no effect on locomotion, anxiety levels, fear learning, depression-like behavior, and memory retention in rats. However, when considering social interactions, we first confirmed the epilepsy-induced strong increase in aggressive behaviors and specific hippocampal neuronal loss. We furthermore observed, in Sham rats, that LEV-treated animals were 2 times faster to attack at first encounter, had 5 times more aggressive behaviors, and had significantly less social behaviors than control rats. In all circumstances, BRV rats behaved like Saline rats, suggesting that BRV treatment in rats leads to significantly less aggressive behaviors than LEV treatment at the doses used, while there are limited differential effects between these two drugs on other types of behaviors. Since increased aggressiveness has been reported in patients well controlled on LEV, this study indicates based on our findings, that BRV could represent an effective alternative to LEV to limit aggressiveness problems due to this antiepileptic drug (AED) therapy.

PMID: 29287214 [PubMed - indexed for MEDLINE]

Metabolic Network Prediction of Drug Side Effects.

Cell Syst. 2016 Mar 23;2(3):209-13

Authors: Shaked I, Oberhardt MA, Atias N, Sharan R, Ruppin E

Abstract
Drug side effects levy a massive cost on society through drug failures, morbidity, and mortality cases every year, and their early detection is critically important. Here, we describe the array of model-based phenotype predictors (AMPP), an approach that leverages medical informatics resources and a human genome-scale metabolic model (GSMM) to predict drug side effects. AMPP is substantially predictive (AUC > 0.7) for >70 drug side effects, including very serious ones such as interstitial nephritis and extrapyramidal disorders. We evaluate AMPP's predictive signal through cross-validation, comparison across multiple versions of a side effects database, and co-occurrence analysis of drug side effect associations in scientific abstracts (hypergeometric p value = 2.2e-40). AMPP outperforms a previous biochemical structure-based method in predicting metabolically based side effects (aggregate AUC = 0.65 versus 0.59). Importantly, AMPP enables the identification of key metabolic reactions and biomarkers that are predictive of specific side effects. Taken together, this work lays a foundation for future detection of metabolically grounded side effects during early stages of drug development.

PMID: 27135366 [PubMed - indexed for MEDLINE]

A critical review of adverse effects to the kidney: mechanisms, data sources, and in silico tools to assist prediction.

Expert Opin Drug Metab Toxicol. 2018 Dec;14(12):1225-1253

Authors: Pletz J, Enoch SJ, Jais DM, Mellor CL, Pawar G, Firman JW, Madden JC, Webb SD, Tagliati CA, Cronin MTD

Abstract
INTRODUCTION: The kidney is a major target for toxicity elicited by pharmaceuticals and environmental pollutants. Standard testing which often does not investigate underlying mechanisms has proven not to be an adequate hazard assessment approach. As such, there is an opportunity for the application of computational approaches that utilize multiscale data based on the Adverse Outcome Pathway (AOP) paradigm, coupled with an understanding of the chemistry underpinning the molecular initiating event (MIE) to provide a deep understanding of how structural fragments of molecules relate to specific mechanisms of nephrotoxicity. Aims covered: The aim of this investigation was to review the current scientific landscape related to computational methods, including mechanistic data, AOPs, publicly available knowledge bases and current in silico models, for the assessment of pharmaceuticals and other chemicals with regard to their potential to elicit nephrotoxicity. A list of over 250 nephrotoxicants enriched with, where possible, mechanistic and AOP-derived understanding was compiled. Expert opinion: Whilst little mechanistic evidence has been translated into AOPs, this review identified a number of data sources of in vitro, in vivo, and human data that may assist in the development of in silico models which in turn may shed light on the interrelationships between nephrotoxicity mechanisms.

PMID: 30345815 [PubMed - indexed for MEDLINE]

Desloratadine and depression, a drug safety signal based on worldwide spontaneous reporting of side effects.

