Rotavirus vaccination and short-term risk of adverse events in US infants.

Paediatr Perinat Epidemiol. 2018 09;32(5):448-457

Authors: Layton JB, Butler AM, Panozzo CA, Brookhart MA

Abstract
BACKGROUND: The aim of this study was to evaluate the short-term risk of adverse events associated with rotavirus vaccine (RV) in infants, overall and by vaccine formulation (three-dose pentavalent, RV5; two-dose monovalent, RV1).
METHODS: We identified US newborns with commercial insurance during 2006-2014 receiving a diphtheria-tetanus-pertussis vaccine (DTaP) dose and assessed if RV was administered concurrently. We followed infants for 30 days after each dose for diagnoses of intussusception, other gastrointestinal events, seizures, Kawasaki disease, thrombocytopenia, otitis media, all-cause emergency department visits, and all-cause hospitalisations. We estimated adjusted hazard ratios (HR) and 95% confidence intervals (CI) with multivariable Cox proportional hazards models comparing: (a) those receiving DTaP+RV vs those receiving DTaP alone; and (b) RV5 vs RV1. Analyses were performed separately within DTaP doses and then meta-analysed across doses.
RESULTS: We identified 1 031 431 first DTaP doses, 821 833 second doses, and 615 293 third doses; 79.2% had a concurrent RV, 94.1% of which were RV5. Absolute risks of serious outcomes were very low. Compared to infants who received DTaP alone, infants who received RV+DTaP did not experience consistently increased risk of intussusception (hazard ratio [HR] 1.13, 95% confidence interval [CI] 0.68, 1.88) or any other outcome except for otitis media after dose 2: HR 1.11, 95% CI 1.08, 1.15. This increased otitis media risk was not as pronounced in RV5 when comparing RV5 to RV1; HR 0.92, 95% CI 0.89, 0.95.
CONCLUSIONS: These data were not consistent with an increased risk of intussusception or other adverse events following vaccination with RV, except potentially for a small increased risk of otitis media, particularly in RV1.

PMID: 30048564 [PubMed - indexed for MEDLINE]

Diverging approaches of pharmacovigilance and pharmacoepidemiology to assessing drug safety: epistemological and ethical implications.

Pharmacoepidemiol Drug Saf. 2017 05;26(5):600-602

Authors: Coste J

PMID: 28239922 [PubMed - indexed for MEDLINE]

Periodic benefit-risk evaluation reports have substantial promise to guide patient care and should be made publicly available.

Pharmacoepidemiol Drug Saf. 2017 05;26(5):597-599

Authors: Fralick M, Kesselheim AS

PMID: 28198116 [PubMed - indexed for MEDLINE]

Secret safety warnings on medicines: A case study of information access requests.

Pharmacoepidemiol Drug Saf. 2019 Mar 06;:

Authors: Torka M, Mintzes B, Bhasale A, Fabbri A, Perry L, Lexchin J

Abstract
PURPOSE: There has been less attention to the transparency of postmarket evidence of harmful effects of medicines than of premarket clinical trial data. This is a case study of requests for Australian "direct health professional communications" (DHPCs). These letters are used by regulators and manufacturers to inform clinicians of emergent evidence of harm. DHPCs are not made public by Australia's Therapeutic Goods Administration (TGA).
METHODS: We requested all DHPCs sent out in Australia from 2007 to 2016 inclusive for 207 drugs that were subject to safety advisories over this decade in Canada, the United Kingdom, and/or the United States. We contacted 39 manufacturers (February to May 2018), with repeat requests to nonrespondents, and a follow-up freedom-of-information (FOI) request to the TGA.
RESULTS: Fifteen companies provided information, either sending DHPCs (n = 4, on five drugs) or affirming none were sent out (n = 11). The remaining 24 of 39 (62%) companies did not provide DHPCs: nine (23%) refused the request, often citing commercial confidentiality; the rest provided no answer despite repeat requests. In total, we had no information for 170 of 207 (82%) of the drugs. Our FOI request to the TGA was unsuccessful.
CONCLUSIONS: Our experience highlights unacceptable secrecy concerning safety warnings previously sent to thousands of Australian clinicians. In the absence of explicit regulatory policy supporting disclosure, companies differed in their response. These letters warn of serious and often life-threatening harm and guide safer care; full ongoing public access is needed, ideally in searchable online databases.

