Vaccine. 2023 Jan 23;41(4):922-929. doi: 10.1016/j.vaccine.2022.12.045.

ABSTRACT

Amid the COVID-19 pandemic, the scientific community has been understandably eager to combat misinformation about issues such as vaccine safety. In highly polarized information environments, however, even well-intentioned messages have the potential to produce adverse effects. In this study, we connect different disciplinary strands of social science to derive and experimentally test the novel hypothesis that although particular efforts to debunk misinformation about mRNA vaccines will reduce relevant misperceptions about that technology, these correctives will harm attitudes toward other types of vaccines. We refer to this as the "collateral damage hypothesis." Our study specifically examines a corrective message stating that "mRNA vaccines do not contain live virus," and our results offer some support for our hypothesis, with the corrective triggering increased societal risk perceptions of live vaccines. We also find that the effect is, predictably, most evident among those whose vaccine acceptance is low. Building on the theoretical grounding we outline, we test a "damage control" adjustment to the corrective message and present evidence supporting that it mitigates the collateral damage.

PMID:36682880 | DOI:10.1016/j.vaccine.2022.12.045

J Thorac Oncol. 2023 Feb;18(2):e11-e13. doi: 10.1016/j.jtho.2022.10.012.

NO ABSTRACT

PMID:36682840 | DOI:10.1016/j.jtho.2022.10.012

Auris Nasus Larynx. 2023 Jan 20:S0385-8146(22)00240-1. doi: 10.1016/j.anl.2022.12.012. Online ahead of print.

ABSTRACT

OBJECTIVES: With the COVID-19 pandemic, there is growing interest and research in olfactory and gustatory dysfunction (OGD). Drug-induced dysfunction is an often overlooked etiology. While several medications include smell or taste disturbance as a side effect, there are no publications describing which medications are most frequently implicated. We aim to describe the patterns of these adverse drug reactions (ADRs) using the FDA Adverse Events Reporting System (FAERS).

METHODS: The FAERS database was queried from 2011 to 2021 for terms describing ADRs related to OGD. Terms included anosmia, hyposmia, olfactory test abnormal, olfactory nerve disorder, hallucination olfactory, parosmia, ageusia, hypogeusia, dysgeusia, and taste disorder. We identified the top reported medications associated with general smell dysfunction, general taste dysfunction, reduced smell, and altered smell.

RESULTS: From 2011 to 2021, 16,091 ADRs were reported with OGD, of which13,641 (84.8%) and 2,450 (15.2%) were associated with gustatory and olfactory reactions, respectively. Zinc products (370 reports) and fluticasone propionate (214) were most commonly associated with olfactory dysfunction, specifically reduced olfaction. Varenicline (24) and fluticasone propionate (23) were most commonly associated with altered smell. Lenalidomide (490) and sunitinib (468) were most commonly associated with gustatory dysfunction. Antineoplastic and immunomodulating medications accounted for 21.6% and 36.3% of olfactory and gustatory ADRs, respectively. Among this category, immunoglobulin drugs were the most commonly associated with OGD ADRs.

CONCLUSION: Gustatory dysfunction is more commonly reported ADR compared with olfactory dysfunction. Immunologic/rheumatologic medications are the leading culprit of reported OGD. With increasing numbers of patients presenting to otolaryngologists for OGD, it is important to consider drug-induced etiology.

LEVEL OF EVIDENCE: III.

PMID:36682949 | DOI:10.1016/j.anl.2022.12.012

Eur J Cancer. 2022 Dec 20;181:198-207. doi: 10.1016/j.ejca.2022.12.006. Online ahead of print.

ABSTRACT

AIMS: This study aimed to assess the efficacy and safety of ODX, a novel, cytotoxic, bone-targeting drug candidate, in castration-resistant prostate cancer bone metastatic disease.

METHODS: Patients with progressive disease were randomised to ten cycles of ODX, intravenous infusion Q2W (3, 6, and 9 mg/kg, respectively). The primary objective was to assess the relative change from baseline in bone alkaline phosphatase (B-ALP) and serum-aminoterminal-propeptide of Type I procollagen (S-P1NP) at 12 weeks. The inclusion criteria selected were broad, and a double-blind design was used to ensure objective recruitment of patients for the assessment of efficacy. None of the patients received bone-protecting agents during the ODX treatment period.

