Mining Adverse Events of Dietary Supplements from Product Labels by Topic Modeling.

Stud Health Technol Inform. 2017;245:614-618

Authors: Wang Y, Gunashekar DR, Adam TJ, Zhang R

Abstract
The adverse events of the dietary supplements should be subject to scrutiny due to their growing clinical application and consumption among U.S. adults. An effective method for mining and grouping the adverse events of the dietary supplements is to evaluate product labeling for the rapidly increasing number of new products available in the market. In this study, the adverse events information was extracted from the product labels stored in the Dietary Supplement Label Data-base (DSLD) and analyzed by topic modeling techniques, specifically Latent Dirichlet Allocation (LDA). Among the 50 topics generated by LDA, eight topics were manually evaluated, with topic relatedness ranging from 58.8% to 100% on the product level, and 57.1% to 100% on the ingredient level. Five out of these eight topics were coherent groupings of the dietary supplements based on their adverse events. The results demonstrated that LDA is able to group supplements with similar adverse events based on the dietary supplement labels. Such information can be potentially used by consumers to more safely use dietary supplements.

PMID: 29295169 [PubMed - indexed for MEDLINE]

Automating the Identification of Patient Safety Incident Reports Using Multi-Label Classification.

Stud Health Technol Inform. 2017;245:609-613

Authors: Wang Y, Coiera E, Runciman W, Magrabi F

Abstract
Automated identification provides an efficient way to categorize patient safety incidents. Previous studies have focused on identifying single incident types relating to a specific patient safety problem, e.g., clinical handover. In reality, there are multiple types of incidents reflecting the breadth of patient safety problems and a single report may describe multiple problems, i.e., it can be assigned multiple type labels. This study evaluated the abilty of multi-label classification methods to identify multiple incident types in single reports. Three multi-label methods were evaluated: binary relevance, classifier chains and ensemble of classifier chains. We found that an ensemble of classifier chains was the most effective method using binary Support Vector Machines with radial basis function kernel and bag-of-words feature extraction, performing equally well on balanced and stratified datasets, (F-score: 73.7% vs. 74.7%). Classifiers were able to identify six common incident types: falls, medications, pressure injury, aggression, documentation problems and others.

PMID: 29295168 [PubMed - indexed for MEDLINE]

Phenotyping and Visualizing Infusion-Related Reactions for Breast Cancer Patients.

Stud Health Technol Inform. 2017;245:599-603

Authors: Sun D, Sarda G, Skube SJ, Blaes AH, Khairat S, Melton GB, Zhang R

Abstract
Infusion-related reactions (IRRs) are typical adverse events for breast cancer patients. Detecting IRRs and visualizing their occurance associated with the drug treatment would potentially assist clinicians to improve patient safety and help researchers model IRRs and analyze their risk factors. We developed and evaluated a phenotyping algorithm to detect IRRs for breast cancer patients. We also designed a visualization prototype to render IRR patients' medications, lab tests and vital signs over time. By comparing with the 42 randomly selected doses that are manually labeled by a domain expert, the sensitivity, positive predictive value, specificity, and negative predictive value of the algorithms are 69%, 60%, 79%, and 85%, respectively. Using the algorithm, an incidence of 6.4% of patients and 1.8% of doses for docetaxel, 8.7% and 3.2% for doxorubicin, 10.4% and 1.2% for paclitaxel, 16.1% and 1.1% for trastuzumab were identified retrospectively. The incidences estimated are consistent with related studies.

PMID: 29295166 [PubMed - indexed for MEDLINE]

Mining Adverse Drug Reactions in Social Media with Named Entity Recognition and Semantic Methods.

Stud Health Technol Inform. 2017;245:322-326

Authors: Chen X, Deldossi M, Aboukhamis R, Faviez C, Dahamna B, Karapetiantz P, Guenegou-Arnoux A, Girardeau Y, Guillemin-Lanne S, Lillo-Le-Louët A, Texier N, Burgun A, Katsahian S

Abstract
Suspected adverse drug reactions (ADR) reported by patients through social media can be a complementary source to current pharmacovigilance systems. However, the performance of text mining tools applied to social media text data to discover ADRs needs to be evaluated. In this paper, we introduce the approach developed to mine ADR from French social media. A protocol of evaluation is highlighted, which includes a detailed sample size determination and evaluation corpus constitution. Our text mining approach provided very encouraging preliminary results with F-measures of 0.94 and 0.81 for recognition of drugs and symptoms respectively, and with F-measure of 0.70 for ADR detection. Therefore, this approach is promising for downstream pharmacovigilance analysis.

