Front Immunol. 2024 Feb 1;15:1368496. doi: 10.3389/fimmu.2024.1368496. eCollection 2024.

NO ABSTRACT

PMID:38380321 | PMC:PMC10877587 | DOI:10.3389/fimmu.2024.1368496

Eur J Hosp Pharm. 2024 Feb 21:ejhpharm-2023-004028. doi: 10.1136/ejhpharm-2023-004028. Online ahead of print.

ABSTRACT

OBJECTIVES: Biological disease-modifying antirheumatic drugs (bDMARDs) require specific storage temperatures, but are frequently stored outside the recommended range of 2-8°C. As incorrect storage may affect therapy effectiveness and consequently lead to higher disease activity, compliance with recommended storage temperatures should be improved. eHealth interventions can provide insight into storage temperatures and alerts in case of deviations from recommended temperatures. Therefore, this study aims to assess the effect of a smart temperature logger on correctly storing bDMARDs at home by patients with rheumatic diseases.

METHODS: A pre-post study was performed in a hospital in the Netherlands. The baseline period consisted of 12 weeks of storage temperature measurement with a passive temperature logger, and the intervention period consisted of 12 weeks of storage temperature measurement with a smart temperature logger. This smart logger included a smartphone application which provided insight into storage temperatures and real-time alerts when exceeding recommended temperatures. The main outcome measure was the difference in the number of patients who stored their bDMARDs correctly between baseline and intervention. Secondary outcomes were the difference in the proportion of measurement time within 2-8°C between baseline and intervention, the distribution of measurement time among temperature categories, and the patient's acceptance measured using a questionnaire based on the Technology Acceptance Model.

RESULTS: In total, 48 participants (median age 55 years (IQR 47-64), 53% male) were analysed. The proportion of participants correctly storing bDMARDs increased from 18.8% (n=9) during baseline to 39.6% (n=19) during intervention (p=0.004). The median proportion of measurement time between 2-8°C improved by 6% (IQR 0-34%) (p<0.0001). Technology acceptance was scored as moderate.

CONCLUSIONS: Temperature monitoring and real-time feedback with a smart temperature logger shows potential to improve at-home storage of bDMARDs, provided that continuous connection is realised to ensure real-time alerts and data collection.

PMID:38383141 | DOI:10.1136/ejhpharm-2023-004028

Korean J Anesthesiol. 2024 Feb 20. doi: 10.4097/kja.23747. Online ahead of print.

ABSTRACT

BACKGROUND: Posterior spinal fusion (PSF), commonly used for adolescent idiopathic scoliosis (AIS), causes severe postoperative pain. Intravenous (IV) administration of acetaminophen has shown promise for opioid-sparing analgesia; however, its analgesic effect and optimal timing for its standard use remain unclear. Our study aimed to evaluate the analgesic effect and optimal timing of IV acetaminophen administration in pediatric and adolescent patients undergoing PSF and requiring adequate pain control.

METHODS: This prospective, randomized, triple-blind trial was conducted in patients aged 11-20 undergoing PSF. Participants were randomized into three groups: the preemptive group (received IV acetaminophen 15 mg/kg after anesthetic induction/before surgical incision), the preventive group (received IV acetaminophen 15 mg/kg at the end of surgery/before skin closure), and the placebo group. The primary outcome was cumulative opioid consumption during the first 24 h postoperatively.

RESULTS: Among the 99 enrolled patients, the mean ± standard deviation (SD) amount of opioid consumption during the postoperative 24 h was 60.66 ± 23.84, 52.23 ± 22.43, and 66.70 ± 23.01 mg in the preemptive, preventive, and placebo groups, respectively (overall p = 0.043). A post hoc analysis revealed that the preventive group had significantly lower opioid consumption than the placebo group (p = 0.013). However, no significant differences between the groups were observed for the secondary outcomes.

CONCLUSIONS: The preventive administration of scheduled IV acetaminophen reduces cumulative opioid consumption without increasing the incidence of drug-induced adverse events in pediatric and adolescent patients undergoing PSF.