RESULTS: Fifty-five 21,20 and 14) patients were randomised to ODX (3, 6 and 9 mg/kg), respectively. The lower number of patients in arm 3 was due to too low a recruitment rate towards the end of the study. The median treatment time were 14, 13 and 14 weeks, respectively. The decrease in B-ALP at 12 weeks in study arms 3, 6 and 9 mg/kg was seen in 6/15 (40%), 8/12 (67%) and 5/12 (42%) patients, respectively, whereas the corresponding numbers for P1NP were 8/15 (53%), 8/12 (67%), and 4/12 (33%), respectively. The median decrease in B-ALP and P1NP at 12 weeks for study arms 3, 6 and 9 mg/kg were 37%, 14% and 43%, respectively, and 51%, 40% and 64%, respectively. The decrease in serum C-terminal telopeptide at 12 weeks was seen in the vast majority of patients and in about one-third of patients in bone scan index. ODX was well tolerated, and no drug-related serious adverse events occurred. There were no significant differences between study arms regarding efficacy and safety.

CONCLUSIONS: ODX was well tolerated and demonstrated inhibitory effects on markers related to the vicious cycle in bone at all three doses. The reduction in metastatic burden, assessed with bone scan index, supports this finding. Studies with continued ODX treatment until disease progression are being planned (ClinicalTrials.gov Identifier: NCT02825628).

PMID:36682096 | DOI:10.1016/j.ejca.2022.12.006

Viruses. 2022 Dec 25;15(1):65. doi: 10.3390/v15010065.

ABSTRACT

As the Corona Disease 2019 (COVID-19) caused by SARS-CoV-2 persists, vaccination is one of the key measures to contain the spread. Side effects (SE) from vaccination are one of the reasons for reluctance to vaccinate. We systematically investigated self-reported SE after the first, second, and booster vaccinations. The data were collected during the TüSeRe: exact study (Tübinger Monitoring Studie zur exakten Analyse der Immunantwort nach Vakzinierung). Employees of health and research institutions were invited to participate. Study participants were asked to fill out an online questionnaire and report their SE after each dose of SARS-CoV-2 vaccination. A total of 1046 participants (mean age: 44 ± 12.9 years; female, n = 815 (78%); male, n = 231 (22%)) were included in the analysis. Local and systemic SE were more frequent after receiving the vector-based vaccine ChAdOx1 nCoV-19 in the first vaccination. However, local and systemic SE were more common after receiving mRNA vaccines (BNT162b2, mRNA-1273) in the second vaccination. Compared to the BNT162b2 vaccine, more SE have been observed after receiving the mRNA-1273 vaccine in the booster vaccination. In multivariate analysis, local and systemic side effects were associated with vaccine type, age and gender. Local and systemic SE are common after SARS-CoV-2 vaccines. The frequency of self-reported local and systemic SE differ significantly between mRNA and vector-based vaccines.

PMID:36680106 | PMC:PMC9864657 | DOI:10.3390/v15010065

Int J Mol Sci. 2023 Jan 16;24(2):1746. doi: 10.3390/ijms24021746.

ABSTRACT

GCSF prophylaxis is recommended in patients on chemotherapy with a >20% risk of febrile neutropenia and is to be considered if there is an intermediate risk of 10-20%. GCSF has been suggested as a possible adjunct to immunotherapy due to increased peripheral neutrophil recruitment and PD-L1 expression on neutrophils with GCSF use and greater tumour volume decrease with higher tumour GCSF expression. However, its potential to increase neutrophil counts and, thus, NLR values, could subsequently confer poorer prognoses on patients with advanced NSCLC. This analysis follows on from the retrospective multicentre observational cohort Spinnaker study on advanced NSCLC patients. The primary endpoints were OS and PFS. The secondary endpoints were the frequency and severity of AEs and irAEs. Patient information, including GCSF use and NLR values, was collected. A secondary comparison with matched follow-up duration was also undertaken. Three hundred and eight patients were included. Median OS was 13.4 months in patients given GCSF and 12.6 months in those not (p = 0.948). Median PFS was 7.3 months in patients given GCSF and 8.4 months in those not (p = 0.369). A total of 56% of patients receiving GCSF had Grade 1-2 AEs compared to 35% who did not receive GCSF (p = 0.004). Following an assessment with matched follow-up, 41% of patients given GCSF experienced Grade 1-2 irAEs compared to 23% of those not given GCSF (p = 0.023). GCSF prophylaxis use did not significantly affect overall or progression-free survival. Patients given GCSF prophylaxis were more likely to experience Grade 1-2 adverse effects and Grade 1-2 immunotherapy-related adverse effects.