Ups J Med Sci. 2018 Sep;123(3):174-178

Authors: Boer J, Ederveen E, Grundmark B

Abstract
OBJECTIVE: Desloratadine, a third-generation antihistamine, is claimed to cause fewer central nervous system (CNS) adverse drug reactions (ADRs) than antihistamines of the first- and second-generation. While literature is inconclusive regarding the possible CNS effects, symptoms like somnolence and hallucinations are acknowledged ADRs of desloratadine, indeed suggesting some passage of this drug across the blood-brain barrier. Depression is currently not described as an ADR in the approved desloratadine product labelling.
MATERIALS AND METHODS: In a joint signal detection workshop with the Uppsala Monitoring Centre and the Netherlands Pharmacovigilance Centre Lareb, case reports of suspected drug-ADR associations were analysed.
RESULTS: Forty-nine unique case reports of desloratadine associated with depression or depressed mood were detected in the WHO global ADR database. In these reports, the median time to onset of depression was three days. Most patients recovered after withdrawal of desloratadine, and in five patients the symptoms of depression recurred after re-administration of desloratadine.
CONCLUSION: We hypothesize that desloratadine may enter the CNS and that it hence in rare cases may cause a clinically relevant state of depression, a relation that patients and their treating physicians should be made aware of.

PMID: 30084285 [PubMed - indexed for MEDLINE]

Untangling Galectin-Driven Regulatory Circuits in Autoimmune Inflammation.

Trends Mol Med. 2018 04;24(4):348-363

Authors: Toscano MA, Martínez Allo VC, Cutine AM, Rabinovich GA, Mariño KV

Abstract
Although progress has been made in understanding the mechanisms implicated in the pathogenesis of autoimmune inflammation, studies aimed at identifying the mediators of these pathways will be necessary to develop more selective therapies. Galectins, a family of glycan-binding proteins, play central roles in immune cell homeostasis. Whereas some members of this family trigger regulatory programs that promote resolution of inflammation, others contribute to perpetuate autoimmune processes. We discuss the roles of endogenous galectins and their specific glycosylated ligands in shaping autoimmune responses by fueling, extinguishing, or rewiring immune circuits. Understanding the relevance of galectin-glycan interactions in autoimmune inflammation could help to uncover novel pathways of tolerance breakdown, define molecular signatures for patient stratification and therapy responses, and open new avenues for immune intervention.

PMID: 29555188 [PubMed - indexed for MEDLINE]

Safer Prescribing and Care for the Elderly (SPACE): a pilot study in general practice.

BJGP Open. 2018 Oct;2(3):bjgpopen18X101594

Authors: Wallis KA, Elley CR, Moyes S, Kerse N

Abstract
Background: High-risk prescribing places patients at increased risk of adverse drug events (ADEs). High-risk prescribing and ADE hospitalisations are increasingly common as people are living longer and taking more medicines for multiple chronic conditions. The Safer Prescribing and Care for the Elderly (SPACE) intervention is designed to foster patient engagement in medicines management and prompt medicines review.
Aim: To pilot the SPACE intervention in preparation for a larger cluster randomised controlled trial (RCT).
Design & setting: A pilot study in two general practices. Study participants were all patients at increased risk of an adverse drug reaction (ADE) from non-steroidal anti-inflammatory drugs (NSAIDs) and/or antiplatelet medicines. The primary outcome was the proportion of participants receiving high-risk prescribing at 6 months and 12 months compared with baseline.
Method: The SPACE intervention comprised automated practice audit to identify and generate for each GP a list of patients with high-risk prescribing for these medicines; an outreach visit by clinical advisory pharmacist to deliver education and to go through with each GP their list of at-risk patients and indicate in a tick-box the intended action for each patient; and a mail-out from GPs to selected patients containing a medicines information brochure and a letter encouraging patients to discuss their medicines when they next see their GP.
Results: SPACE can be delivered within existing primary care infrastructure. The rate of high-risk prescribing was reduced at 6 months following the delivery of the intervention, but these improvements were not evident at 12 months.
Conclusion: SPACE prompts medicines review and shows promising signs of supporting safer prescribing in general practice in the short term. A randomised trial of SPACE started in 2018.