PMID:38383005 | DOI:10.4097/kja.23747

Eur J Drug Metab Pharmacokinet. 2024 Feb 21. doi: 10.1007/s13318-024-00877-5. Online ahead of print.

ABSTRACT

BACKGROUND AND OBJECTIVES: Tetramethylpyrazine nitrone (TBN) is a novel tetramethylpyrazine derivative armed with a strong free radical scavenging nitrone moiety. This study aims to evaluate the pharmacokinetics, safety profile, and tolerability of TBN tablets after a single ascending dose (SAD) and multiple ascending doses (MAD) in healthy Chinese volunteers.

METHODS: This phase I, single-center, open-label study was conducted in China. The SAD portion consisted of four cohorts with dose levels of 400-1800 mg. The MAD portion included three cohorts in which subjects received doses of 600-1800 mg twice daily for 7 days (13 consecutive doses). The third portion was a randomized, two-period, crossover design to assess the influence of food with a single dose of TBN tablets (1200 mg). The safety profile was evaluated by monitoring adverse events (AEs), vital signs, electrocardiograms, physical examinations, and laboratory test results.

RESULTS: Fifty-two healthy subjects aged 18 to 45 years with a body mass index between 19.0 and 26.0 kg/m2 were enrolled. After a single dose of TBN, the median time to maximum plasma concentration (Tmax) was 2.48-3.24 h and the mean half-life (t1/2) was 1.28 to 2.10 h across all doses. In the MAD study, the median Tmax was 2.48 to 3.48 h. In the 400-1800 mg dose range, there was a tendency for less than proportional increases in the maximum plasma concentration (Cmax), the area under the concentration-time curve from 0 to time of last measurable concentration (AUC0-t), and the area under the concentration-time curve from 0 to infinity (AUC0-inf) in both single- and multiple-dose periods. A significantly higher TBN exposure was observed in females than males in both a single and multiple doses of the 600 mg and 1200 mg groups, with a geometric mean female-to-male ratio of 138.69-203.18%. Food decreased the Cmax and AUC0-t of TBN to 45.19% and 59.73%, respectively. Each dose group reached a steady state after 4 days. No drug accumulation was observed. Two subjects had drug-related AEs. A decreased neutrophil count and drug eruption in the SAD portion (1200 mg group) and an increased alanine aminotransferase level in the food effect group were found. All AEs were mild and tolerable (CTCAE grade 1) and resolved without any medical intervention.

CONCLUSION: TBN tablets had a good safety profile and were well tolerated in healthy Chinese volunteers. Steady-state concentrations were reached after 4 consecutive days of oral administration. The results of this phase I study will provide guidance for the design of future TBN clinical studies.

CHINESE CLINICAL TRIAL REGISTRY: ChiCTR1900022092.

PMID:38381348 | DOI:10.1007/s13318-024-00877-5

Front Neurol. 2024 Feb 6;15:1342111. doi: 10.3389/fneur.2024.1342111. eCollection 2024.

ABSTRACT

BACKGROUND: Migraine imposes a substantial global burden, impacting patients and society. Pharmacotherapy, as a primary treatment, entails specific adverse reactions. Emphasizing these reactions is pivotal for improving treatment strategies and enhancing patients' well-being. Thus, we conducted a comprehensive bibliometric and visual analysis of relevant literature.

METHODOLOGY: We conducted a comprehensive search on the Science Citation Index Expanded within the Web of Science, restricting the literature for analysis based on criteria such as document type, publication date, and language. Subsequently, we utilized various analytical tools, including VOSviewer, Scimago Graphica, the R package 'bibliometrix', CiteSpace, and Excel programs, for a meticulous examination and systematic organization of data concerning journals, authors, countries/regions, institutions, keywords, and references.

RESULTS: By August 31, 2023, the literature was distributed across 379 journals worldwide, authored by 4,235 individuals from 1726 institutions. It featured 2,363 keywords and 38,412 references. 'HEADACHE' led in publication count, with 'SILBERSTEIN S' as the most prolific author. The United States ranked highest in publication volume, with 'UNIV COPENHAGEN' leading among institutions.

