Hydrocarbon-induced hormesis: 101 years of evidence at the margin?

Environ Pollut. 2020 Oct;265(Pt B):114846

Authors: Agathokleous E, Barceló D, Tsatsakis A, Calabrese EJ

Abstract
Hydrocarbons are used worldwide for an array of purposes ranging from transportation to making plastics and synthetic fibers. Hydrocarbons pollution can occur from local to global scales, becoming a focus of regulatory authorities since a long time ago. While studies show numerous adverse effects on biota, such effects usually occur at very high doses. This paper collates significant evidence showing that hydrocarbons induce hormesis in biota, with dual effects of low versus high doses. Hydrocarbon-induced hormetic responses should be considered in relevant dose-response studies as well as in risk assessment. Dismissing hormesis could lead to incorrect predictions of hydrocarbons effects, which can occur at doses up to 100 times smaller than the traditional toxicological threshold, and would raise serious concerns regarding human and ecological health safety.

PMID: 32474358 [PubMed - indexed for MEDLINE]

Incidence and Management of Olaratumab Infusion-Related Reactions.

J Oncol Pract. 2019 11;15(11):e925-e933

Authors: Van Tine BA, Govindarajan R, Attia S, Somaiah N, Barker SS, Shahir A, Barrett E, Lee P, Wacheck V, Ramage SC, Tap WD

Abstract
PURPOSE: Olaratumab is a human monoclonal immunoglobulin G1 antibody against platelet-derived growth factor receptor-α. We report the nature and frequency of infusion-related reactions (IRRs) with olaratumab in clinical trials and postmarketing reports.
METHODS: Data from patients exposed to olaratumab across nine clinical trials were reviewed for IRRs. Blood samples were also analyzed for pre-existing immunoglobulin E anti-galactose-α-1,3-galactose (anti-α-Gal) antibodies.
RESULTS: In the clinical trials, IRRs were identified in 70 of 485 patients (14.4%). The most frequent symptoms included flushing, fever or chills, and dyspnea. For 68 of 70 patients (97.1%), the first IRR occurred during the first two cycles of treatment. Grade 3 or worse IRRs were reported in 11 patients (2.3%), all during the first infusion and usually within 15 minutes of the start of the infusion. One IRR-related fatality (0.2%) occurred in a nonpremedicated patient with grade 3 or worse cardiac comorbidities. There was an association between grade 3 or worse IRRs and pre-existing anti-α-Gal antibodies, with a trend toward higher IRR rates in US geographies known to have a higher prevalence of anti-α-Gal antibodies. IRRs in postmarketing reports were consistent in nature and severity with those in the clinical trials.
CONCLUSION: Premedication with corticosteroids and antihistamines should occur in all patients before olaratumab infusion, as indicated in labels in the United States and the European Union. Patients receiving olaratumab should be monitored for IRRs in a setting where resuscitation equipment is available for the treatment of IRRs.

PMID: 31268811 [PubMed - indexed for MEDLINE]

Improved Prediction of Drug-Target Interactions Using Self-Paced Learning with Collaborative Matrix Factorization.

J Chem Inf Model. 2019 07 22;59(7):3340-3351

Authors: Xia LY, Yang ZY, Zhang H, Liang Y

Abstract
Identifying drug-target interactions (DTIs) plays an important role in the field of drug discovery, drug side-effects, and drug repositioning. However, in vivo or biochemical experimental methods for identifying new DTIs are extremely expensive and time-consuming. Recently, in silico or various computational methods have been developed for DTI prediction, such as ligand-based approaches and docking approaches, but these traditional computational methods have several limitations. This work utilizes the chemogenomic-based approaches for efficiently identifying potential DTI candidates, namely, self-paced learning with collaborative matrix factorization based on weighted low-rank approximation (SPLCMF) for DTI prediction, which integrates multiple networks related to drugs and targets into regularized least-squares and focuses on learning a low-dimensional vector representation of features. The SPLCMF framework can select samples from easy to complex into training by using soft weighting, which is inclined to more faithfully reflect the latent importance of samples in training. Experimental results on synthetic data and five benchmark data sets show that our proposed SPLCMF outperforms other existing state-of-the-art approaches. These results indicate that our proposed SPLCMF can provide a useful tool to predict unknown DTIs, which may provide new insights into drug discovery, drug side-effect prediction, and repositioning existing drug.

PMID: 31260620 [PubMed - indexed for MEDLINE]

Medication therapy problems and vaccine needs identified during initial appointment-based medication synchronization visits.