PMID:36675262 | PMC:PMC9867035 | DOI:10.3390/ijms24021746

Int J Environ Res Public Health. 2023 Jan 4;20(2):902. doi: 10.3390/ijerph20020902.

ABSTRACT

Many Polish patients do not inform physicians about supplements they use in addition to prescribed medicines. This may be because they consider dietary supplements as being rather natural products that cannot cause health problems. Although dietary supplements may produce side effects, Poland's food safety system and medical statistics do not recognise the necessity of reporting such cases. However, a different approach is observed in France and the United States where adverse effects of food supplements as well as drugs are reported. The aim of this study was to determine the need for creating in Poland a general model of a register monitoring dietary supplements and their adverse effects. In order to achieve this goal, a detailed comparison between the American and European monitoring systems was made. It showed the relationship between negative symptoms caused by specific components in supplements and t profiles of patients who reported side effects. Additionally, it was found that there is a real risk associated with side effects caused by dietary supplements. Therefore, it necessary to establish in Poland a special system for recording such cases as it should be beneficial to patients, including polypragmatic patients.

PMID:36673658 | PMC:PMC9859348 | DOI:10.3390/ijerph20020902

Hepatol Res. 2023 Jan 20. doi: 10.1111/hepr.13883. Online ahead of print.

ABSTRACT

AIM: This study aimed to analyze the current trends of drug-induced liver-related adverse events in the Food and Drug Administration Adverse Event Reporting System (FAERS) and Japanese Adverse Drug Event Report (JADER) databases.

METHODS: The characteristics of implicated drugs were investigated by analyzing big data on drug-induced liver-related adverse events over the past 20 years in FAERS, comparing drug rankings between the JADER and FAERS databases, and calculating rankings of drugs inducing liver-related adverse events using the Medical Dictionary for Regulatory Activities Terminology.

RESULTS: In the 452,272 cases registered in FAERS from 1997 to 2019, warfarin, paracetamol, and adalimumab were the drugs most related to DILI. In the 38,919 cases registered in the JADER from 2004 to 2019, sorafenib, nivolumab, and herbal extracts were the drugs most related to DILI. No associations were found between the top 30 drugs in either of the two databases. Notably, the number of drug-induced liver-related adverse event reports and total adverse events has sharply increased in recent years.

CONCLUSIONS: Although liver-related adverse events are largely caused by host immunity and other constitutional factors, differences in primary diseases, countries, and historical backgrounds lead to differences in the number of reports. Securing an appropriate database and a mechanism to collect real-time information on the frequency of adverse drug reactions is warranted. This article is protected by copyright. All rights reserved.

PMID:36680351 | DOI:10.1111/hepr.13883

Int J Mol Sci. 2023 Jan 6;24(2):1117. doi: 10.3390/ijms24021117.

ABSTRACT

Studies conducted on large populations show a lack of connection between vaccination and serious neurological symptoms. However, there are isolated cases that indicate such a relationship. These reports on adverse effects following immunization (AEFI) reduce social confidence in vaccination; however, their background may be rare genetic defects. The aim of the presented study was to examine if neurological AEFI in children may be associated with variants in genes related to neurodevelopment. To identify such possible associations, a descriptive study of the Polish case series was conducted. We performed next-generation sequencing in patients who, up to 4 weeks of injection of any vaccine, manifested neurological AEFI. We included 23 previously normally developing children with first seizures that occurred after vaccination. We identified pathogenic/likely pathogenic variants in genes engaged in neurodevelopment in nine patients and variants of uncertain significance in another nine patients. The mutated genes belonged to the group of genes related to epilepsy syndromes/epileptic encephalopathy. We showed that AEFI might have a genetic background. We hypothesized that in some AEFI patients, the vaccine might only trigger neurological symptoms that would have been manifested anyway as a result of a pathogenic variant in a gene engaged in neurodevelopment.