PMID: 29295108 [PubMed - indexed for MEDLINE]

Unblinded ASCOT study results do not rule out that muscle symptoms are an adverse effect of statins.

Evid Based Med. 2017 12;22(6):210

Authors: Adhyaru BB, Jacobson TA

PMID: 29056606 [PubMed - indexed for MEDLINE]

Incidence of early anxiety aggravation in trials of selective serotonin reuptake inhibitors in depression.

Acta Psychiatr Scand. 2017 10;136(4):343-351

Authors: Näslund J, Hieronymus F, Emilsson JF, Lisinski A, Nilsson S, Eriksson E

Abstract
OBJECTIVE: Selective serotonin reuptake inhibitors (SSRIs) may aggravate anxiety and agitation during the first days of treatment but the frequency of such reactions remains unknown.
METHOD: We analysed patient-level data from placebo-controlled trials of sertraline, paroxetine or citalopram in depressed adults. Somatic anxiety, psychic anxiety and psychomotor agitation as assessed using the Hamilton Depression Rating Scale (HDRS) were analysed in all trials (n = 8262); anxiety-related adverse events were analysed in trials investigating paroxetine and citalopram (n = 5712).
RESULTS: After one but not two weeks, patients on an SSRI were more likely than those on placebo to report enhanced somatic anxiety (adjusted risk 9.3% vs. 6.7%); likewise, mean rating of somatic anxiety was higher in the SSRI group. In contrast, patients receiving an SSRI were less likely to report aggravation of psychic anxiety (adjusted risk: 7.0% vs. 8.5%) with mean rating of psychic anxiety and agitation being lower in the SSRI group. The adverse event 'nervousness' was more common in patients given an SSRI (5.5% vs. 2.5%). Neither aggravation of HDRS-rated anxiety nor anxiety-related adverse events predicted poor antidepressant response.
CONCLUSION: Whereas an anxiety-reducing effect of SSRIs is notable already during the first week of treatment, these drugs may also elicit an early increase in anxiety in susceptible subjects that however does not predict a poor subsequent response to treatment.

PMID: 28859218 [PubMed - indexed for MEDLINE]

Safety of the 2D/3D direct-acting antiviral regimen in HCV-induced Child-Pugh A cirrhosis - A pooled analysis.

J Hepatol. 2017 Oct;67(4):700-707

Authors: Poordad F, Nelson DR, Feld JJ, Fried MW, Wedemeyer H, Larsen L, Cohen DE, Cohen E, Mobashery N, Tatsch F, Foster GR

Abstract
BACKGROUND & AIMS: Chronic hepatitis C virus (HCV)-infected patients with cirrhosis are a high-priority population for treatment. To help inform the benefit-risk profile of the all-oral direct-acting antiviral (DAA) combination regimen of ombitasvir, paritaprevir, and ritonavir, with or without dasabuvir (OBV/PTV/r±DSV) in patients with Child-Pugh A cirrhosis, we undertook a comprehensive review of AbbVie-sponsored clinical trials enrolling patients with Child-Pugh A cirrhosis.
METHODS: Twelve phase II or III clinical trials of the 2-DAA regimen of OBV/PTV/r±ribavirin (RBV) or the 3-DAA regimen of OBV/PTV/r+DSV±RBV that included patients with Child-Pugh A cirrhosis were reviewed; patients who completed treatment by November 16, 2015 were included in a pooled, post hoc safety assessment. The number and percentage of patients with treatment-emergent adverse events (TEAEs), serious TEAEs, and TEAEs consistent with hepatic decompensation were reported.
RESULTS: In 1,066 patients with Child-Pugh A cirrhosis, rates of serious TEAEs and TEAEs leading to study drug discontinuation were 5.3% (95% confidence interval [CI]: 4.1-6.8) and 2.2% (95% CI: 1.4-3.2), respectively. Thirteen patients (1.2%; 95% CI: 0.7-2.1) had a TEAE that was consistent with hepatic decompensation. The most frequent TEAEs consistent with hepatic decompensation were ascites (n=8), esophageal variceal hemorrhage (n=4), and hepatic encephalopathy (n=2).
CONCLUSIONS: This pooled analysis in 1,066 HCV-infected patients with Child-Pugh A cirrhosis confirms the safety of OBV/PTV/r±DSV±RBV in this population. These results support the use of OBV/PTV/r±DSV±RBV in this high-priority population. Lay summary: This pooled safety analysis in 1,066 HCV-infected patients with compensated cirrhosis, receiving treatment with ombitasvir, paritaprevir, and ritonavir with or without dasabuvir, with or without ribavirin, shows that the rate of hepatic decompensation events was similar to previously reported rates in untreated patients.