CONCLUSION: Our research findings indicate that researchers in the field continue to maintain a focus on the calcitonin gene-related peptide (CGRP) system and explore diverse mechanisms for drug development through the application of novel biotechnological approaches. Furthermore, it is imperative to enhance the assessment of clinical trial outcomes, consistently monitor the efficacy and safety of prominent drugs such as Erenumab and Fremanezumab. There is a need for further evaluation of acute and preventive treatments tailored to different populations and varying types of migraine.

PMID:38379705 | PMC:PMC10878131 | DOI:10.3389/fneur.2024.1342111

BMC Bioinformatics. 2024 Feb 20;25(1):79. doi: 10.1186/s12859-024-05705-w.

ABSTRACT

BACKGROUND: Identification of potential drug-disease associations is important for both the discovery of new indications for drugs and for the reduction of unknown adverse drug reactions. Exploring the potential links between drugs and diseases is crucial for advancing biomedical research and improving healthcare. While advanced computational techniques play a vital role in revealing the connections between drugs and diseases, current research still faces challenges in the process of mining potential relationships between drugs and diseases using heterogeneous network data.

RESULTS: In this study, we propose a learning framework for fusing Graph Transformer Networks and multi-aggregate graph convolutional network to learn efficient heterogenous information graph representations for drug-disease association prediction, termed WMAGT. This method extensively harnesses the capabilities of a robust graph transformer, effectively modeling the local and global interactions of nodes by integrating a graph convolutional network and a graph transformer with self-attention mechanisms in its encoder. We first integrate drug-drug, drug-disease, and disease-disease networks to construct heterogeneous information graph. Multi-aggregate graph convolutional network and graph transformer are then used in conjunction with neural collaborative filtering module to integrate information from different domains into highly effective feature representation.

CONCLUSIONS: Rigorous cross-validation, ablation studies examined the robustness and effectiveness of the proposed method. Experimental results demonstrate that WMAGT outperforms other state-of-the-art methods in accurate drug-disease association prediction, which is beneficial for drug repositioning and drug safety research.

PMID:38378479 | DOI:10.1186/s12859-024-05705-w

J Child Adolesc Psychopharmacol. 2024 Feb;34(1):28-33. doi: 10.1089/cap.2023.0043.

ABSTRACT

Introduction: Combinatorial pharmacogenetic testing panels are widely available in clinical practice and often separate medications into columns/bins associated with low, medium, or high probability of gene-drug interactions. The objective of the Adolescent Management of Depression (AMOD) study was to determine the clinical utility of combinatorial pharmacogenetic testing in a double-blind, randomized, controlled effectiveness study by comparing patients who had genetic testing results at time of medication initiation to those that did not have results until week 8. The objective of this post hoc analysis was to assess and report additional outcomes with respect to significant gene-drug interactions (i.e., a medication in the high probability gene-drug interaction bin as defined by a proprietary algorithm) compared with patients taking a medication with minimal to moderate gene-drug interactions (i.e., a medication from the low or medium probability gene-drug interaction bin, respectively). Methods: Adolescents 13-18 years (N = 170) with moderate to severe major depressive disorder received pharmacogenetic testing. Symptom improvement and side effects were assessed at baseline, week 4, week 8, and 6 months. Patients were grouped into three categories based on whether the medication they were prescribed was associated with low, medium, or high risk for gene-drug interactions. Patients taking a medication from the low/medium gene-drug interaction bin were compared with patients taking a medication from the high gene-drug interaction bin. Results: Patients taking a medication from the high gene-drug interaction bin were more likely to endorse side effects compared with patients taking a medication in the low/medium gene-drug interaction bin at week 8 (p = 0.001) and 6 months (p < 0.0001). Depressive symptom severity scores did not differ significantly across the medication bins. Conclusions: This study demonstrates the utility of gene-drug interaction testing to guide medication decisions to minimize side effect burden rather than solely prioritizing the search for the most efficacious medication. (Clinical Trials Registration Identifier: NCT02286440).