PMID: 30564727 [PubMed]

ATP-Binding Cassette Transporters in the Clinical Implementation of Pharmacogenetics.

J Pers Med. 2018 Dec 05;8(4):

Authors: López-Fernández LA

Abstract
ATP-binding cassette (ABC) transporters are involved in a large number of processes and contribute to various human genetic diseases. Among other functions, ABC proteins are involved in the transport of multiple drugs through cells. Most of the genes coding for these transporters are highly polymorphic and DNA variants in these genes can affect the normal functioning of these proteins, affecting the way drugs are transported, increasing or decreasing drug levels. These changes in the intracellular and extracellular drug levels may be associated with altered drug effectiveness or severe drug-induced adverse events. This review presents a state-of-art of the most pharmacogenetics clinically relevant ABC transporters closed to the clinical implementation.

PMID: 30563187 [PubMed]

Variations in drug-related problems detected by multidisciplinary teams in Norwegian nursing homes and home nursing care.

Scand J Prim Health Care. 2018 Sep;36(3):291-299

Authors: Devik SA, Olsen RM, Fiskvik IL, Halbostad T, Lassen T, Kuzina N, Enmarker I

Abstract
OBJECTIVE: Traditionally, nursing homes have been associated with suboptimal drug therapy and drug-related problems (DRPs). In contrast, less is known about drug safety in homecare. The aim of this study was to describe and compare DRPs in older persons across two care settings: nursing homes and home nursing care.
DESIGN: Cross-sectional study using descriptive and inferential statistics.
SETTING: Nursing homes (n = 5) and home nursing care units (n = 8) across nine municipalities in the middle of Norway.
PARTICIPANTS: Multidisciplinary medication reviews for 61 nursing home residents and 93 patients receiving home nursing care performed over the 2013-2014 period, were mapped and examined (N = 154).
MAIN OUTCOME MEASURES: DRPs classified by a Norwegian Classification Tool.
RESULTS: In all, 740 DRPs were detected in the total sample, 227 in nursing homes and 513 in home nursing care. DRPs were significantly higher among patients receiving home-based care (Mean =5.5) compared to patients in nursing homes (Mean =3.7, p = 0.002). Among the problem categories, the need for additional drug was most frequent in nursing homes (p = 0.001), while documentation discrepancies reached the highest numbers in patients receiving home nursing care (p = 0.000). Additionally, patients in home nursing care had more problems concerning adverse reactions (p = 0.060); however, this was not statistically significant. Differences in DRP categories leading to changes in the patients' medication lists were also discovered.
CONCLUSIONS: The frequency of unclear documentation and adverse reactions found in the homecare setting is alarming. This is an important issue given the trend in aged care towards caring people in their own homes. Further research is warranted to explore how different care settings may influence the safety of pharmacotherapy for older persons. Key Points Drug related problems are a significant cause of concern among patients receiving home nursing care as well as for patients living in nursing homes. The findings of this study showed that: •Significantly more DRPs were detected among patients receiving home nursing care than patients living in nursing homes. •While patients living in nursing homes were often undermedicated, documentation discrepancies were more frequent in home nursing care. •DRP categories leading to changes on the medication lists differed between the settings.

PMID: 30139278 [PubMed - indexed for MEDLINE]

Anticoagulant-associated adverse drug reactions in 2013-15.

Tidsskr Nor Laegeforen. 2018 08 21;138(12):