PMID: 28645740 [PubMed - indexed for MEDLINE]

Impact of an Integrated Antibiotic Allergy Testing Program on Antimicrobial Stewardship: A Multicenter Evaluation.

Clin Infect Dis. 2017 Jul 01;65(1):166-174

Authors: Trubiano JA, Thursky KA, Stewardson AJ, Urbancic K, Worth LJ, Jackson C, Stevenson W, Sutherland M, Slavin MA, Grayson ML, Phillips EJ

Abstract
Background: Despite the high prevalence of patient-reported antibiotic allergy (so-called antibiotic allergy labels [AALs]) and their impact on antibiotic prescribing, incorporation of antibiotic allergy testing (AAT) into antimicrobial stewardship (AMS) programs (AAT-AMS) is not widespread. We aimed to evaluate the impact of an AAT-AMS program on AAL prevalence, antibiotic usage, and appropriateness of prescribing.
Methods: AAT-AMS was implemented at two large Australian hospitals during a 14-month period beginning May 2015. Baseline demographics, AAL history, age-adjusted Charlson comorbidity index, infection history, and antibiotic usage for 12 months prior to testing (pre-AAT-AMS) and 3 months following testing (post-AAT-AMS) were recorded for each participant. Study outcomes included the proportion of patients who were "de-labeled" of their AAL, spectrum of antibiotic courses pre- and post-AAT-AMS, and antibiotic appropriateness (using standard definitions).
Results: From the 118 antibiotic allergy-tested patients, 226 AALs were reported (mean, 1.91/patient), with 53.6% involving 1 or more penicillin class drug. AAT-AMS allowed AAL de-labeling in 98 (83%) patients-56% (55/98) with all AALs removed. Post-AAT, prescribing of narrow-spectrum penicillins was more likely (adjusted odds ratio [aOR], 2.81, 95% confidence interval [CI], 1.45-5.42), as was narrow-spectrum β-lactams (aOR, 3.54; 95% CI, 1.98-6.33), and appropriate antibiotics (aOR, 12.27; 95% CI, 5.00-30.09); and less likely for restricted antibiotics (aOR, 0.16; 95% CI, .09-.29), after adjusting for indication, Charlson comorbidity index, and care setting.
Conclusions: An integrated AAT-AMS program was effective in both de-labeling of AALs and promotion of improved antibiotic usage and appropriateness, supporting the routine incorporation of AAT into AMS programs.

PMID: 28520865 [PubMed - indexed for MEDLINE]

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Using a cancer registry to capture signals of adverse events following immune and targeted therapy for melanoma.

Int J Clin Pharm. 2018 Jun 02;:

Authors: Aguiar JP, Cardoso Borges F, Murteira R, Ramos C, Gouveia E, Passos MJ, Miranda A, da Costa FA

Abstract
Background Toxicity of oncology treatments in real-life patients is frequently disregarded and hence underreported. Objective To characterize adverse events (AEs) of immunotherapy and targeted therapy reported in patients with locally advanced or metastatic melanoma. Setting District Hospital for Cancer treatment (Instituto Português de Oncologia de Lisboa Francisco Gentil). Method A retrospective cohort of melanoma patients was established, comprising adult patients diagnosed with malignant melanoma treated with immunotherapy or targeted therapy. Exposure was characterized by nature, time and intensity of exposure. To account for different exposure periods, person-time was used as unit of analysis. Main outcomes measure Occurrence of AEs. Results Data from 111 patients included in the cohort indicates the majority received immunotherapy regimens (CTLA-4, anti-PD-1 and combination therapy; (n = 70; 63.1%), among which anti-PD-1 were the predominant treatment. Pembrolizumab was the most frequently prescribed drug (n = 30; 45.7%). Three hundred and seventy-one AEs were extracted. The incidence of AEs was lower in the anti-PD-1 mAc group (54 AEs per 1000 person.months) and the number of AEs/patient was also lower (3.1 ± 2.0). Grade 3 to 4 AEs occurred in 15.3% (n = 17) of the cohort, being more common in the targeted therapy group. Forty-two (11.6%) of the extracted AEs were not described in the Summary of Product Characteristics of the drugs under study. Conclusion This study suggests various known and unknown AEs of immunotherapy and targeted therapy may be identified using the Cancer Registry database. These events should be considered as signals worth further investigation for assessment of causality as the underreporting of AEs in cancer may have potential implications for the patient's quality of life.