J Am Pharm Assoc (2003). 2019 Jul - Aug;59(4S):S67-S71

Authors: Ariyo O, Kinney O, Brookhart A, Nadpara P, Goode JKR

Abstract
OBJECTIVE: To characterize medication therapy problems (MTPs) and vaccines recommended and administered by pharmacists during initial appointment-based medication synchronization (ABMS) visits, in a community pharmacy setting.
METHODS: A retrospective observational study evaluated comprehensive medication reviews documented by pharmacists during initial ABMS visits in 16 supermarket chain pharmacies in Central Virginia from September to December 2017. The documentation was examined to obtain patient demographics, MTPs, and recommended and administered vaccines. Other data collected included disease states, number of medications synchronized per patient, and average time spent per initial ABMS visit. Classifications of MTPs were adherence (overuse and underuse), adverse drug reaction, cost-efficacy management, drug interactions (drug-drug/drug-disease), excessive dose/duration, needs additional therapy (for chronic conditions), suboptimal drug selection, and unnecessary therapy. Data were analyzed using descriptive statistics, and Wilcoxon-Mann-Whitney test was used to compare group differences.
RESULTS: One hundred eighty-four patients received an initial ABMS visit (118 female and 66 male patients). The mean age was 70 years for women and 65 years for men, range 18 to 19 years (P < 0.08). Disease states documented included asthma, benign prostatic hyperplasia, chronic pain, epilepsy, depression, diabetes mellitus, dementia, gastroesophageal reflux disease, history of myocardial infarction, human immunodeficiency virus, hyperlipidemia, and hypertension. Women had a significantly higher number of disease states than men did (P < 0.03). Thirty-seven MTPs were identified with no statistical difference between men and women (P < 0.98). Pharmacists reported spending an average of 17 minutes with patients during the initial visit for an average of 6 medications synchronized per patient. Six hundred thirty-three vaccines were recommended, and 51 were administered.
CONCLUSION: Initial ABMS visit with a comprehensive medication review facilitated pharmacists in detecting medication therapy problems. Although vaccines administered were lower than recommended, community pharmacists play an important role in preventive health through vaccine screenings and recommendations. Future plans include evaluating the outcomes of MTPs identified and resolved in the ABMS service.

PMID: 31153823 [PubMed - indexed for MEDLINE]

A Phase 3, Randomized, Placebo-Controlled Evaluation of the Safety of Intravenous Meloxicam Following Major Surgery.

Clin Pharmacol Drug Dev. 2019 11;8(8):1062-1072

Authors: Bergese SD, Melson TI, Candiotti KA, Ayad SS, Mack RJ, McCallum SW, Du W, Gomez A, Marcet JE

Abstract
An intravenous (IV) formulation of meloxicam is being studied for moderate to severe pain management. This phase 3, randomized, multicenter, double-blind, placebo-controlled trial evaluated the safety of once-daily meloxicam IV 30 mg in subjects following major elective surgery. Eligible subjects were randomized (3:1) to receive meloxicam IV 30 mg or placebo administered once daily. Safety was evaluated via adverse events, clinical laboratory tests, vital signs, wound healing, and opioid consumption. The incidence of adverse events was similar between meloxicam IV- and placebo-treated subjects (63.0% versus 65.0%). Investigators assessed most adverse events as mild or moderate in intensity and unrelated to treatment. Adverse events of interest (injection-site reactions, bleeding, cardiovascular, hepatic, renal, thrombotic, and wound-healing events) were similar between groups. Over the treatment period, meloxicam IV was associated with a 23.6% (P = .0531) reduction in total opioid use (9.2 mg morphine equivalent) compared to placebo-treated subjects. The results suggest that meloxicam IV had a safety profile similar to that of placebo with respect to numbers and frequencies of adverse events and reduced opioid consumption in subjects with moderate to severe postoperative pain following major elective surgery.

PMID: 30786162 [PubMed - indexed for MEDLINE]

Pharmacokinetics of Once-Daily Extended-Release Tacrolimus Tablets Versus Twice-Daily Capsules in De Novo Liver Transplant.

Clin Pharmacol Drug Dev. 2019 11;8(8):995-1008

Authors: DuBay DA, Teperman L, Ueda K, Silverman A, Chapman W, Alsina AE, Tyler C, Stevens DR

Abstract
The pharmacokinetics of once-daily extended-release tacrolimus tablets (LCPT) in de novo liver transplantation have not been previously reported. In this phase II, randomized, open-label study, de novo liver transplant recipients were randomized to LCPT 0.07-0.13 mg/kg/day (taken once daily; n = 29) or twice-daily immediate-release tacrolimus capsules (IR-Tac) at 0.10-0.15 mg/kg/day (divided twice daily; n = 29). Subsequent doses of both drugs were adjusted to maintain tacrolimus trough concentrations of 5 to 20 ng/mL through day 90, and 5-15 ng/mL thereafter. Twenty-four-hour pharmacokinetic profiles were obtained on days 1, 7, and 14, with trough concentration and efficacy/safety monitoring through year 1. Similar proportions of patients in both groups achieved therapeutic trough concentrations on days 7 and 14 (day 7: LCPT = 78%, IR-Tac = 75%; day 14: LCPT = 86%, IR-Tac = 91%) as well as similar systemic and peak exposure. There was a robust correlation between drug concentration at time 0 and area under the concentration-time curve for both LCPT and IR-Tac (respectively, day 7: r = 0.86 and 0.79; day 14: r = 0.93 and 0.86; P < .0001 for all). Dose adjustments during days 1 to 14 were frequent. Thirty-five patients completed the extended-use period. No significant differences in adverse events were seen between groups. Incidence of biopsy-proven acute rejection (LCPT = 6 and IR-Tac = 4) was similar on day 360. Between formulations, overall exposure was similar at 1 week after transplant with the characteristic delayed-release pharmacokinetic profile of LCPT demonstrated in this novel population. These data support further investigation of the safety and efficacy of LCPT in de novo liver transplantation.