Authors: Eek AK, Strøm BO, Bakkehøi G, Stenberg-Nilsen H

Abstract
BACKGROUND: The aim of this study was to obtain a better insight into the adverse effects profiles of the new direct-acting oral anticoagulants (DOACs).
MATERIAL AND METHOD: A review was undertaken of all reports of adverse effects for warfarin, dabigatran, rivaroxaban and apixaban reported to the regional medicines information and pharmacovigilance centres (RELIS) in the period June 2013-May 2015.
RESULTS: Approximately 65 000 persons used direct-acting oral anticoagulants and 80 000 used warfarin in the period of the study. A total of 409 reports of adverse effects were included. Altogether 55 % of the reports applied to men. In 76 % of the reports for direct-acting oral anticoagulants and 85 % for warfarin, the patients were more than 70 years of age. The most common adverse effects were haemorrhages (48 % for direct-acting oral anticoagulants and 75 % for warfarin), most of which were cerebral haemorrhages (91 for direct-acting oral anticoagulants and 92 for warfarin). Blood clots (therapeutic failure), cognitive effects, headache and hair loss were some of the other adverse effects. The highest comorbidity was among the patients who died. The number of reported deaths was highest for rivaroxaban (1.1 deaths/1000 users) with a declining incidence for apixaban (0.9 ‰), dabigatran (0.7 ‰) and warfarin (0.6 ‰). There were different degrees of reporting for these medications, and the spontaneous reporting system cannot therefore be used to compare the incidence of adverse effects for the drugs.
INTERPRETATION: Adverse effects, including serious effects, may occur when using all anticoagulants. Factors that may increase the risk of adverse effects are advanced age, high comorbidity, reduced renal function, and polypharmacy.

PMID: 30132616 [PubMed - indexed for MEDLINE]

Clinically relevant drug-drug interactions among elderly people with dementia.

Eur J Clin Pharmacol. 2018 Oct;74(10):1351-1360

Authors: Sönnerstam E, Sjölander M, Lövheim H, Gustafsson M

Abstract
PURPOSE: Increased numbers of drugs and changes in pharmacokinetic and pharmacodynamic parameters among elderly people contribute to increased prevalence of adverse drug reactions. Drug-drug interactions (DDIs) are an important reason for admission to hospital and elderly people with dementia are particularly vulnerable. The aims of the present study were to assess the occurrence and characteristics of clinically relevant DDIs and to investigate potential risk factors associated with DDIs among elderly people with dementia.
METHODS: People ≥ 65 years with dementia, admitted to two hospitals in Northern Sweden, were included. The medical records of 458 patients were reviewed. Clinically relevant DDIs were identified using the Janusmed interactions database. Pharmacological classification was conducted using Stockley's classification system.
RESULTS: A total of 401 DDIs were identified among 43.2% of the study population, of which 98.5% had interactions that may require dose adjustment and 7.6% had drug combinations that should be avoided. Pharmacodynamic interactions were most common, of which furosemide-citalopram (n = 35) were most frequently observed. Omeprazol-citalopram (n = 25) was the most common drug combination among pharmacokinetic interactions. Citalopram and warfarin were the most commonly involved drug substances. An association was found between a higher number of medications being prescribed and having at least one DDI.
CONCLUSION: Clinically relevant drug-drug interactions are prevalent among elderly people with dementia living in Northern Sweden. Drug-drug interactions should be identified in order to manage and prevent adverse outcomes. This is particularly important among this group of people especially when multiple medications are being prescribed.

PMID: 29967921 [PubMed - indexed for MEDLINE]

Analysis of the activity and safety of weekly low-dose bevacizumab-based regimens in heavily pretreated patients with metastatic breast cancer.

Thorac Cancer. 2018 05;9(5):613-620

Authors: Zhai X, Hong R, Fan Y, Yuan P, Wang J, Sang D, Chen J, Zhao C, Ou K, Ma F, Xu B