PMID: 29860707 [PubMed - as supplied by publisher]

A randomized phase 2B trial of vancomycin versus daptomycin for the treatment of methicillin-resistant Staphylococcus aureus bacteremia due to isolates with high vancomycin minimum inhibitory concentrations - results of a prematurely terminated study.

Trials. 2018 Jun 01;19(1):305

Authors: Kalimuddin S, Chan YFZ, Phillips R, Ong SP, Archuleta S, Lye DC, Tan TT, Low JGH

Abstract
BACKGROUND: Studies have suggested the reduced effectiveness of vancomycin against methicillin-resistant Staphylococcus aureus (MRSA) bloodstream infections with high vancomycin minimum inhibitory concentrations. Alternative agents such as daptomycin may be considered. We conducted a randomized controlled study comparing daptomycin against vancomycin in the treatment of MRSA bloodstream infections with high vancomycin minimum inhibitory concentrations.
METHODS: Patients were randomized to receive vancomycin or daptomycin for a minimum of 14 days. The primary end point was the rate of all-cause mortality at day 60.
RESULTS: A total of 14 patients were randomized in this study, with 7 patients in each treatment arm. The study was terminated early due to slow patient accrual. At day 60, there was one death in the vancomycin arm and none in the daptomycin arm. The median time to microbiological clearance was 4 days in both arms (IQR 3-5 days in the vancomycin arm and 3-7 days in daptomycin arm). Only one patient in the vancomycin arm had recurrence of bacteremia. Rates of adverse events were similar in both arms. There was one case of musculoskeletal toxicity and one case of drug-related nephrotoxicity - both events occurred in the daptomycin arm. None of the patients in either treatment arm required cessation of study treatment or addition of a second anti-MRSA agent because of worsening infection.
CONCLUSION: Based on the limited number of patients evaluated in this study, it remains unclear if alternative, more expensive agents such as daptomycin are superior to vancomycin in the treatment of high vancomycin minimum inhibitory concentration MRSA bloodstream infections. More studies are urgently needed but investigators may wish to consider employing novel, alternative trial methodologies to ensure a greater chance of success.
TRIAL REGISTRATION: ClinicalTrials.gov, NCT01975662 . Registered on 5 November 2013.

PMID: 29859132 [PubMed - in process]

Lesson of the month 2: An unusual adverse reaction associated with pramipexole.

Clin Med (Lond). 2018 Jun;18(3):259-260

Authors: Tashkent Y, Aiyappan V

Abstract
Dopamine agonists such as pramipexole are commonly used in the treatment of restless legs syndrome (RLS) as well as Parkinson's disease. Pramipexole's common side effects are well documented; however, adverse skin reactions are less well known. In this case, a 45-year-old male farmer presented with excessive daytime tiredness and reported a history suggestive of RLS. He was initiated on pramipexole but developed a maculopapular erythematous rash in sun-exposed areas 8 days after its commencement. The skin rash resolved following pramipexole's cessation and it is thought the patient experienced a drug-induced photosensitivity reaction to pramipexole. This case highlights the potential for photosensitivity reactions to pramipexole, which is especially significant in countries like Australia where UV solar radiation is especially high.

PMID: 29858440 [PubMed - in process]

Addressing the Side Effects of Contemporary Antidepressant Drugs: A Comprehensive Review.

Chonnam Med J. 2018 May;54(2):101-112

Authors: Wang SM, Han C, Bahk WM, Lee SJ, Patkar AA, Masand PS, Pae CU

Abstract
Randomized trials have shown that selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) have better safety profiles than classical tricyclic antidepressants (TCAs). However, an increasing number of studies, including meta-analyses, naturalistic studies, and longer-term studies suggested that SSRIs and SNRIs are no less safe than TCAs. We focused on comparing the common side effects of TCAs with those of newer generation antidepressants including SSRIs, SNRIs, mirtazapine, and bupropion. The main purpose was to investigate safety profile differences among drug classes rather than the individual antidepressants, so studies containing comparison data on drug groups were prioritized. In terms of safety after overdose, the common belief on newer generation antidepressants having fewer side effects than TCAs appears to be true. TCAs were also associated with higher drop-out rates, lower tolerability, and higher cardiac side-effects. However, evidence regarding side effects including dry mouth, gastrointestinal side effects, hepatotoxicity, seizure, and weight has been inconsistent, some studies demonstrated the superiority of SSRIs and SNRIs over TCAs, while others found the opposite. Some other side effects such as sexual dysfunction, bleeding, and hyponatremia were more prominent with either SSRIs or SNRIs.