PMID: 30840349 [PubMed - as supplied by publisher]

Histological study of the protective role of ginger on piroxicam-induced liver toxicity in mice.

J Chin Med Assoc. 2019 Jan;82(1):11-18

Authors: Badawi MS

Abstract
BACKGROUND: Piroxicam is a non-steroidal anti-inflammatory drug widely used in rheumatic diseases. It has analgesic and antipyretic activity, and is one of the drugs being introduced in clinical practice. Piroxicam-hepatotoxicity has been reported as one of its principal side effects. Several natural antioxidants were found to be effective against drug induced toxicity. Ginger is known by its antioxidant activities and hepatoprotective effects. The present study aimed at studying the protective effect of Ginger on Piroxicam-induced histopathological changes in livers of male mice.
METHODS: Forty adult mice were randomly divided into 4 groups: Group I served as the control group. Group II received Ginger orally in a dose of 200 mg/kg per day for four weeks. Group III received Piroxicam intraperitoneally in a dose of 0.3 mg/kg per day for four weeks. Group IV received (Piroxicam + Ginger). At the end of the experiment, liver functions were estimated and then the liver was removed, and sampled for histopathological, immunohistochemistry and biochemical studies.
RESULTS: Administration of ginger decreased elevated serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP) and immunoexpression of the proapoptotic protein (Bax), induced by piroxicam. It increased immunoexpression of the antiapoptotic protein (Bcl2). It also ameliorated the morphological changes induced by piroxicam.
CONCLUSION: Piroxicam has toxic effects on the liver as indicated by biochemical, histological and immunohistochemical results. Ginger has protective effects against piroxicam-hepatotoxicity by reducing serum marker enzymes, liver fibrosis and apoptosis.

PMID: 30839397 [PubMed - in process]

The Impact and Mechanism of a Novel Allosteric AMPA Receptor Modulator LCX001 on Protection Against Respiratory Depression in Rodents.

Front Pharmacol. 2019;10:105

Authors: Dai W, Gao X, Xiao D, Li YL, Zhou XB, Yong Z, Su RB

Abstract
Analgesics and sedative hypnotics in clinical use often give rise to significant side effects, particularly respiratory depression. For emergency use, specific antagonists are currently administered to counteract respiratory depression. However, antagonists are often short-lasting and eliminate drug generated analgesia. To resolve this issue, novel positive AMPA modulators, LCX001, was tested to alleviate respiratory depression triggered by different drugs. The acetic acid writhing and hot-plate test were conducted to evaluate analgesic effect of LCX001. Binding assay, whole-cell recording, live cell imaging, and Ca2+ imaging were used to clarify mechanism and impact of LCX001 on respiratory protection. Results showed that LCX001 effectively rescued and prevented opioid (fentanyl and TH-030418), propofol, and pentobarbital-induced respiratory depression by strengthening respiratory frequency and minute ventilation. The acetic acid writhing test and hot-plate test revealed potent anti-nociceptive efficacy of LCX001, in contrast to other typical ampakines that did not affect analgesia. Furthermore, LCX001 potentiated [3H]AMPA and L-glutamate binding affinity to AMPA receptors, and facilitated glutamate-evoked inward currents in HEK293 cells stably expressing GluA2(R). LCX001 had a typical positive modulatory impact on AMPAR-mediated function. Importantly, application of LCX001 generated a significant increase in GluA2(R) surface expression, and restrained opioid-induced abnormal intracellular Ca2+ load, which might participate in breathing modulation. Our study improves therapeutic interventions for the treatment of drug induced respiratory depression, and increases understanding of potential mechanism of AMPA receptor modulators.

PMID: 30837875 [PubMed]

[Medicaments and oral healthcare. Mechanisms of interaction between medicaments].