PMID:36674629 | DOI:10.3390/ijms24021117

Biomolecules. 2023 Jan 14;13(1):176. doi: 10.3390/biom13010176.

ABSTRACT

Drug-induced liver injury (DILI) is the principal reason for failure in developing drug candidates. It is the most common reason to withdraw from the market after a drug has been approved for clinical use. In this context, data from animal models, liver function tests, and chemical properties could complement each other to understand DILI events better and prevent them. Since the chemical space concept improves decision-making drug design related to the prediction of structure-property relationships, side effects, and polypharmacology drug activity (uniquely mentioning the most recent advances), it is an attractive approach to combining different phenomena influencing DILI events (e.g., individual "chemical spaces") and exploring all events simultaneously in an integrated analysis of the DILI-relevant chemical space. However, currently, no systematic methods allow the fusion of a collection of different chemical spaces to collect different types of data on a unique chemical space representation, namely "consensus chemical space." This study is the first report that implements data fusion to consider different criteria simultaneously to facilitate the analysis of DILI-related events. In particular, the study highlights the importance of analyzing together in vitro and chemical data (e.g., topology, bond order, atom types, presence of rings, ring sizes, and aromaticity of compounds encoded on RDKit fingerprints). These properties could be aimed at improving the understanding of DILI events.

PMID:36671561 | DOI:10.3390/biom13010176

Antibiotics (Basel). 2023 Jan 9;12(1):125. doi: 10.3390/antibiotics12010125.

ABSTRACT

(1) Background: Colistin-only susceptible (COS) Acinetobacter baumannii (AB) ventilator-associated pneumonia (VAP) represents a clinical challenge in the Intensive Care Unit (ICU) due to the negligible lung diffusion of this molecule and the low-grade evidence on efficacy of its nebulization. (2) Methods: We conducted a prospective observational study on 134 ICU patients with COS-AB VAP to describe the 'real life' clinical use of high-dose (5 MIU q8) aerosolized colistin, using a vibrating mesh nebulizer. Lung pharmacokinetics and microbiome features were investigated. (3) Results: Patients were enrolled during the COVID-19 pandemic with the ICU presenting a SAPS II of 42 [32-57]. At VAP diagnosis, the median PaO2/FiO2 was 120 [100-164], 40.3% were in septic shock, and 24.6% had secondary bacteremia. The twenty-eight day mortality was 50.7% with 60.4% and 40.3% rates of clinical cure and microbiological eradication, respectively. We did not observe any drug-related adverse events. Epithelial lining fluid colistin concentrations were far above the CRAB minimal-inhibitory concentration and the duration of nebulized therapy was an independent predictor of microbiological eradication (12 [9.75-14] vs. 7 [4-13] days, OR (95% CI): 1.069 (1.003-1.138), p = 0.039). (4) Conclusions: High-dose and prolonged colistin nebulization, using a vibrating mesh, was a safe adjunctive therapeutic strategy for COS-AB VAP. Its right place and efficacy in this setting warrant investigation in interventional studies.

PMID:36671325 | DOI:10.3390/antibiotics12010125

BMJ Open. 2023 Jan 20;13(1):e068127. doi: 10.1136/bmjopen-2022-068127.

ABSTRACT

OBJECTIVE: Cardiac therapy drugs are widely used in the treatment of heart disease. However, the concern regarding adverse events (AEs) of cardiac therapy drugs have been rising. This study aimed to analyse cardiac therapy drug-related AEs using the Jinan adverse event reporting system (JAERS) database mining and conduct a comprehensive evaluation to provide safe medication information for patients.

DESIGN: Retrospective observational study.