PMID: 30667591 [PubMed - indexed for MEDLINE]

The Efficacy and Safety of Apatinib in Refractory/Relapse Advanced Pediatric Solid Tumor: A Retrospective Study.

Cancer Manag Res. 2020;12:6177-6185

Authors: Sun F, Lu S, Zhen Z, Zhu J, Wang J, Huang J, Zhang Y, Li H, Cai R, Liu M, Wu L, Sun X, Zhang Y

Abstract
Background: The prognosis of recurrent or refractory advanced childhood solid tumor patients is very poor and new therapeutic strategies are in urgent need. This study aimed to determine the efficacy and safety of apatinib in pediatric refractory/relapse advanced solid tumor patients.
Patients and Methods: The study retrospectively reviewed recurrent or refractory advanced pediatric solid tumor patients who were treated with apatinib, an oral small-molecule tyrosine kinase inhibitor (TKI) that targets vascular endothelial growth factor receptor-2 (VEGFR2), at the Sun Yat-sen University Cancer Center (China) from January 2016 to March 2019.
Results: Fifty-six patients were included in the safety evaluation and 49 patients were included in the efficacy evaluation. The objective responses rate (ORR) was 26.5% (95% CI 15-41): 0 CR (complete response) and 13 PR (partial response). Disease control rate (DCR) (CR+PR+SD) was 79.6% (95% CI 65-90). The median progression-free survival (PFS) was 4.0 months (95% CI 2.6-5.4). There was no significant difference for ORR or PFS between the A (apatinib monotherapy), A+MT (apatinib combined with oral metronomic therapy) and A+SC (apatinib combined with salvage combination chemotherapy) group (p>0.05). The most common grade 3 or 4 adverse events were neutropenia (9[16.1%]), thrombocytopenia (8[14.3%]), hand-foot syndrome (3[5.4%]), hypertension (3[5.4%]), anaemia (3[5.4%]) and mucositis (2[3.6%]). Hypertension was the most serious adverse event and one death that occurred was considered as drug-related.
Conclusion: Apatinib showed promising clinical activity in heavily treated recurrent or refractory advanced childhood solid tumor patients. However, it is necessary to pay special attention to monitoring blood pressure when using apatinib in children. Prospective randomized controlled clinical trial is warranted.

PMID: 32801866 [PubMed - as supplied by publisher]

Analysis of Reporting Adverse Drug Reactions in Paediatric Patients in a University Hospital in the Netherlands.

Paediatr Drugs. 2020 Aug;22(4):425-432

Authors: Dittrich ATM, Draaisma JMT, van Puijenbroek EP, Loo DMWMT

Abstract
AIMS: The risk to develop adverse drug reactions (ADRs) is high for paediatric patients. This is, amongst other reasons, due to the inevitable use of off-label and unlicensed medicines. Moreover, there is limited knowledge on ADRs in children. Thus, adequate recognition may be challenging. The lack of dedicated studies and the voluntary nature of pharmacovigilance systems used to gain insight into the characteristics of ADRs contribute to this problem. The goal of this study is to identify whether ADRs in paediatric patients are adequately documented by the medical team and whether they are subsequently reported to the national pharmacovigilance system.
METHODS: All patients admitted to the paediatric medium care of the Radboudumc Amalia Children's hospital during 1 month, and using one or more drugs, were included. Two researchers analysed retrospectively and independently the number of possible ADRs in the medical records. The ADRs were listed per paediatric subspecialty, to evaluate any differences in documentation and reporting of the ADRs. Subsequently, the causality, severity, and seriousness of the ADRs were assessed. The ADRs were categorised by system organ class and drug class. The national pharmacovigilance centre was consulted to check if there were any reports coming from our hospital and to collect the total number of reports.
RESULTS: The medical records of 301 patients were analysed, 81 patients were suffering from one or more ADRs. In total 132 suspected ADRs were found, divided among 19 different paediatric subspecialties. Numbers were too small to investigate the differences in ADR documentation. Of these found ADRs, 55% were not explicitly noted as such in the medical records by the treating physician. None of the ADRs were reported to the national pharmacovigilance centre. Most ADRs scored 'possible' in the causality assessment, were mild or moderate, and a small number were serious. The ADRs occurred in 25 different organ systems. In total 25 different drug classes were involved.
CONCLUSIONS: The results of the present study show that a large number of ADRs are not registered in the medical records and are not reported to the national pharmacovigilance system. Furthermore, it is shown that the number of ADRs occurring at our centre is much higher than the number reported to the national pharmacovigilance centre. Only an average of 513 ADRs in paediatric patients are reported per year nationwide, suggesting that there is extensive underreporting.