Ned Tijdschr Tandheelkd. 2019 01;126(1):31-36

Authors: Vissink A, de Baat C, Brinkman DJ, Roggen W, Stegenga B, Spijkervet FKL

Abstract
Interactions between medicaments or between a medicament and another product used by the patient may result in a medicamentbecoming inactive or in an increase in the side effects. By proper historytaking, a dentist will often know which medicaments a patient uses and can take this into account in prescribing a medicament. Self-care medications and specific foods are often not spontaneously reported by a patient but can still interact with a medicament prescribed. A dentist should be aware of the interactions a prescribed medicament can have with other medicaments and products used by the patient. Therefore dentists have to ask directly about such medicaments and products, and record them in the patients' file.

PMID: 30636263 [PubMed - indexed for MEDLINE]

Out of sight, out of mind? Germ cells and the potential impacts of epigenomic drugs.

F1000Res. 2018;7:

Authors: Jarred EG, Bildsoe H, Western PS

Abstract
Epigenetic modifications, including DNA methylation and histone modifications, determine the way DNA is packaged within the nucleus and regulate cell-specific gene expression. The heritability of these modifications provides a memory of cell identity and function. Common dysregulation of epigenetic modifications in cancer has driven substantial interest in the development of epigenetic modifying drugs. Although these drugs have the potential to be highly beneficial for patients, they act systemically and may have "off-target" effects in other cells such as the patients' sperm or eggs. This review discusses the potential for epigenomic drugs to impact on the germline epigenome and subsequent offspring and aims to foster further examination into the possible effects of these drugs on gametes. Ultimately, the information gained by further research may improve the clinical guidelines for the use of such drugs in patients of reproductive age.

PMID: 30613387 [PubMed - indexed for MEDLINE]

Hypereosinophilia: Biological investigations and etiologies in a French metropolitan university hospital, and proposed approach for diagnostic evaluation.

PLoS One. 2018;13(9):e0204468

Authors: Peju M, Deroux A, Pelloux H, Bouillet L, Epaulard O

Abstract
OBJECTIVES: We aimed to evaluate the usefulness of biological investigations in cases of eosinophilia in our area (French Alps).
METHODS: We retrospectively included all adult patients attending the infectious disease and internal medicine units between 2009 and 2015 with eosinophilia ≥1 G/l.
RESULTS: We identified 298 cases (129 women and 169 men). In 139 patients, eosinophilia had not been addressed. In the 159 others, the cause of eosinophilia was identified in 118 (74.2%). The main identified causes at the time were drug reactions (24.5%, mostly β-lactams and allopurinol), infectious diseases (17.0%), vasculitis (8.2%), autoimmune diseases (6.9%), and malignant diseases (6.2%). In patients with a skin rash, eosinophilia was significantly more often investigated, and a diagnosis significantly more often made. Helminthosis were mainly diagnosed in tropical travelers (18/24) excepting toxocariasis (3 non-travelers). Stool examination for helminthosis was positive in 5/76 patients (6.6%) (all tropical travelers); 391 helminth serologies were performed in 91 patients, with 7.9% being positive (all but 3 positive cases were travelers). Anti-neutrophil cytoplasmic antibodies (ANCA) were positive in 26/112 patients (23.2%), with 9 cases of vasculitis identified.
CONCLUSIONS: Drug-related eosinophilia is the main etiology. Search for helminthosis is not recommended among non-travelers (excepting toxocariasis). ANCA should be performed early so as not to overlook vasculitis.

PMID: 30256812 [PubMed - indexed for MEDLINE]

Proposed Proarrhythmic Cardiac Safety Education in Medical, Pharmacy, and Nursing Schools: An Interprofessional Model.

Ther Innov Regul Sci. 2018 09;52(5):529-530

Authors: Turner JR

PMID: 30204494 [PubMed - indexed for MEDLINE]

Doxorubicin induces prostate cancer drug resistance by upregulation of ABCG4 through GSH depletion and CREB activation: Relevance of statins in chemosensitization.