SETTING: In this study, cardiac therapy drug-related AEs were detected using the JAERS database from January 2000 to March 2022.

METHODS: Reports of cardiac therapy drug-related AEs were extracted from JAERS database, and the basic information of patients, reports and common AEs were analysed. Four disproportionality analysis methods, proportional reporting ratio (PRR), reporting odds ratio (ROR), Bayesian Confidence Propagation Neural Network (BCPNN), Medicines and Healthcare products Regulatory Agency (MHRA), were used to detect cardiac therapy drug-related signals. We further checked whether the detected signals exist on drug labels in China and two developed countries, the USA and Japan.

RESULTS: In total, 168 314 AEs were reported, of which 4788 were associated with cardiac therapy drugs. Using the PRR, ROR, MHRA and BCPNN method, we detected 52 signals, 52 signals, 33 signals and 43 signals, respectively. Among the 52 signals, 14 were not included on the drug labels of China. One (isosorbide mononitrate-head bilges) was not included on the drug labels of the three countries.

CONCLUSION: We identified 14 new cardiac therapy drug signals that did not appear on drug labels in China and 1 new signal that did not appear on drug labels in 3 counties. A causal link between cardiac therapy drugs and AEs should be evaluated in further studies.

PMID:36669842 | DOI:10.1136/bmjopen-2022-068127

J Clin Oncol. 2023 Jan 20:JCO2201285. doi: 10.1200/JCO.22.01285. Online ahead of print.

ABSTRACT

PURPOSE: This study evaluated the safety, pharmacokinetics, pharmacodynamics, and preliminary efficacy of milademetan, a small-molecule murine double minute-2 (MDM2) inhibitor, in patients with advanced cancers.

PATIENTS AND METHODS: In this first-in-human phase I study, patients with advanced solid tumors or lymphomas received milademetan orally once daily as extended/continuous (days 1-21 or 1-28 every 28 days) or intermittent (days 1-7, or days 1-3 and 15-17 every 28 days) schedules. The primary objective was to determine the recommended phase II dose and schedule. Secondary objectives included tumor response according to standard evaluation criteria. Predefined analyses by tumor type were performed. Safety and efficacy analyses included all patients who received milademetan.

RESULTS: Between July 2013 and August 2018, 107 patients were enrolled and received milademetan. The most common grade 3/4 drug-related adverse events were thrombocytopenia (29.0%), neutropenia (15.0%), and anemia (13.1%). Respective rates at the recommended dose and schedule (260 mg once daily on days 1-3 and 15-17 every 28 days, ie, 3/14 days) were 15.0%, 5.0%, and 0%. Across all cohorts (N = 107), the disease control rate was 45.8% (95% CI, 36.1 to 55.7) and median progression-free survival was 4.0 months (95% CI, 3.4 to 5.7). In the subgroup with dedifferentiated liposarcomas, the disease control rate and median progression-free survival were 58.5% (95% CI, 44.1 to 71.9) and 7.2 months overall (n = 53), and 62.0% (95% CI, 35.4 to 84.8) and 7.4 months with the recommended intermittent schedule (n = 16), respectively.

CONCLUSION: An intermittent dosing schedule of 3/14 days of milademetan mitigates dose-limiting hematologic abnormalities while maintaining efficacy. Notable single-agent activity with milademetan in dedifferentiated liposarcomas has prompted a randomized phase III trial (MANTRA).

PMID:36669146 | DOI:10.1200/JCO.22.01285

Prog Mater Sci. 2022 Oct;130:100997. doi: 10.1016/j.pmatsci.2022.100997. Epub 2022 Jun 17.