PMID: 29854675 [PubMed]

Reducing the Toxicity Risk in Antibiotic Prescriptions by Combining Ontologies with a Multiple Criteria Decision Model.

AMIA Annu Symp Proc. 2017;2017:1625-1634

Authors: Souissi SB, Abed M, Elhiki L, Fortemps P, Pirlot M

Abstract
We consider the risk of adverse drug events caused by antibiotic prescriptions. Antibiotics are the second most common cause of drug related adverse events and one of the most common classes of drugs associated with medical malpractice claims. To cope with this serious issue, physicians rely on guidelines, especially in the context of hospital prescriptions. Unfortunately such guidelines do not offer sufficient support to solve the problem of adverse events. To cope with these issues our work proposes a clinical decision support system based on expert medical knowledge, which combines semantic technologies with multiple criteria decision models. Our model links and assesses the adequacy of each treatment through the toxicity risk of side effects, in order to provide and explain to physicians a sorted list of possible antibiotics. We illustrate our approach through carefully selected case studies in collaboration with the EpiCURA Hospital Center in Belgium.

PMID: 29854233 [PubMed - in process]

Molecular Aspects of Circadian Pharmacology and Relevance for Cancer Chronotherapy.

Int J Mol Sci. 2017 Oct 17;18(10):

Authors: Ozturk N, Ozturk D, Kavakli IH, Okyar A

Abstract
The circadian timing system (CTS) controls various biological functions in mammals including xenobiotic metabolism and detoxification, immune functions, cell cycle events, apoptosis and angiogenesis. Although the importance of the CTS is well known in the pharmacology of drugs, it is less appreciated at the clinical level. Genome-wide studies highlighted that the majority of drug target genes are controlled by CTS. This suggests that chronotherapeutic approaches should be taken for many drugs to enhance their effectiveness. Currently chronotherapeutic approaches are successfully applied in the treatment of different types of cancers. The chronotherapy approach has improved the tolerability and antitumor efficacy of anticancer drugs both in experimental animals and in cancer patients. Thus, chronobiological studies have been of importance in determining the most appropriate time of administration of anticancer agents to minimize their side effects or toxicity and enhance treatment efficacy, so as to optimize the therapeutic ratio. This review focuses on the underlying mechanisms of the circadian pharmacology i.e., chronopharmacokinetics and chronopharmacodynamics of anticancer agents with the molecular aspects, and provides an overview of chronotherapy in cancer and some of the recent advances in the development of chronopharmaceutics.

PMID: 29039812 [PubMed - indexed for MEDLINE]

Prevalence of thiopurine S-methyltransferase gene polymorphisms in patients with inflammatory bowel disease from the island of Crete, Greece.

Eur J Gastroenterol Hepatol. 2017 Nov;29(11):1284-1289

Authors: Coucoutsi C, Emmanouil G, Goulielmos G, Sfakianaki O, Koutroubakis IE, Kouroumalis EA

Abstract
BACKGROUND: There is evidence that genotyping for the thiopurine S-methyltransferase (TPMT) gene variants is useful for the prediction of response to thiopurine analogs (azathioprine and 6-mercaptopurine) in patients with inflammatory bowel disease (IBD). The aim of the present study was to determine the prevalence of TPMT gene polymorphisms in a genetic homogenous population of IBD patients in Crete and to correlate the results with adverse reactions to thiopurine drugs.
PATIENTS AND METHODS: Genotyping for the most common TPMT variants TPMT*2, TPMT*3A, TPMT3*C, and TPMT*3B was performed using the PCR-restriction fragment length polymorphism method in 223 consecutive IBD patients and 119 age-matched and sex-matched healthy controls. The hospital medical records were reviewed for thiopurine use in these patients and related adverse events.
RESULTS: The prevalence of TPMT variants TPMT*2, TPMT*3A, TPMT*3B, and TPMT*3C was 1.8, 2.7, 1.3, and 1.8%, respectively. The G238C mutation was detected in four (1.8%) out of 223 patients, three (1.3%) patients were carriers of the G460A mutation, four (1.8%) of the A719G mutation, and six (2.7%) of both G460A and A719G mutations. In healthy controls, only one (0.8%) carried both the G460A and the A719G mutation, whereas TPMT*2, TPMT*3C, and TPMT*3B were not detected. None of the genotypes was homozygous. A statistically significant correlation between the presence of the G460A mutation and the development of leucopenia after the administration of thiopurines was observed (P=0.048).
CONCLUSION: This study showed a lower frequency of total TPMT variants and a higher frequency of TPMT*3B in Cretan IBD patients compared with other Caucasian populations. The presence of the G460A mutation is associated with the development of leukopenia.