PMID: 32557243 [PubMed - indexed for MEDLINE]

Engaging Pharmacists to Crowdsource a Fine-grained Medication Risk Scale: An Initial Measurement Study Using Paired Comparisons of Medications.

AMIA Annu Symp Proc. 2019;2019:428-437

Authors: Flynn AJ, Farris G, Meng G, Allan J, Kurosu S, Lampa N, Sasagawa K

Abstract
A coarse classification of medications into two risk categories, one for high-risk medications and one for all others, allows people to focus safety improvement work on medications that carry the highest risks of harm. However, such coarse categorization does not distinguish the relative risk of harm for the majority of medications. To begin to develop a more fine-grained measurement scale for the relative risk of harm spanning many medications, we performed an experiment with 18 practicing pharmacists. Each pharmacist-participant made 210 paired comparisons of 21 commonly prescribed medications to reveal a subjective scale of perceived medication worrisomeness (PMW). Statistical analyses of their collective judgments of medication pairs differentiated five levels of PMW. This study illuminates one path towards a fine-grained medication risk scale based on PMW. It also shows how the method of paired comparisons can be used to remotely crowdsource expert knowledge in support of learning health systems.

PMID: 32308836 [PubMed - indexed for MEDLINE]

Intervention protocol: OPtimising thERapy to prevent avoidable hospital Admission in the Multi-morbid elderly (OPERAM): a structured medication review with support of a computerised decision support system.

BMC Health Serv Res. 2020 Mar 17;20(1):220

Authors: Crowley EK, Sallevelt BTGM, Huibers CJA, Murphy KD, Spruit M, Shen Z, Boland B, Spinewine A, Dalleur O, Moutzouri E, Löwe A, Feller M, Schwab N, Adam L, Wilting I, Knol W, Rodondi N, Byrne S, O'Mahony D

Abstract
BACKGROUND: Several approaches to medication optimisation by identifying drug-related problems in older people have been described. Although some interventions have shown reductions in drug-related problems (DRPs), evidence supporting the effectiveness of medication reviews on clinical and economic outcomes is lacking. Application of the STOPP/START (version 2) explicit screening tool for inappropriate prescribing has decreased inappropriate prescribing and significantly reduced adverse drug reactions (ADRs) and associated healthcare costs in older patients with multi-morbidity and polypharmacy. Therefore, application of STOPP/START criteria during a medication review is likely to be beneficial. Incorporation of explicit screening tools into clinical decision support systems (CDSS) has gained traction as a means to improve both quality and efficiency in the rather time-consuming medication review process. Although CDSS can generate more potential inappropriate medication recommendations, some of these have been shown to be less clinically relevant, resulting in alert fatigue. Moreover, explicit tools such as STOPP/START do not cover all relevant DRPs on an individual patient level. The OPERAM study aims to assess the impact of a structured drug review on the quality of pharmacotherapy in older people with multi-morbidity and polypharmacy. The aim of this paper is to describe the structured, multi-component intervention of the OPERAM trial and compare it with the approach in the comparator arm.
METHOD: This paper describes a multi-component intervention, integrating interventions that have demonstrated effectiveness in defining DRPs. The intervention involves a structured history-taking of medication (SHiM), a medication review according to the systemic tool to reduce inappropriate prescribing (STRIP) method, assisted by a clinical decision support system (STRIP Assistant, STRIPA) with integrated STOPP/START criteria (version 2), followed by shared decision-making with both patient and attending physician. The developed method integrates patient input, patient data, involvement from other healthcare professionals and CDSS-assistance into one structured intervention.
DISCUSSION: The clinical and economical effectiveness of this experimental intervention will be evaluated in a cohort of hospitalised, older patients with multi-morbidity and polypharmacy in the multicentre, randomized controlled OPERAM trial (OPtimising thERapy to prevent Avoidable hospital admissions in the Multi-morbid elderly), which will be completed in the last quarter of 2019.
TRIAL REGISTRATION: Universal Trial Number: U1111-1181-9400 Clinicaltrials.gov: NCT02986425, Registered 08 December 2016. FOPH (Swiss national portal): SNCTP000002183. Netherlands Trial Register: NTR6012 (07-10-2016).

PMID: 32183810 [PubMed - indexed for MEDLINE]

Danger in the jungle: sensible care to reduce avoidable acute kidney injury in hospitalized children.

Kidney Int. 2020 03;97(3):458-460

Authors: Bell S, Selby NM, Bagshaw SM

Abstract
When children require hospital admission, many receive medications with nephrotoxic potential. As such, this can translate into an increased risk of acute kidney injury. In this context, acute kidney injury is hospital acquired, often iatrogenic, and portends risk of adverse outcomes. The Nephrotoxic Injury Negated by Just-in-Time Action study implemented a multicenter hospital-wide quality improvement initiative to detect and reduce nephrotoxin exposure in children aimed at decreasing the rates of potentially avoidable acute kidney injury. This commentary explores the findings and implications of the Nephrotoxic Injury Negated by Just-in-Time Action study.