ABSTRACT

When blood first encounters the artificial surface of a medical device, a complex series of biochemical reactions is triggered, potentially resulting in clinical complications such as embolism/occlusion, inflammation, or device failure. Preventing thrombus formation on the surface of blood-contacting devices is crucial for maintaining device functionality and patient safety. As the number of patients reliant on blood-contacting devices continues to grow, minimizing the risk associated with these devices is vital towards lowering healthcare-associated morbidity and mortality. The current standard clinical practice primarily requires the systemic administration of anticoagulants such as heparin, which can result in serious complications such as post-operative bleeding and heparin-induced thrombocytopenia (HIT). Due to these complications, the administration of antithrombotic agents remains one of the leading causes of clinical drug-related deaths. To reduce the side effects spurred by systemic anticoagulation, researchers have been inspired by the hemocompatibility exhibited by natural phenomena, and thus have begun developing medical-grade surfaces which aim to exhibit total hemocompatibility via biomimicry. This review paper aims to address different bio-inspired surface modifications that increase hemocompatibility, discuss the limitations of each method, and explore the future direction for hemocompatible surface research.

PMID:36660552 | PMC:PMC9844968 | DOI:10.1016/j.pmatsci.2022.100997

Mediterr J Hematol Infect Dis. 2023 Jan 1;15(1):e2023003. doi: 10.4084/MJHID.2023.003. eCollection 2023.

ABSTRACT

BACKGROUND AND OBJECTIVE: Patients with latent tuberculosis infection (LTBI) receiving chemotherapy for hematological malignancy (HM) are at high risk of developing active tuberculosis (TB) infection. The aim of this study is to show real-life data and results of the T-SPOT test and preventive isoniazid (INH) therapy in pre-chemotherapy LTBI screening in the HM patient group.

METHODS: This retrospective study includes 209 HM patients who had T-SPOT test between 2016 and 2021 in Sultan 2. Abdulhamid Han Training and Research Hospital in Istanbul, Turkey.

RESULTS: The prevalence of LTBI was 26.8% in 209 patients (n=56). Preventive INH therapy was initiated in 82.1% (n=46) of 56 patients with LTBI. 23.9% (n=11) of the 46 patients who received preventive INH therapy were unable to complete the treatment. Nine patients died due to malignancy; one was lost to follow-up, and only one had to stop INH treatment due to elevated liver enzymes. Elevated liver enzymes occurred in 4 (8.7%) patients using INH, while gastrointestinal symptoms occurred in 3 (6.5%) patients. Active TB infection emerged in none of the T-SPOT positive or indeterminate individuals but in one HIV(+) patient in the T-SPOT negative group. The active TB infection incidence rate was 217 cases/100.000hab/year (95% CI, 29-748).

CONCLUSIONS: INH treatment was generally well tolerated, and very few serious drug-related side effects were observed. Although LTBI cannot be demonstrated in patients with HIV(+) HM who are scheduled for chemotherapy, these patients should be closely monitored for the development of active TB infection.

PMID:36660361 | PMC:PMC9833312 | DOI:10.4084/MJHID.2023.003

Int J Burns Trauma. 2022 Dec 15;12(6):251-260. eCollection 2022.

ABSTRACT

INTRODUCTION: Atrial fibrillation is associated with increased morbidity and mortality in critically ill patients. Few studies have specifically examined this arrhythmia in burn patients. Given the significant clinical implications of atrial fibrillation, understanding the optimal management strategy of this arrhythmia in burn patients is important. Consequently, the purpose of this study was to examine rate- and rhythm-control strategies in the management of new onset atrial fibrillation (NOAF) and assess their short term outcomes in critically ill burn patients.

METHODS: We identified all patients admitted to our institution's burn intensive care unit between January 2007 and May 2018 who developed NOAF. Demographic information and burn injury characteristics were captured. Patients were grouped into two cohorts based on the initial pharmacologic treatment strategy: rate-(metoprolol or diltiazem) or rhythm-control (amiodarone). The primary outcome was conversion to sinus rhythm. Secondary outcomes included relapse or recurrence of atrial fibrillation, drug-related adverse events, and complications and mortality within 30 days of the NOAF episode.

RESULTS: There were 68 patients that experienced NOAF, and the episodes occurred on median days 8 and 9 in the rate- and rhythm-control groups, respectively. The length of the episodes was not significantly different between the groups. Conversion to sinus rhythm occurred more often in the rhythm-control group (P = 0.04). There were no differences in the incidences of relapse and recurrence of atrial fibrillation, and the complications and mortality between the groups. Hypotension was the most common drug-related adverse event and occurred more frequently in the rate-control group, though this difference was not significant.