PMID:38377526 | DOI:10.1089/cap.2023.0043

J Cancer Res Ther. 2023 Oct 1;19(7):2076-2078. doi: 10.4103/jcrt.jcrt_2165_21. Epub 2023 Jan 12.

ABSTRACT

The incidence of 5-Fluorouracil (5FU)- induced leukoencephalopathy is <5% among the patients treated with this agent. It may present with disorientation, confusion, agitation, seizure, and coma. It should be suspected when patients present with any of these symptoms during or immediately after 5FU chemotherapy. Early detection of drug-induced leukoencephalopathy is important as the clinical symptoms can be reversed by early discontinuation of the drug. Therefore, clinicians should be aware of the possibility of this adverse neurologic effect of 5FU. We describe the case of a 35-year-old female with carcinoma esophagus with 5FU-induced leukoencephalopathy.

PMID:38376324 | DOI:10.4103/jcrt.jcrt_2165_21

Antivir Ther. 2024 Feb;29(1):13596535241233128. doi: 10.1177/13596535241233128.

ABSTRACT

BACKGROUND: In British Columbia, antiretrovirals (ARVs) for HIV treatment (HIV-Tx) and pre-exposure prophylaxis (PrEP) are free-of-charge through publicly-funded Drug Treatment Programs (DTPs). When available, less costly generics are substituted for brand-name ARVs. We describe the incidence and type of product substitution issue (PSI) adverse drug reactions (ADRs) attributed to generic ARVs.

METHODS: Cohorts included DTP clients ≥19 years who received generic ARVs for HIV-Tx (abacavir-lamivudine, emtricitabine-tenofovir DF, efavirenz-emtricitabine-tenofovir DF, atazanavir or darunavir between 01 Jun 2017 and 30 Jun 2022) or PrEP (emtricitabine-tenofovir DF, 01 Apr 2018 to 30 Jun 2022). Demographic, ARV and ADR data were extracted from DTP databases and summarized by descriptive statistics. PSI incidence was calculated for each product during the year following brand-to-generic and generic-to-generic transitions (first-year-post-rollout), and compared between generic versions using generalized estimating equations. For context, incidence of any ARV product-related ADR was calculated in the same 1-year periods.

RESULTS: During first-year-post-rollout periods, 5339 HIV-Tx (83% male, median age 52 years) and 8095 PrEP (99% male, median 33 years) clients received generic ARVs, and reported 78 and 23 generic PSIs, respectively. PSI incidence was <1% for most generic ARVs, with mild-moderate symptoms including gastrointestinal upset, headache, dizziness, fatigue/malaise and skin rash. In HIV-Tx clients, the efavirenz-containing product had higher PSI incidence than other ARVs (2.2%, p = .004), due to more neuropsychiatric adverse reactions. Any ADR incidence was stable across measurement periods, and generic PSIs represented less than one third of all product-related ADRs.

CONCLUSIONS: Generic substitution of antiretrovirals for HIV-Tx and PrEP was well tolerated, with ≤2% incidence of mild-moderate PSI ADRs.

PMID:38375582 | DOI:10.1177/13596535241233128

Drug Des Devel Ther. 2024 Feb 15;18:453-462. doi: 10.2147/DDDT.S438703. eCollection 2024.

ABSTRACT

INTRODUCTION: Methotrexate (MTX) is one of the most widely used drugs in cancer chemotherapy and treating rheumatoid arthritis. The hepatotoxicity of MTX is one of its major side effects. Roflumilast (ROF) has been recognized to have antioxidant and anti-inflammatory activity in in-vivo and in-vitro models. The present study aimed to explore the potential protective effects of roflumilast against MTX-induced liver toxicity in male Wistar rats.

METHODS: High dose of 5 mg/kg for 4 consecutive days subcutaneous (S.C) injection of methotrexate for induction of acute liver injury. A total of 24 Wistar rats, rats were used in four different groups. The NS injections were given S.C to the control group once a day for 4 consecutive days. SC injections of MTX (5 mg/kg) were given to the MTX group daily for four days. At 5 mg/kg once daily for four days, the roflumilast group was given daily oral roflumilast. An injection of MTX and oral roflumilast were given to the MTX + roflumilast group once daily for four consecutive days.