Mol Carcinog. 2019 Mar 04;:

Authors: Mallappa S, Neeli PK, Karnewar S, Kotamraju S

Abstract
Multidrug resistance mediated by ATP-binding cassette (ABC) transporters remains a major impediment to cancer chemotherapy. In the present study, we documented that doxorubicin (Dox) or cisplatin-induced prostate cancer (PCa) chemoresistance is predominantly mediated by the induction of ABCG4 in androgen-independent PCa cells. Treatment of DU-145 or PC-3 cells with Dox significantly enhanced the expression of ABCG4 that resulted in the efflux of intracellular Dox. However, incubation of cells with ABCG4 short hairpin RNA resulted in a significant accumulation of Dox and sensitized cells to Dox-induced cytotoxicity. Interestingly, simvastatin synergistically potentiated Dox-induced cytotoxicity by inhibiting ABCG4 in DU-145 and DU-145 Doxres cells. Mechanistically, ABCG4 expression was regulated redox-dependently by intracellular glutathione (GSH) levels. Treatment of cells with N-acetylcysteine or simvastatin restored Dox-induced depletion of GSH levels that in turn inhibited ABCG4 levels. In addition, a reduction in GSH levels by Dox caused a nuclear factor-κB dependent enhancement of c-Myc expression, which led to cAMP-regulatory element-binding protein (CREB) activation. Furthermore, chromatin immunoprecipitation experiments revealed that Dox-induced CREB activation transcriptionally upregulates ABCG4 expression. These results were further confirmed in an in vivo PCa xenograft mice model. Combination of simvastatin and Dox significantly regressed the tumor growth and size with no noticeable Dox-induced cardiotoxic side effects. Intriguingly, DU-145 cells with stably depleted ABCG4 levels not only significantly delayed the development of the tumor but also greatly sensitized the tumor to a low dose of Dox that resulted in complete tumor regression. Collectively, this data reinforces a novel function of ABCG4 in Dox-mediated chemoresistance, and as a potential therapeutic target in drug-induced PCa chemoresistance.

PMID: 30834613 [PubMed - as supplied by publisher]

Non-vitamin K oral anticoagulant use in the elderly: a prospective real-world study - data from the REGIstry of patients on Non-vitamin K oral Anticoagulants (REGINA).

Vasc Health Risk Manag. 2019;15:19-25

Authors: Monelli M, Molteni M, Cassetti G, Bagnara L, De Grazia V, Zingale L, Zilli F, Bussotti M, Totaro P, De Maria B, Dalla Vecchia LA

Abstract
Purpose: Numerous studies on thromboembolic prevention for non-valvular atrial fibrillation (NVAF) have shown either equal or better efficacy and safety of non-vitamin K oral anticoagulants (NOACs) compared to warfarin, even for patients aged ≥75 years. Data on elderly patients, in particular, octogenarians, are lacking. Paradoxically, this population is the one with the highest risk of bleeding and stroke with a worse prognosis. This study aims to describe safety and effectiveness of NOACs in an elderly comorbid population.
Patients and methods: REGIstry of patients on Non-vitamin K oral Anticoagulants (REGINA) is a prospective observational study enrolling consecutive NVAF patients started on NOACs and followed up to 1 year (at 1, 6, 12 months). The primary endpoint was the incidence rate of major bleeding (MB) and clinically relevant non-major bleeding (CRNMB). The secondary endpoints were the incidence of 1) stroke or systemic embolism, 2) hospitalization, 3) death, and 4) drug-related adverse events.
Results: We enrolled 227 patients aged 81.6±6.1 years (range 67-95 years; ≥80 years in 59.4%). The median CHA2DS2-VASc was 5 (IQR 4-5) and HAS-BLED was 4 (IQR 3-5). The estimated glomerular filtration rate was 59.27±24.12 mL/min. During follow-up, only 10 MB and 23 CRNMB occurred, with a total incidence of 4.4% (95% CI: 1.7%-7.17%) and 5.7% (95% CI: 2.68%-8.72%), respectively. There were 2 cerebral ischemic events, with a total incidence of 0.88% (95% CI: 0.84%-0.92%), 23 NOAC-related hospitalizations, no NOAC-related deaths, and 4 minor drug-related adverse effects.
Conclusion: In a population of aged and clinically complex patients, mainly octogenarians, NOACs were safe and effective.