CONCLUSIONS: Conversion to sinus rhythm occurred more often in the rhythm-control group. Outcomes were otherwise similar in terms of mortality, complications, and adverse events. Hypotension occurred less frequently in the rhythm-control group, and although this difference was not significant, episodes of hypotension can have important clinical implications. Given these factors, along with burn patients having unique injury characteristics and a hypermetabolic state that may contribute to the development of NOAF, when choosing between rate- and rhythm control strategies, rhythm-control with amiodarone may be a better choice for managing NOAF in burn patients.

PMID:36660265 | PMC:PMC9845808

Bioinformatics. 2023 Jan 1;39(1):btad006. doi: 10.1093/bioinformatics/btad006.

ABSTRACT

MOTIVATION: Side effects of drugs could cause severe health problems and the failure of drug development. Drug-target interactions are the basis for side effect production and are important for side effect prediction. However, the information on the known targets of drugs is incomplete. Furthermore, there could be also some missing data in the existing side effect profile of drugs. As a result, new methods are needed to deal with the missing features and missing labels in the problem of side effect prediction.

RESULTS: We propose a novel computational method based on transductive matrix co-completion and leverage the low-rank structure in the side effects and drug-target data. Positive-unlabelled learning is incorporated into the model to handle the impact of unobserved data. We also introduce graph regularization to integrate the drug chemical information for side effect prediction. We collect the data on side effects, drug targets, drug-associated proteins and drug chemical structures to train our model and test its performance for side effect prediction. The experiment results show that our method outperforms several other state-of-the-art methods under different scenarios. The case study and additional analysis illustrate that the proposed method could not only predict the side effects of drugs but also could infer the missing targets of drugs.

AVAILABILITY AND IMPLEMENTATION: The data and the code for the proposed method are available at https://github.com/LiangXujun/GTMCC.

SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

PMID:36655793 | PMC:PMC9869719 | DOI:10.1093/bioinformatics/btad006

Sci Rep. 2023 Jan 19;13(1):1082. doi: 10.1038/s41598-023-28309-5.

ABSTRACT

Chemotherapy, although beneficial for improving outcomes in both localized and metastatic cancers, may be associated with significant adverse effects, especially for patients with decreased functional reserves. Prediction of patients who will not tolerate well chemotherapy treatment may help in modifying treatment plans and in reallocating resources to vulnerable patients. One hundred seventeen consecutive cancer patients over the age of 70 scheduled for chemotherapy treatment in a single cancer center were included in the study. Prediction of adverse chemotherapy outcomes were calculated using a prediction tool proposed and validated from the Cancer and Aging Research Group (CARG) and a prediction tool proposed by us, called Index4. The 2 tools were compared for their ability to predict grade 3 and 4 toxicities, Emergency Department (ED) and hospital admissions and chemotherapy discontinuation. The accuracy of both predictive tools was suboptimal. A high CARG score had a sensitivity of 46.3% and a specificity of 82% and an Index4 of 1 or above had a sensitivity of 53.7% and a specificity of 60% in predicting grade 3-4 adverse effects. The performance of the 2 tools in predicting ED and hospital admissions and chemotherapy discontinuation was comparable. An Index4 score of 0 was superior in predicting absence of grade 3-4 toxicities than a low CARG score (p = 0.002, McNemar's test). The CARG tool for chemotherapy adverse effect prediction in geriatric cancer patients and the Index4 were able to predict adverse outcomes with moderate accuracy. Given its ease of calculation Index4 may be an alternative to CARG tool, suitable for a busy oncology practice.

PMID:36658198 | PMC:PMC9852555 | DOI:10.1038/s41598-023-28309-5

Asia Pac J Clin Oncol. 2023 Jan 19. doi: 10.1111/ajco.13916. Online ahead of print.

ABSTRACT

AIM: To study the safety and efficacy of anlotinib, a multitargeted tyrosine kinase inhibitor, in the treatment of advanced osteosarcoma (OSS) with metastases.