RESULTS: Administration of high dose MTX (5 mg/kg) today 4 produced a significant decrease in hepatic glutathione (GSH) levels and a significant increase in ALT and AST liver enzymes, hepatic malondialdehyde (MDA), tumor suppressor protein (p53), interleukin 6, interleukin 1 levels compared to the control group. Treatment with roflumilast for 4 days significantly attenuated unfavorable changes in these parameters. According to histopathological findings, Roflumilast significantly reduced MTX-induced inflammation and degeneration in the liver. In conclusion, the findings indicate that roflumilast may have a potential therapeutic benefit in treating rats with MTX-induced liver toxicity by mitigating its effects.

PURPOSE: The aim of this study is to investigate the potential protective effects of roflumilast against MTX-induced liver toxicity in Wistar rats.

PMID:38374827 | PMC:PMC10875972 | DOI:10.2147/DDDT.S438703

Urol Pract. 2024 Mar;11(2):312-323. doi: 10.1097/UPJ.0000000000000497. Epub 2024 Feb 6.

ABSTRACT

INTRODUCTION: Medical misinformation regarding COVID-19 immunization remains rampant and a public concern, and as such, there is a need for national studies evaluating the immunization's safety profile. We sought to quantify and analyze urologic adverse events and symptoms after COVID-19 immunization, compare these events reported between COVID-19 vaccine types, and compare these events reported following COVID-19 immunization relative to those reported following other immunizations.

METHODS: We conducted a retrospective case-control disproportionality analysis by querying the Food and Drug Administration Vaccine Adverse Event Reporting System for all reported symptoms following COVID-19 immunization through December 23, 2022, as well as for all non-COVID immunizations.

RESULTS: Using a total of 704,231 event reports containing 2,982,187 symptoms related to COVID vaccination and a total of 770,975 event reports containing 2,198,993 symptoms related to all vaccinations other than COVID-19 for disproportionality analysis, no urologic symptom produced a positive signal when grouping all vaccinations. When stratifying by manufacturer, some symptoms related to Janssen vaccination were positive, but this may be in part due to overreporting secondary to media attention rather than a strong association between Janssen vaccination and urologic adverse events.

CONCLUSIONS: Although there have been anecdotal reports of adverse events associated with the COVID-19 vaccine, our review of the Vaccine Adverse Event Reporting System database did not produce positive signals across all 4 measures for any potential adverse event. Our findings do not suggest increased scrutiny is required regarding these adverse events potentially related to the COVID-19 immunization. Further evaluation and analysis of the COVID-19 immunization is ongoing.

PMID:38377155 | DOI:10.1097/UPJ.0000000000000497

Comput Methods Biomech Biomed Engin. 2024 Feb 20:1-18. doi: 10.1080/10255842.2023.2282951. Online ahead of print.

ABSTRACT

Drug discovery relies on the precise prognosis of drug-target interactions (DTI). Due to their ability to learn from raw data, deep learning (DL) methods have displayed outstanding performance over traditional approaches. However, challenges such as imbalanced data, noise, poor generalization, high cost, and time-consuming processes hinder progress in this field. To overcome the above challenges, we propose a DL-based model termed DrugSchizoNet for drug interaction (DI) prediction of Schizophrenia. Our model leverages drug-related data from the DrugBank and repoDB databases, employing three key preprocessing techniques. First, data cleaning eliminates duplicate or incomplete entries to ensure data integrity. Next, normalization is performed to enhance security and reduce costs associated with data acquisition. Finally, feature extraction is applied to improve the quality of input data. The three layers of the DrugSchizoNet model are the input, hidden and output layers. In the hidden layer, we employ dropout regularization to mitigate overfitting and improve generalization. The fully connected (FC) layer extracts relevant features, while the LSTM layer captures the sequential nature of DIs. In the output layer, our model provides confidence scores for potential DIs. To optimize the prediction accuracy, we utilize hyperparameter tuning through OB-MOA optimization. Experimental results demonstrate that DrugSchizoNet achieves a superior accuracy of 98.70%. The existing models, including CNN-RNN, DANN, CKA-MKL, DGAN, and CNN, across various evaluation metrics such as accuracy, recall, specificity, precision, F1 score, AUPR, and AUROC are compared with the proposed model. By effectively addressing the challenges of imbalanced data, noise, poor generalization, high cost and time-consuming processes, DrugSchizoNet offers a promising approach for accurate DTI prediction in Schizophrenia. Its superior performance demonstrates the potential of DL in advancing drug discovery and development processes.