PMID: 30833810 [PubMed - in process]

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Dexmedetomidine versus propofol at different sedation depths during drug-induced sleep endoscopy: A randomized trial.

Laryngoscope. 2019 Mar 01;:

Authors: Padiyara TV, Bansal S, Jain D, Arora S, Gandhi K

Abstract
OBJECTIVES/HYPOTHESIS: The aim of this study was to compare the effect of dexmedetomidine and propofol on airway dynamics, cardiorespiratory system, and emergence following drug-induced sleep endoscopy (DISE).
STUDY DESIGN: Prospective, randomized, single-blinded study.
METHODS: Sixty patients age 18 to 65 years in American Society of Anesthesiologists physical status groups 1 and 2 scheduled to undergo DISE were randomly allocated to either Group P (N = 30; receiving propofol infusion at 50-150 μg/kg/min) or Group D (N = 30; receiving dexmedetomidine bolus of 1 μg/kg followed by infusion at 0.5-1.0 μg/kg/hr). DISE was done at light sleep and deep sleep. Airway obstruction at tongue base was recorded as primary outcome. Airway obstruction at velum, oropharyngeal lateral wall, and epiglottis level during light and deep sedation, hemodynamic and respiratory parameters, time to attain sufficient sedation, time for emergence from sedation, and any adverse events during DISE with the two study drugs were recorded as secondary outcomes.
RESULTS: There was a greater degree of obstruction at the tongue base level in Group P compared with Group D during deep sedation (P = .016). Increase in airway obstruction from light to deep sleep was seen with propofol at the oropharynx (P = .042) and tongue base (P = .042) levels. Two patients (6.6%) in Group D and 10 patients (35%) in Group P showed oxygen saturation below the minimum oxygen saturation recorded during polysomnography. Time to open eyes to call after stopping sedation was significantly less in Group P (P = .000).
CONCLUSIONS: Dexmedetomidine shows a lesser degree of airway collapse and higher oxygen saturation levels at greater sedation depth during DISE. Propofol has a faster onset and emergence from sedation.
LEVEL OF EVIDENCE: 1b Laryngoscope, 2019.

PMID: 30821349 [PubMed - as supplied by publisher]

EPIGIST: An observational real-life study on patients with metastatic gastrointestinal stromal tumors receiving imatinib.

PLoS One. 2018;13(9):e0204117

Authors: Bouché O, Cesne AL, Rios M, Chaigneau L, Italiano A, Duffaud F, Lecomte T, Arsène D, Manfredi S, Aparicio T, Remy S, Isambert N, Collard O, Priou F, Bertucci F, Sambuc R, Bisot-Locard S, Bourges O, Chabaud S, Blay JY

Abstract
BACKGROUND: Gastrointestinal stromal tumors (GISTs) are rare, but represent the most common mesenchymal neoplasms of the gastrointestinal tract. EPIdemiology GIST, is an observational multicenter longitudinal follow-up cohort study reporting the prescribing patterns of imatinib in patients with GIST and the impact of the treatment in a real-world (standard clinical) setting.
METHODS: Eligible patients had a confirmed diagnosis of unresectable or metastatic KIT-positive GIST and started treatment with imatinib for the first time between May 24, 2002, and June 30, 2010. During routine visits, annual collection of clinical characteristics was requested, i.e., age, GIST stage at diagnosis, history, imatinib treatment duration and dosage, adherence, and concomitant medications. Survival outcomes were estimated using the Kaplan-Meier method. Other data were analyzed using descriptive statistics.
RESULTS: Of 151 patients enrolled, imatinib was initiated for 126 patients before enrollment and for 25 patients on the day of enrollment or soon after. The patient characteristics were similar to those in published prospective trials. The estimated 1-, 2-, 3-, and 4-year overall survival rates were 90.4% (95% confidence interval [CI; 84.8%-94.0%]), 84.7% (95% CI [78.1%-89.4%]), 73.0% (95% CI [65.0%-79.4%]), and 60.7% (95% CI [51.4%-68.8%]), respectively. The most common adverse events (AEs) were diarrhea (39%), asthenia (39%), eyelid or periorbital edema (32%), abdominal pain (23%), and anemia (21%). Eight of 126 serious AEs were possibly related to the treatment as assessed by investigators.
CONCLUSIONS: Study results showed that patients in real-life populations are generally treated in accordance with national and international clinical recommendations and have outcomes comparable to those of patients in clinical trials.