PMID: 32087888 [PubMed - indexed for MEDLINE]

Assessing an ASCO Decision Aid for Improving the Accuracy and Attribution of Serious Adverse Event Reporting From Investigators to Sponsors.

J Oncol Pract. 2019 12;15(12):e1050-e1065

Authors: Mileham KF, Schenkel C, Chuk MK, Buchmeier A, Perez RP, Hurley P, Levit LA, Garrett-Mayer E, Davis C, Bruinooge SS, Vose J

Abstract
PURPOSE: Investigators often send reports to sponsors that incorrectly categorize adverse event (AE)s as serious or attribute AEs to investigational drugs. Such errors can contribute to high volumes of uninformative investigational new drug safety reports that sponsors submit to the US Food and Drug Administration and participating investigators, which strain resources and impede the detection of valid safety signals. To improve the quality of serious AE (SAE) reporting by physician-investigators and research staff, ASCO developed and tested a Decision Aid.
METHODS: A preliminary study with crossover design was conducted in a convenience sample. Physician-investigators and research staff were randomly assigned to receive case studies. Case studies were assessed for seriousness and attribution, first unassisted and then with the Decision Aid. Participants completed a feedback survey about the Decision Aid. Effectiveness of reporting and attribution are reported as odds ratios (ORs) with 95% CI. Power to detect associations was limited because of a small sample size.
RESULTS: The Decision Aid did not significantly affect accuracy of determining seriousness (OR, 0.87; 95% CI, 0.31 to 2.46), but it did significantly increase accuracy of attributing an SAE to a drug (OR, 3.60; 95% CI, 1.15 to 11.4). Most of the 29 participants reported that the Decision Aid was helpful (93%) and improved decision-making time (69%) and confidence in reporting (83%), and that they would use the Decision Aid in practice (83%).
CONCLUSION: The Decision Aid shows promise as a method to improve the quality of SAE attribution, which may improve the detection of valid safety signals and reduce the administrative burden of uninformative investigational new drug safety reports. Study of the Decision Aid in a larger sample with analysis stratified by participant role and SAE reporting experience would further assess the tool's impact.

PMID: 31647695 [PubMed - indexed for MEDLINE]

Prescribing decisions at buprenorphine treatment initiation: Do they matter for treatment discontinuation and adverse opioid-related events?

J Subst Abuse Treat. 2019 10;105:37-43

Authors: Meinhofer A, Williams AR, Johnson P, Schackman BR, Bao Y

Abstract
INTRODUCTION: Buprenorphine is a highly effective medication treatment for opioid use disorder (OUD) that can be prescribed in multiple treatment settings. Treatment retention, however, remains a challenge. In this study, we examined the association of days of supply as well as daily dosage of the initial buprenorphine prescription with treatment discontinuation and adverse opioid-related events following buprenorphine initiation.
METHODS: 2011 to 2015 Health Care Cost Institute commercial claims data were analyzed for individuals aged 18-64 years initiating buprenorphine treatment (N = 17,158). Treatment discontinuation was defined as a gap of 30 days or more in buprenorphine use within 180 days of initiation. Adverse opioid-related events were defined as having at least one emergency department visit or inpatient admission involving opioid poisoning, dependence or abuse within 360 days of initiation. We conducted multivariate logistic regressions to estimate adjusted odds ratios of outcomes associated with daily dose (≤4 mg vs. >4 mg) and days of supply (≤7, 8-15, 16-27, or ≥ 28 days) of the initial buprenorphine prescription.
RESULTS: Over one-half (55%) of individuals discontinued buprenorphine within 180 days and 13% experienced at least one adverse opioid-related event within 360 days of initiation. Both a lower initial dose [≤4 mg, OR = 1.79, p < 0.01] and fewer initial days of supply [≤7 days vs. ≥28 days, OR = 1.32, p < 0.01] [8-15 days vs. ≥28 days, OR = 1.22, p < 0.01] were associated with increased odds of discontinuation. While a lower initial dose was not associated with adverse events, fewer initial days of supply were associated with a higher risk of adverse events, even after controlling for treatment discontinuation.
CONCLUSION: In this population of commercially insured, non-elderly adults, we found that fewer initial days of supply as well as a lower initial dose were associated with increased likelihood of treatment discontinuation, highlighting the importance of prescribing decisions when initiating buprenorphine for OUD.

PMID: 31443889 [PubMed - indexed for MEDLINE]

Preexisting Autoimmune Disease: Implications for Immune Checkpoint Inhibitor Therapy in Solid Tumors.