Abstract
BACKGROUND: Currently, there are no standard regimens for metastatic breast cancer patients (MBC) who have failed ≥ 3 chemotherapy treatments. The aim of this study was to assess whether weekly low-dose bevacizumab-based regimens were well tolerated and would improve efficacy in MBC patients who had failed numerous therapies.
METHODS: Seventeen patients with MBC who were heavily pretreated with a median of five regimens of therapy (range 1-10) between 2012 and 2016 were included in the analysis. Bevacizumab was administered at a dose of 100 mg intravenously once a week combined with one or two types of chemotherapeutic drugs until confirmed disease progression or an intolerable adverse event was observed. Patient characteristics, objective response rate, clinical benefit rate, progression-free survival, and toxicity were assessed.
RESULTS: All 17 patients had been pretreated with taxane-based and anthracycline-based chemotherapy. Weekly low-dose bevacizumab combined with one or two types of chemotherapeutic drugs, which had usually not been previously used (e.g. etoposide, irinotecan, pemetrexed, methotrexate, and nab-paclitaxel), was administered. Three patients achieved a partial response, while one had stable disease for > 24 weeks, and the clinical benefit rate was 23.5%. Median progression-free survival was 3.4 months (95% confidence interval 2.0-4.8). The most common hematological adverse events were neutropenia, anemia, and thrombocytopenia. Bevacizumab-related adverse events included grade 1 bleeding (17.6%) and grade 2 hypertension (5.9%).
CONCLUSIONS: Weekly low-dose bevacizumab combined with chemotherapy shows a relatively favorable clinical response and tolerable toxicity, providing a feasible option for heavily pretreated MBC patients.

PMID: 29575760 [PubMed - indexed for MEDLINE]

Endostar (rh-endostatin) versus placebo in combination with vinorelbine plus cisplatin chemotherapy regimen in treatment of advanced non-small cell lung cancer: A meta-analysis.

Thorac Cancer. 2018 05;9(5):606-612

Authors: An J, Lv W

Abstract
BACKGROUND: This meta-analysis was conducted to investigate the efficacy and safety of Endostar (rh-endostatin) versus a placebo in combination with a vinorelbine plus cisplatin (NP) chemotherapy regimen for the treatment of advanced non-small cell lung cancer (NSCLC).
METHODS: Two reviewers independently searched Medline, PubMed, the Cochrane Central Register of Controlled Trials (CENTRAL), Embase, ASCO, ESMO, the Web of Science, and CNKI databases to locate relevant controlled clinical trials. The treatment efficacy and drug-related toxicity of NP + Endostar (NPE) and NP groups were pooled through meta-analysis according to random or fixed effect models.
RESULTS: Fifteen prospective clinical studies were included in this meta-analysis. The pooled risk ratio (RR) for objective response rate was 1.74 (95% confidence interval [CI] 1.43-2.11); the objective response rate in the NPE group was significantly higher than in the NP group (P < 0.05). Nine publications evaluated the incidence of leucopenia between Endostar versus a placebo in combination with an NP chemotherapy regimen. The pooled results showed no statistically significant difference between NPE and NP chemotherapy regimens for leucopenia, thrombocytopenia, and nausea/vomiting risk (P > 0.05). The one-year survival rate in the NPE group was higher than in the NP group, with a statistically significant difference (RR = 1.70, 95% CI 1.07-2.89; P < 0.05).
CONCLUSION: Endostar combined with an NP chemotherapy regimen can improve the prognosis of patients with advanced NSCLC without increasing the risk of toxicity.

PMID: 29575575 [PubMed - indexed for MEDLINE]

Adverse reactions of sorafenib, sunitinib, and imatinib in treating digestive system tumors.

Thorac Cancer. 2018 05;9(5):542-547

Authors: Fu Y, Wei X, Lin L, Xu W, Liang J

Abstract
BACKGROUND: This study was conducted to assess the adverse reactions caused by multi-target tyrosine kinase inhibitor treatment of gastrointestinal tumors.
METHODS: We carried out a retrospective study of drug-related adverse reactions in 115 patients who were treated with sorafenib, sunitinib, and imatinib for primary hepatocellular carcinoma or gastrointestinal stromal tumors from October 2003 to March 2012 at the Peking University International Hospital.
RESULTS: The total incidence of adverse reactions of sorafenib, sunitinib, and imatinib in patients with hepatocellular carcinoma and gastrointestinal stromal tumors was > 80%. The main adverse reactions of sorafenib were hypertension in 38 patients (33.3%) and diarrhea in 28 patients (24.4%). Sunitinib was associated with higher incidence and greater grade 3-4 toxicity. The common toxicities were skin color changes in 105 patients (90.9%), hand-foot skin reactions in 65 patients (54.6%), and leukopenia (63.6%), hypertension (22.7%), proteinuria (22.7%), liver function impairment (22.7%), and hypomagnesemia (27.3%). While imatinib was well tolerated, it was associated with the highest number of adverse reactions, including skin color change (55.6%) and edema (38.9%). Hypophosphatemia (4.4%) and hoarseness (2.2%) only occurred in the sorafenib treatment group.
CONCLUSIONS: The adverse reactions of multi-target tyrosine kinase inhibitor treatments are generally mild to moderate, and most patients can tolerate these without the need for further intervention. Some serious adverse reactions may be alleviated by discontinuing the drugs or by administering symptomatic treatment.