PMID: 30226855 [PubMed - indexed for MEDLINE]

Direct-acting antiviral treatment in real world patients with hepatitis C not associated with psychiatric side effects: a prospective observational study.

BMC Psychiatry. 2018 05 29;18(1):157

Authors: Sundberg I, Lannergård A, Ramklint M, Cunningham JL

Abstract
BACKGROUND: Treatment of Hepatitis C virus (HCV) infection has evolved from interferon (IFN)-based treatments to direct-acting antivirals (DAAs). Patients with HCV have an elevated psychiatric morbidity (including substance abuse) and patients with such comorbidity have often been excluded from treatment with IFN. To date, little is known about psychiatric adverse effects of DAA-based regimens. We therefore aimed to study the psychiatric side effects of new IFN-free treatment for HCV (including depressive symptoms and sleep) in real world patients also including those with a history of psychiatric diagnosis, substance abuse or drug dependence.
METHODS: Consecutive patients were monitored during treatment with three of the latest DAA agents (sofosbuvir, simeprevir and daclatasvir). Repeated expert psychiatric assessments from baseline to 12 weeks post-treatment were performed with the Structured Clinical Interview for DSM-IV Axis I Disorders (SCID-I) clinical version and the self-report versions of the Montgomery Åsberg Depression Rating Scale (MADRS-S) and the Pittsburgh Sleep Quality Index (PSQI). Friedman's test was performed to calculate differences in the MADRS-S and PSQI over time. In a post-hoc analysis Wilcoxon's test was used to compare baseline depressive symptoms with those at post-treatment. Spearman's rank correlation test was conducted in another post-hoc analysis to evaluate the correlation between symptoms of depression and HCV viral load at baseline.
RESULTS: At baseline, 15/17 patients (88%) had a history of any psychiatric diagnosis; 11 (65%) had a history of substance abuse or dependence; and 11 (65%) had previously been treated with IFN and six of those had experienced psychiatric side effects. There was no correlation between depressive symptoms and HCV viral load at baseline. Symptoms of depression did not increase during DAA treatment and were lower 12 weeks post-treatment compared with baseline: MADRS-S 10.7 vs. 8.3 (p = 0.01). This observation held when excluding patients taking antidepressant medication. Sleep quality did not significantly change during treatment. Adherence to treatment was estimated to 95% and sustained virological response was 88%.
CONCLUSIONS: Despite high psychiatric morbidity, including previous substance abuse, patients successfully completed DAA treatment without increasing depressive symptoms or sleep disturbance. Symptoms of depression were significantly reduced 12 weeks after DAA treatment.

PMID: 29843679 [PubMed - indexed for MEDLINE]

Efficacy and tolerability of perampanel and levetiracetam as first add-on therapy in patients with epilepsy: A retrospective single center study.

Epilepsy Behav. 2018 03;80:173-176

Authors: Liguori C, Izzi F, Manfredi N, D'Elia A, Mari L, Mercuri NB, Fabio P

Abstract
Perampanel (PER) is a third generation antiepileptic drug (AED), recently approved as add-on therapy in both focal and generalized seizures. Levetiracetam (LEV) is a second generation AED, widely used in patients with epilepsy because of its favorable safety and efficacy profiles. Perampanel and LEV treatments have been associated with the occurrence of similar adverse events (AEs) (sleepiness, irritability, depression, anxiety, aggressiveness). The aim of the present retrospective single center study was to verify the efficacy and tolerability of PER and LEV used as first add-on therapy in patients with epilepsy affected by secondarily generalized seizures. We collected data from 15 patients treated with PER and 26 patients treated with LEV and followed at our site with follow-up visits at 3, 6, and 12months. This retrospective study documented the comparable efficacy of PER and LEV as first add-on treatments in patients affected by uncontrolled secondarily generalized seizures. However, more patients withdrawn LEV because of AEs compared with PER at the 3- and 12-month follow-up visits. The better tolerability of PER observed in this study could be related to the low therapeutic dose of PER prescribed when it is used as first adjunctive treatment for better controlling secondarily generalized seizures.