PMID: 28857898 [PubMed - indexed for MEDLINE]

Lycium barbarum polysaccharide attenuates chemotherapy-induced ovarian injury by reducing oxidative stress.

J Obstet Gynaecol Res. 2017 Oct;43(10):1621-1628

Authors: Yang DM, Zhang JQ, Fei YF

Abstract
AIM: We aimed to examine the effects of Lycium barbarum polysaccharide (LBP) on ovarian damage induced by cyclophosphamide (CTX) and to investigate the underlying mechanism.
METHODS: A total of 240 female Sprague-Dawley rats were randomly divided into five groups: the control group, the CTX-induced ovarian injury (OI) group, and three LBP groups. Different concentrations of LBP solution were administered to the LBP groups by gastric infusion for 15 days, and the OI group and LBP groups were then subjected to CTX treatment for another 15 days. On days 7, 14, and 28 after CTX injection, femoral vein blood and ovarian tissues were collected for the measurements of antioxidant enzymes and oxidation products. Serum indicators were measured by enzyme-linked immunosorbent assay; and Nrf2, heme oxygenase-1, and quinone oxidoreductase 1 protein levels were detected by Western blot analysis.
RESULTS: LBP attenuated CTX-induced ovarian damage and reversed associated adverse effects. LBP reduced oxidative stress by enhancing the potency of antioxidant enzymes and attenuating elevated levels of oxidation products following CTX injection. Furthermore, LBP upregulated Nrf2, heme oxygenase-1, and quinone oxidoreductase 1 protein expression.
CONCLUSION: LBP exerts protective effects against CTX-induced ovarian injury by reducing oxidative stress and activating the Nrf2/ARE-signaling pathway.

PMID: 28817219 [PubMed - indexed for MEDLINE]

FDA Approval of Nivolumab for the First-Line Treatment of Patients with BRAFV600 Wild-Type Unresectable or Metastatic Melanoma.

Clin Cancer Res. 2017 Jul 15;23(14):3479-3483

Authors: Beaver JA, Theoret MR, Mushti S, He K, Libeg M, Goldberg K, Sridhara R, McKee AE, Keegan P, Pazdur R

Abstract
On November 23, 2015, the FDA approved nivolumab (OPDIVO; Bristol-Myers Squibb) as a single agent for the first-line treatment of patients with BRAFV600 wild-type, unresectable or metastatic melanoma. An international, double-blind, randomized (1:1) trial conducted outside of the United States allocated 418 patients to receive nivolumab 3 mg/kg intravenously every 2 weeks (n = 210) or dacarbazine 1,000 mg/m2 intravenously every 3 weeks (n = 208). Patients with disease progression who met protocol-specified criteria (∼25% of each trial arm) were permitted to continue with the assigned treatment in a blinded fashion until further disease progression is documented. Overall survival was statistically significantly improved in the nivolumab arm compared with the dacarbazine arm [hazard ratio (HR), 0.42; 95% confidence interval (CI), 0.30-0.60; P < 0.0001]. Progression-free survival was also statistically significantly improved in the nivolumab arm (HR, 0.43; 95% CI, 0.34-0.56; P < 0.0001). The most common adverse reactions (≥20%) of nivolumab were fatigue, diarrhea, constipation, nausea, musculoskeletal pain, rash, and pruritus. Nivolumab demonstrated a favorable benefit-risk profile compared with dacarbazine, supporting regular approval; however, it remains unclear whether treatment beyond disease progression contributes to the overall clinical benefit of nivolumab. Clin Cancer Res; 23(14); 3479-83. ©2017 AACR.