J Natl Compr Canc Netw. 2019 06 01;17(6):750-757

Authors: Kennedy LC, Bhatia S, Thompson JA, Grivas P

Abstract
The use of immune checkpoint inhibitors (ICIs) is rapidly expanding to the treatment of many cancer types, both in the metastatic setting and as an adjuvant to other therapies. Clinical trials using ICIs have largely excluded patients with preexisting autoimmune diseases due to concerns for increased toxicity. However, emerging evidence shows that ICIs may be considered in some patients with autoimmunity. This review discusses the commonalities between clinical autoimmune diseases and ICI-induced immunotherapy-related adverse events, and summarizes the existing case series that describes patients with solid tumors who have a preexisting autoimmune disease. This review also discusses which patients with autoimmunity could be considered reasonable candidates for ICI therapy.

PMID: 31200356 [PubMed - indexed for MEDLINE]

A Multidisciplinary Toxicity Team for Cancer Immunotherapy-Related Adverse Events.

J Natl Compr Canc Netw. 2019 06 01;17(6):712-720

Authors: Naidoo J, Zhang J, Lipson EJ, Forde PM, Suresh K, Moseley KF, Mehta S, Kwatra SG, Parian AM, Kim AK, Probasco JC, Rouf R, Thorne JE, Shanbhag S, Riemer J, Shah AA, Pardoll DM, Bingham CO, Brahmer JR, Cappelli LC

Abstract
BACKGROUND: Immune checkpoint inhibitors (ICIs) may cause immune-related adverse events (irAEs). Methods to obtain real-time multidisciplinary input for irAEs that require subspecialist care are unknown. This study aimed to determine whether a virtual multidisciplinary immune-related toxicity (IR-tox) team of oncology and medicine subspecialists would be feasible to implement, be used by oncology providers, and identify patients for whom multidisciplinary input is sought.
PATIENTS AND METHODS: Patients treated with ICIs and referred to the IR-tox team in August 2017 through March 2018 were identified. Feasibility was defined as receipt of electronic referrals and provision of recommendations within 24 hours of referral. Use was defined as the proportion of referring providers who used the team's recommendations, which was determined through a postpilot survey. Demographics and tumor, treatment, and referral data were collected. Patient features and irAE associations were analyzed.
RESULTS: The IR-tox team was found to be feasible and used: 117 referrals from 102 patients were received in 8 months, all providers received recommendations within 24 hours, 100% of surveyed providers used the recommendations, and 74% changed patient management based on IR-tox team recommendations. Referrals were for suspected irAEs (n=106; 91%) and suitability to treat with ICIs (n=11; 10%). In referred patients, median age was 64 years, 54% were men, 13% had prior autoimmunity, and 46% received ICI combinations versus monotherapy (54%). The most commonly referred toxicities were pneumonitis (23%), arthritis (16%), and dermatitis (15%); 15% of patients had multisystem toxicities. Multiple referrals were more common in those treated with combination ICIs (odds ratio [OR], 6.0; P=.035) or with multisystem toxicities (OR, 8.1; P=.005). The IR-tox team provided a new multidisciplinary forum to assist providers in diagnosing and managing complex irAEs. This model identifies educational and service needs, and patients with irAEs for whom multidisciplinary care is most sought.
CONCLUSIONS: A virtual multidisciplinary toxicity team for irAEs was a feasible and used service, and facilitated toxicity identification and management.

PMID: 31200355 [PubMed - indexed for MEDLINE]

A multilayered epithelial mucosa model of head neck squamous cell carcinoma for analysis of tumor-microenvironment interactions and drug development.

Biomaterials. 2020 Aug 06;258:120277

Authors: Gronbach L, Wolff C, Klinghammer K, Stellmacher J, Jurmeister P, Alexiev U, Schäfer-Korting M, Tinhofer I, Keilholz U, Zoschke C

Abstract
Pharmacotherapy of head and neck squamous cell carcinoma (HNSCC) often fails due to the development of chemoresistance and severe systemic side effects of current regimens limiting dose escalation. Preclinical models comprising all major elements of treatment resistance are urgently needed for the development of new strategies to overcome these limitations. For model establishment, we used tumor cells from patient-derived HNSCC xenografts or cell lines (SCC-25, UM-SCC-22B) and characterized the model phenotype. Docetaxel and cetuximab were selected for comparative analysis of drug-related effects at topical and systemic administration. Cetuximab cell binding was mapped by cluster-based fluorescence lifetime imaging microscopy.The tumor oral mucosa (TOM) models displayed unstructured, hyper-proliferative, and pleomorphic cell layers, reflecting well the original tumor morphology and grading. Dose- and time-dependent effects of docetaxel on tumor size, apoptosis, hypoxia, and interleukin-6 release were observed. Although the spectrum of effects was comparable, significantly lower doses were required to achieve similar docetaxel-induced changes at topical compared to systemic application. Despite displaying anti-proliferative effects in monolayer cultures, cetuximab treatment showed only minor effects in TOM models. This was not due to inefficient cetuximab uptake or target cell binding but likely mediated by microenvironmental components.We developed multi-layered HNSCC models, closely reflecting tumor morphology and displaying complex interactions between the tumor and its microenvironment. Topical application of docetaxel emerged as promising option for HNSCC treatment. Aside from the development of novel strategies for topical drug delivery, our tumor model might help to better understand key regulators of drug-tumor-interactions.