PMID: 29414548 [PubMed - indexed for MEDLINE]

Single-arm, neoadjuvant, phase II trial of pertuzumab and trastuzumab administered concomitantly with weekly paclitaxel followed by 5-fluoruracil, epirubicin, and cyclophosphamide (FEC) for stage I-III HER2-positive breast cancer.

Breast Cancer Res Treat. 2018 Jun;169(2):333-340

Authors: Foldi J, Mougalian S, Silber A, Lannin D, Killelea B, Chagpar A, Horowitz N, Frederick C, Rispoli L, Burrello T, Abu-Khalaf M, Sabbath K, Sanft T, Brandt DS, Hofstatter EW, Hatzis C, DiGiovanna MP, Pusztai L

Abstract
PURPOSE: The purpose of this two-cohort Phase II trial was to estimate the pathologic complete response (pCR: ypT0/is ypN0) rate when trastuzumab plus pertuzumab are administered concurrently during both the taxane and anthracycline phases of paclitaxel and 5-fluorouracil/epirubicin/cyclophosphamide (FEC) neoadjuvant chemotherapy.
METHODS: The pCR rates were assessed separately in hormone receptor (HR) positive and negative cases following Simon's two-stage design, aiming to detect a 20% absolute improvement in pCR rates from 50 to 70 and 70 to 90% in the HR-positive and HR-`negative cohorts, respectively.
RESULTS: The HR-negative cohort completed full accrual of 26 patients; pCR rate was 80% (95% CI 60-91%). The HR+ cohort was closed early after 24 patients due to lower than expected pCR rate of 26% (95% CI 13-46%) at interim analysis. Overall, 44% of patients (n = 22/50) experienced grade 3/4 adverse events. The most common were neutropenia (n = 10) and diarrhea (n = 7). There was no symptomatic heart failure, but 28% (n = 14) had ≥ 10% asymptomatic decrease in LVEF; in one patient, LVEF decreased to < 50%. Cardiac functions returned to baseline by the next assessment in 57% (8/14) of cases.
CONCLUSIONS: Eighty percent of HR-negative, HER2-positive breast cancers achieve pCR with paclitaxel/FEC neoadjuvant chemotherapy administered concomitantly with pertuzumab and trastuzumab. These results are similar to pCR rates seen in trials using HER2-targeted therapy during the taxane phase only of sequential taxane-anthracycline regimens and suggest that we have reached a therapeutic plateau with HER2-targeted therapies combined with chemotherapy in the neoadjuvant setting.

PMID: 29396664 [PubMed - indexed for MEDLINE]

Inadequate safety reporting in pre-eclampsia trials: a systematic evaluation.

BJOG. 2018 Jun;125(7):795-803

Authors: Duffy J, Hirsch M, Pealing L, Showell M, Khan KS, Ziebland S, McManus RJ, International Collaboration to Harmonise Outcomes in Pre-eclampsia (iHOPE)