PMID: 28073844 [PubMed - indexed for MEDLINE]

Phase I Study of ONT-380, a HER2 Inhibitor, in Patients with HER2+-Advanced Solid Tumors, with an Expansion Cohort in HER2+ Metastatic Breast Cancer (MBC).

Clin Cancer Res. 2017 Jul 15;23(14):3529-3536

Authors: Moulder SL, Borges VF, Baetz T, Mcspadden T, Fernetich G, Murthy RK, Chavira R, Guthrie K, Barrett E, Chia SK

Abstract
Purpose: ONT-380 (ARRY-380) is a potent and selective oral HER2 inhibitor. This Phase I study determined the MTD, pharmacokinetics (PK) and antitumor activity of ONT-380 in HER2-positive advanced solid tumors, with an expansion cohort of patients with HER2+ MBC.Experimental Design: ONT-380 was administered twice daily (BID) in continuous 28-day cycles. After a modified 3+3 dose-escalation design determined the MTD, the expansion cohort was enrolled. PK properties of ONT-380 and a metabolite were determined. Response was evaluated by Response Evaluation Criteria in Solid Tumors (RECIST).Results: Fifty patients received ONT-380 (escalation = 33; expansion = 17); 43 patients had HER2+ MBC. Median prior anticancer regimens = 5. Dose-limiting toxicities of increased transaminases occurred at 800 mg BID, thus 600 mg BID was the MTD. Common AEs were usually Grade 1/2 in severity and included nausea (56%), diarrhea (52%), fatigue (50%), vomiting (40%) constipation, pain in extremity and cough (20% each). 5 patients (19%) treated at MTD had grade 3 AEs (increased transaminases, rash, night sweats, anemia, and hypokalemia). The half-life of ONT-380 was 5.38 hours and increases in exposure were approximately dose proportional. In evaluable HER2+ MBC (n = 22) treated at doses ≥ MTD, the response rate was 14% [all partial response (PR)] and the clinical benefit rate (PR + stable disease ≥ 24 weeks) was 27%.Conclusions: ONT-380 had a lower incidence and severity of diarrhea and rash than that typically associated with current dual HER2/EGFR inhibitors and showed notable antitumor activity in heavily pretreated HER2+ MBC patients, supporting its continued development. Clin Cancer Res; 23(14); 3529-36. ©2017 AACR.

PMID: 28053022 [PubMed - indexed for MEDLINE]

AIDS Clinical Research in Spain-Large HIV Population, Geniality of Doctors, and Missing Opportunities.

Viruses. 2018 May 30;10(6):

Authors: Soriano V, Ramos JM, Barreiro P, Fernandez-Montero JV

Abstract
The first cases of AIDS in Spain were reported in 1982. Since then over 85,000 persons with AIDS have been cumulated, with 60,000 deaths. Current estimates for people living with HIV are of 145,000, of whom 20% are unaware of it. This explains the still high rate of late HIV presenters. Although the HIV epidemic in Spain was originally driven mostly by injection drug users, since the year 2000 men having sex with men (MSM) account for most new incident HIV cases. Currently, MSM represent over 80% of new yearly HIV diagnoses. In the 80s, a subset of young doctors and nurses working at Internal Medicine hospital wards became deeply engaged in attending HIV-infected persons. Before the introduction of antiretrovirals in the earlier 1990s, diagnosis and treatment of opportunistic infections was their major task. A new wave of infectious diseases specialists was born. Following the wide introduction of triple combination therapy in the late 1990s, drug side effects and antiretroviral resistance led to built a core of highly devoted HIV specialists across the country. Since then, HIV medicine has improved and currently is largely conducted by multidisciplinary teams of health care providers working at hospital-based outclinics, where HIV-positive persons are generally seen every six months. Antiretroviral therapy is currently prescribed to roughly 75,000 persons, almost all attended at clinics belonging to the government health public system. Overall, the impact of HIV/AIDS publications by Spanish teams is the third most important in Europe. HIV research in Spain has classically been funded mostly by national and European public agencies along with pharma companies. Chronologically, some of the major contributions of Spanish HIV research are being in the field of tuberculosis, toxoplasmosis, leishmaniasis, HIV variants including HIV-2, drug resistance, pharmacology, antiretroviral drug-related toxicities, coinfection with viral hepatitis, design and participation in clinical trials with antiretrovirals, immunopathogenesis, ageing, and vaccine development.

PMID: 29848987 [PubMed - in process]