METHODS: We retrospectively studied patients with advanced OSS and metastases who received anlotinib treatment in our hospital from June 2018 to April 2020. All patients had received standard multimodal therapies, before taking anlotinib. Therapeutic doses of anlotinib were 12 mg for adults and 10 mg for children and adolescents once a day for 2 consecutive weeks, followed by a week of withdrawal. This 3-week cycle of treatment was continued until the tumor progressed rapidly or the patients failed to tolerate the side effects. Adverse drug reactions were recorded, and therapeutic efficacy was evaluated based on progression-free survival (PFS), disease control rate (DCR), overall survival (OS), and objective response rate (ORR).

RESULTS: The median PFS was 9.8 ± .9 months, and the 6- and 10-month PFS rates were 73% and 33%, respectively. The median OS was 11.4 ± .6 months. No patients achieved complete response. After 6 months of treatment, the DCR and ORR were 80% and 13%, respectively. No drug-related deaths or Grade 4 adverse events occurred in the patients. Five patients (33%) had Grade 3 adverse events. The most common drug-related adverse events were hand-food syndrome, fatigue, high blood pressure, anorexia, and pneumothorax.

CONCLUSIONS: Anlotinib had a modest therapeutic effect in patients with advanced OSS after the failure of standard treatment. The adverse events were mostly tolerable or relieved after treatment.

PMID:36658675 | DOI:10.1111/ajco.13916

J Immunother Cancer. 2023 Jan;11(1):e006222. doi: 10.1136/jitc-2022-006222.

ABSTRACT

BACKGROUND: Non-invasive biomarkers of immune checkpoint inhibitor-associated acute tubulointerstitial nephritis (ICI-nephritis) are urgently needed. Because ICIs block immune checkpoint pathways that include cytotoxic T lymphocyte antigen 4 (CTLA4), we hypothesized that biomarkers of immune dysregulationpreviously defined in patients with congenital CTLA4 deficiency, including elevated soluble interleukin-2 receptor alpha (sIL-2R) and flow cytometric cell-based markers of B and T cell dysregulation in peripheral blood may aid the diagnosis of ICI-nephritis.

METHODS: A retrospective cohort of patients diagnosed with ICI-nephritis was compared with three prospectively enrolled control cohorts: ICI-treated controls without immune-related adverse events, patients not on ICIs with hemodynamic acute kidney injury (hemodynamic AKI), and patients not on ICIs with biopsy proven acute interstitial nephritis from other causes (non-ICI-nephritis). sIL-2R level and flow cytometric parameters were compared between groups using Wilcoxon rank sum test or Kruskal-Wallis test. Receiver operating characteristic curves were generated to define the accuracy of sIL-2R and flow cytometric biomarkers in diagnosing ICI-nephritis. The downstream impact of T cell activation in the affected kidney was investigated using archived biopsy samples to evaluate the gene expression of IL2RA, IL-2 signaling, and T cell receptor signaling in patients with ICI-nephritis compared with other causes of drug-induced nephritis, acute tubular injury, and histologically normal controls.

RESULTS: sIL-2R level in peripheral blood was significantly higher in patients with ICI-nephritis (N=24) (median 2.5-fold upper limit of normal (ULN), IQR 1.9-3.3), compared with ICI-treated controls (N=10) (median 0.8-fold ULN, IQR 0.5-0.9, p<0.001) and hemodynamic AKI controls (N=6) (median 0.9-fold-ULN, IQR 0.7-1.1, p=0.008). A sIL-2R cut-off point of 1.75-fold ULN was highly diagnostic of ICI-nephritis (area under the curve >96%) when compared with either ICI-treated or hemodynamic AKI controls. By peripheral blood flow cytometry analysis, lower absolute CD8+T cells, CD45RA+CD8+ T cells, memory CD27+B cells, and expansion of plasmablasts were prominent features of ICI-nephritis compared with ICI-treated controls. Gene expressions for IL2RA, IL-2 signaling, and T cell receptor signaling in the kidney tissue with ICI-nephritis were significantly higher compared with controls.

CONCLUSION: Elevated sIL-2R level and flow cytometric markers of both B and T cell dysregulation may aid the diagnosis of ICI-nephritis.

PMID:36657813 | DOI:10.1136/jitc-2022-006222