PMID: 32795620 [PubMed - as supplied by publisher]

Ipilimumab plus nivolumab and chemoradiotherapy followed by surgery in patients with resectable and borderline resectable T3-4N0-1 non-small cell lung cancer: the INCREASE trial.

BMC Cancer. 2020 Aug 14;20(1):764

Authors: Dickhoff C, Senan S, Schneiders FL, Veltman J, Hashemi S, Daniels JMA, Fransen M, Heineman DJ, Radonic T, van de Ven PM, Bartelink IH, Meijboom LJ, Garcia-Vallejo JJ, Oprea-Lager DE, de Gruijl TD, Bahce I

Abstract
BACKGROUND: The likelihood of a tumor recurrence in patients with T3-4N0-1 non-small cell lung cancer following multimodality treatment remains substantial, mainly due distant metastases. As pathological complete responses (pCR) in resected specimens are seen in only a minority (28-38%) of patients following chemoradiotherapy, we designed the INCREASE trial (EudraCT-Number: 2019-003454-83; Netherlands Trial Register number: NL8435) to assess if pCR rates could be further improved by adding short course immunotherapy to induction chemoradiotherapy. Translational studies will correlate changes in loco-regional and systemic immune status with patterns of recurrence.
METHODS/DESIGN: This single-arm, prospective phase II trial will enroll 29 patients with either resectable, or borderline resectable, T3-4N0-1 NSCLC. The protocol was approved by the institutional ethics committee. Study enrollment commenced in February 2020. On day 1 of guideline-recommended concurrent chemoradiotherapy (CRT), ipilimumab (IPI, 1 mg/kg IV) and nivolumab (NIVO, 360 mg flat dose IV) will be administered, followed by nivolumab (360 mg flat dose IV) after 3 weeks. Radiotherapy consists of once-daily doses of 2 Gy to a total of 50 Gy, and chemotherapy will consist of a platinum-doublet. An anatomical pulmonary resection is planned 6 weeks after the last day of radiotherapy. The primary study objective is to establish the safety of adding IPI/NIVO to pre-operative CRT, and its impact on pathological tumor response. Secondary objectives are to assess the impact of adding IPI/NIVO to CRT on disease free and overall survival. Exploratory objectives are to characterize tumor inflammation and the immune contexture in the tumor and tumor-draining lymph nodes (TDLN), and to explore the effects of IPI/NIVO and CRT and surgery on distribution and phenotype of peripheral blood immune subsets.
DISCUSSION: The INCREASE trial will evaluate the safety and local efficacy of a combination of 4 modalities in patients with resectable, T3-4N0-1 NSCLC. Translational research will investigate the mechanisms of action and drug related adverse events.
TRIAL REGISTRATION: Netherlands Trial Registration (NTR): NL8435 , Registered 03 March 2020.

PMID: 32795284 [PubMed - as supplied by publisher]

Extracts from Almond (Terminalia catappa) leaf and stem bark mitigate the activities of crucial enzymes and oxidative stress associated with hypertension in cyclosporine A-stressed rats.

J Food Biochem. 2020 Aug 14;:e13435

Authors: Dada FA, Oyeleye SI, Adefegha SA, Oboh G

Abstract
We investigated the effect of extracts from the leaf (ALE) and stem bark (ABE) of Almond tree on activities of some crucial enzymes [angiotensin-1 converting enzyme (ACE), arginase, acetylcholinesterase (AChE), phosphodiesterase-5 (PDE-5), adenosine deaminase (ADA), superoxide dismutase (SOD), catalase], and thiobarbituric acid reactive species (TBARS) associated with hypertension in normal adult male Wistar albino rats and Cyclosporine A (CsA)-stressed rats. The result revealed that CsA-stressed rats treated with captopril and extracts (ALE and ABE) had lowered ACE, arginase, AChE, PDE-5, ADA activities, and TBARS level, coupled with improved SOD and catalase activities compared with untreated CsA-stressed rats, which had reversed these biochemicals compared to normal rats. This suggests that the extracts could be explored to suppress hypertension and other cardiac injury known with CsA treatment; the potentials that could be linked with the constituent polyphenols. However, further studies including blood pressure should be determined to ascertain this claim. PRACTICAL APPLICATIONS: Drug-induced cardiotoxicity, hypertension, and organ damage are among the most common side effects of pharmaceutics. Therefore, it becomes imperative to find natural, effective, and alternative therapy with little or no side effect to combat drug toxicity. The use of Almond (leaf and stem bark) in folklore for the treatment/management of hypertension and other heart-related diseases without full scientific basis is on the increase. Hence, this study provides some biochemical evidences on the effect of Almond leaf and stem back extracts on crucial enzymes and oxidative stress markers involve in the incidence of hypertension in the course of Cyclosporine A administration. The findings of this study indicated that the studied plant materials could be promoted as nutraceutical agents to neutralize drug-induced cardiac injury and hypertension.