PMID: 29575544 [PubMed - indexed for MEDLINE]

Rare disease prevention and treatment: the need for a level playing field.

Pharmacogenomics. 2018 02;19(3):243-247

Authors: Hughes DA, Plumpton CO

Abstract
Pharmacogenetic tests are being used increasingly to prevent rare and potentially life-threatening adverse drug reactions. For many tests, however, cost-effectiveness is hard to demonstrate, and with the exception of a few cases, widespread implementation remains a distant prospect. Many orphan drugs for rare diseases are also not cost effective but are nonetheless normally reimbursed. In this article, we argue that the health technology assessment of pharmacogenetic tests aimed to prevent rare but severe adverse drug reactions should be on a level playing field with orphan drugs. This is supported by a number of arguments, concerning the severity, rarity and iatrogenic nature of adverse drug reactions, the distribution of benefits and costs and societal preference towards prevention over treatment.

PMID: 29327657 [PubMed - indexed for MEDLINE]

The pharmacogenetics of medications used in general anesthesia.

Pharmacogenomics. 2018 02;19(3):285-298

Authors: Xie S, Ma W, Guo Q, Liu J, Li W, McLeod HL, He Y

Abstract
General anesthesia is a state of unconsciousness, amnesia, analgesia and akinesia induced by drugs including opioids, hypnotic-sedative agents, muscle relaxants and antiemetics. Clinical and genetic factors are reported to influence the efficacy and side effects of these agents. Based on the evidence, clinical action is needed to improve clinical outcomes. This review summarizes the latest knowledge with regards to the pharmacogenetics of anesthetics and general anesthesia related complications.

PMID: 29318929 [PubMed - indexed for MEDLINE]

Epilepsy field workers, a smartphone application and telephone telemedicine: Safe and effective epilepsy care in rural Nepal.

Seizure. 2018 Dec 10;64:54-58

Authors: Rajbhandari H, Joshi S, Malakar S, Paudel P, Jain P, Uppadaya K, Singh M, Patterson V

Abstract
PURPOSE: Most people with epilepsy live in low- or middle-income countries (LMICs) where there are relatively few doctors. Over 50% of people with epilepsy in these countries are untreated so other models of care are needed. In this report we evaluate a novel model of care.
METHODS: We trained four residents of Myagdi, a rural district in Nepal as epilepsy field workers (EFWs). They provided epilepsy awareness to their communities. When they identified someone with possible epilepsy they used a smartphone application (app) to determine the probability score for an episode being epileptic and contacted an epilepsy specialist by phone. If the specialist thought treatment was indicated this was arranged by the EFW. We recorded mortality, change of diagnosis at face-to-face consultation and drug-related events as measures of safety. Seizure frequency and general wellbeing were also recorded, and a questionnaire was devised to measure satisfaction.
RESULTS: 112 patients with app scores suggesting epileptic seizures were identified and managed in 18 months, of whom 15 had provoked seizures. Forty-three percent of epilepsy patients were untreated. At follow-up one had died of a cause other than epilepsy. Diagnostic agreement at face-to-face assessment was 93%. Overall 5% had side-effects of medication. Seizures were stopped in 33% and reduced in 57%. Ninety-six percent of patients preferred this service to travelling to other doctors.
CONCLUSION: This novel service met all criteria of safety and was effective in reducing frequency of seizures. Patients preferred it to conventional services. It should be transferable to other LMICs.

PMID: 30562653 [PubMed - as supplied by publisher]