Abstract
BACKGROUND: Randomised trials and their syntheses in meta-analyses offer a unique opportunity to assess the frequency and severity of adverse reactions.
OBJECTIVE: To assess safety reporting in pre-eclampsia trials.
SEARCH STRATEGY: Systematic search using bibliographic databases, including Cochrane Central Register of Controlled Trials, Embase, and MEDLINE, from inception to August 2017.
SELECTION CRITERIA: Randomised trials evaluating anticonvulsant or antihypertensive medication for pre-eclampsia.
DATA COLLECTION AND ANALYSIS: Descriptive statistics appraising the adequacy of adverse reaction and toxicity reporting.
MAIN RESULTS: We included 60 randomised trials. Six trials (10%) were registered with the International Clinical Trials Registry Platform, two registry records referred to adverse reactions, stating 'safety and toleration' and 'possible side effects' would be collected. Twenty-six trials (43%) stated the frequency of withdrawals within each study arm, and five trials (8%) adequately reported these withdrawals. Adverse reactions were inconsistently reported across eligible trials: 24 (40%) reported no serious adverse reactions and 36 (60%) reported no mild adverse reactions. The methods of definition or measurement of adverse reactions were infrequently reported within published trial reports.
CONCLUSIONS: Pre-eclampsia trials regularly omit critical information related to safety. Despite the paucity of reporting, randomised trials collect an enormous amount of safety data. Developing and implementing a minimum data set could help to improve safety reporting, permitting a more balanced assessment of interventions by considering the trade-off between the benefits and harms.
FUNDING: National Institute for Health Research (DRF-2014-07-051), UK; Maternity Forum, Royal Society of Medicine, UK.
TWEETABLE ABSTRACT: Developing @coreoutcomes could help to improve safety reporting in #preeclampsia trials. @NIHR_DC.

PMID: 29030992 [PubMed - indexed for MEDLINE]

Putting in harm to cure: Drug related adverse events do not affect outcome of patients receiving treatment for multidrug-resistant Tuberculosis. Experience from a tertiary hospital in Italy.

PLoS One. 2019;14(2):e0212948

Authors: Gualano G, Mencarini P, Musso M, Mosti S, Santangelo L, Murachelli S, Cannas A, Di Caro A, Navarra A, Goletti D, Girardi E, Palmieri F

Abstract
RATIONALE: Treatment of multi-drug resistant Tuberculosis (MDR-TB) is challenging because it mostly relies on drugs with lower efficacy and greater toxicity than those used for drug-susceptible TB.
OBJECTIVES: Aim of the study was to describe the frequency and type of adverse drug reactions in a cohort of MDR-TB patients and their potential impact on treatment outcome.
METHODS: We conducted a retrospective study in a cohort of MDR-TB patients enrolled at a tertiary referral hospital in Italy from January 2008 to December 2016. The records of patients were reviewed for epidemiological, clinical, microbiological and adverse drug reactions data.
RESULTS: Seventy-four MDR-TB patients (mean age 32 years, 58.1% males, 2 XDR, 12 pre-XDR TB) were extracted from the Institute data base and included in the retrospective study cohort in the evaluation period (January 2008-December 2016). Median length of treatment duration was 20 months (IQR 14-24). Treatment outcome was successful in 57 patients (77%; 51 cured, 6 treatment completed); one patient died and one failed (2.7% overall); 15 patients were lost to follow-up (20.3%). Sixty-six (89.2%) presented adverse drug reactions during the whole treatment period. Total number of adverse drug reactions registered was 409. Three hundred forty-six (84.6%) were classified as adverse events (AEs) and 63 (15.4%) were serious AEs (SAEs). One third of the total adverse drug reactions (134/409; 32.8%) was of gastrointestinal origin, followed by 47/409 (11.5%) ototoxic drug reactions, thirty-five (8.6%) regarded central nervous system and 33 (8.1%) affected the liver. All 63 SAEs required treatment suspension with 61 SAEs out of 63 (96.8%) occurring during the first six months of treatment. Factors associated with unsuccessful treatment outcome were smoking (p = 0.039), alcohol abuse (p = 0.005) and homeless condition (p = 0.044). Neither the number of antitubercular drugs used in different combinations nor the number of AEs showed significant impact on outcome. Patients who completed the treatment experienced a greater number of AEs and SAEs (p < 0.001) if compared to lost to follow-up patients.
CONCLUSIONS: Our data demonstrate that, despite the high frequency of adverse drug reactions and long term therapy, the clinical management of MDR-TB patients in a referral center could reach successful treatment according to WHO target, by implementing active and systematic clinical and laboratory assessment to detect, report and manage suspected and confirmed adverse drug reactions.

PMID: 30817779 [PubMed - in process]