PMID: 32794232 [PubMed - as supplied by publisher]

Personalized Connectome Mapping to Guide Targeted Therapy and Promote Recovery of Consciousness in the Intensive Care Unit.

Neurocrit Care. 2020 Aug 13;:

Authors: Edlow BL, Barra ME, Zhou DW, Foulkes AS, Snider SB, Threlkeld ZD, Chakravarty S, Kirsch JE, Chan ST, Meisler SL, Bleck TP, Fins JJ, Giacino JT, Hochberg LR, Solt K, Brown EN, Bodien YG

Abstract
There are currently no therapies proven to promote early recovery of consciousness in patients with severe brain injuries in the intensive care unit (ICU). For patients whose families face time-sensitive, life-or-death decisions, treatments that promote recovery of consciousness are needed to reduce the likelihood of premature withdrawal of life-sustaining therapy, facilitate autonomous self-expression, and increase access to rehabilitative care. Here, we present the Connectome-based Clinical Trial Platform (CCTP), a new paradigm for developing and testing targeted therapies that promote early recovery of consciousness in the ICU. We report the protocol for STIMPACT (Stimulant Therapy Targeted to Individualized Connectivity Maps to Promote ReACTivation of Consciousness), a CCTP-based trial in which intravenous methylphenidate will be used for targeted stimulation of dopaminergic circuits within the subcortical ascending arousal network (ClinicalTrials.gov NCT03814356). The scientific premise of the CCTP and the STIMPACT trial is that personalized brain network mapping in the ICU can identify patients whose connectomes are amenable to neuromodulation. Phase 1 of the STIMPACT trial is an open-label, safety and dose-finding study in 22 patients with disorders of consciousness caused by acute severe traumatic brain injury. Patients in Phase 1 will receive escalating daily doses (0.5-2.0 mg/kg) of intravenous methylphenidate over a 4-day period and will undergo resting-state functional magnetic resonance imaging and electroencephalography to evaluate the drug's pharmacodynamic properties. The primary outcome measure for Phase 1 relates to safety: the number of drug-related adverse events at each dose. Secondary outcome measures pertain to pharmacokinetics and pharmacodynamics: (1) time to maximal serum concentration; (2) serum half-life; (3) effect of the highest tolerated dose on resting-state functional MRI biomarkers of connectivity; and (4) effect of each dose on EEG biomarkers of cerebral cortical function. Predetermined safety and pharmacodynamic criteria must be fulfilled in Phase 1 to proceed to Phase 2A. Pharmacokinetic data from Phase 1 will also inform the study design of Phase 2A, where we will test the hypothesis that personalized connectome maps predict therapeutic responses to intravenous methylphenidate. Likewise, findings from Phase 2A will inform the design of Phase 2B, where we plan to enroll patients based on their personalized connectome maps. By selecting patients for clinical trials based on a principled, mechanistic assessment of their neuroanatomic potential for a therapeutic response, the CCTP paradigm and the STIMPACT trial have the potential to transform the therapeutic landscape in the ICU and improve outcomes for patients with severe brain injuries.

PMID: 32794142 [PubMed - as supplied by publisher]

Suvorexant for the prevention of delirium: A meta-analysis.

Medicine (Baltimore). 2020 Jul 24;99(30):e21043

Authors: Xu S, Cui Y, Shen J, Wang P

Abstract
BACKGROUND: Delirium is a frequently encountered complication, which is associated with increased mortality. Suvorexant, an approved agent for the treatment of insomnia, is recently suggested to be also effective for prevention of delirium by some authors. However, a consensus has yet to be reached. The goal of this study was to perform a meta-analysis to overall estimate the effectiveness of suvorexant in preventing delirium and its related consequences.
METHODS: Eligible studies were identified by searching online databases of PubMed, EMBASE, and Cochrane Library. The pooled OR was calculated for binary outcomes (e.g., the incidence of delirium, mortality, or adverse events), while standardized mean difference (SMD) were expressed for continuous outcomes (e.g., time to delirium onset, length of stay in hospital and ICU, time on ventilation).
RESULTS: Seven studies which comprised 402 suvorexant treatment patients and 487 patients with control treatment were included in this meta-analysis. Overall, pooled analysis indicated the incidence of delirium could be significantly reduced (OR, 0.30; P < .001) and time to delirium onset was significantly lengthened (SMD, 0.44; P = .006) in patients undergoing suvorexant treatment compared with controls. Suvorexant had no beneficial effects on the secondary outcomes [length of stay in hospital (SMD, -0.65; P = .161) and ICU (SMD, 0.34; P = .297), time on ventilation (SMD, 1.09; P = .318), drug-related adverse events (OR, drug-related adverse events (OR, 1.66; P = .319) and mortality (OR, 2.21; P = .261)]. Subgroup analysis also confirmed the benefit of suvorexant on the development of delirium, which was significant in any subgroup.
CONCLUSION: Suvorexant should be recommended for the prevention of delirium in clinic.

PMID: 32791676 [PubMed - in process]