PMID:38375638 | DOI:10.1080/10255842.2023.2282951

Inn Med (Heidelb). 2024 Feb 19. doi: 10.1007/s00108-024-01669-4. Online ahead of print.

ABSTRACT

Drug-induced liver injury (DILI) is a rare yet potentially life-threatening disease. Besides intrinsic DILI, which is mainly caused by paracetamol overdosing and which is dose-dependent and predictable, there is idiosyncratic DILI-an unpredictable and dose-independent injury of the liver caused by certain medications that only occurs in a minority of patients taking this drug. The reason why some patients react with DILI towards a specific drug is still unknown. However, the immune system plays a central role, which is underlined by the association of certain human leukocyte antigen (HLA) polymorphisms and DILI caused by specific drug classes. Due to the immunological processes that lead to the liver injury in DILI, there are great overlaps regarding laboratory and histological parameters between DILI and autoimmune hepatitis (AIH). Differentiating DILI and AIH can therefore be challenging, especially at the time of presentation. In addition, there are other immunologically mediated DILI phenotypes, in particular the newly defined drug-induced autoimmune-like hepatitis (DI-ALH) and liver injuries caused by checkpoint inhibitors (CPI). DI-ALH is characterized by autoimmune features and good responses towards corticosteroids, with the difference that DI-ALH mostly does not relapse after discontinuation of corticosteroids. CPI-induced liver injury has become more frequent with the rising use of those drugs and is characterized by a distinct histopathological pattern with granulomatous hepatitis and infiltration dominated by cytotoxic T cells. Similarly, the recently recognized liver injury following vaccinations also shows an autoimmune phenotype; however, in contrast to AIH, cytotoxic T cells seem to dominate the inflammatory infiltrates in the liver.

PMID:38374310 | DOI:10.1007/s00108-024-01669-4

J Leukoc Biol. 2024 Feb 19:qiae031. doi: 10.1093/jleuko/qiae031. Online ahead of print.

ABSTRACT

The cell surface molecule CD40 is a member of the tumor necrosis factor receptor superfamily and is broadly expressed by immune cells including B cells, dendritic cells (DC), and monocytes, as well as other normal cells and some malignant cellsCD40 is constitutively expressed on antigen-presenting cells (APCs) and ligation promotes functional maturation leading to an increase in antigen presentation, cytokine production, and a subsequent increase in the activation of antigen specific T cells. It is postulated that CD40 agonists can mediate both T-cell-dependent and T-cell-independent immune mechanisms of tumor regression in mice and patients. In addition, it is believed that CD40 activation also promotes apoptotic death of tumor cells and that the presence of the molecule on the surface of cancer cells is an important factor in the generation of tumor-specific T-cell responses that contribute to tumor cell elimination. Notably, CD40-agonistic therapies were evaluated in patients with solid tumors and hematologic malignancies with reported success as a single agent. Preclinical studies have shown that subcutaneous administration of CD40-agonistic antibodies reduces systemic toxicity and elicits a stronger and localized pharmacodynamic response. Two independent studies in cynomolgus macaque (Macaca fascicularis) studies were performed to further evaluate, potentially immunotoxicological effects associated with drug-induced adverse events seen in human subjects. Studies conducted in monkeys showed that when selicrelumab is administered at doses currently used in clinical trial patients, via subcutaneous injection, it is safe and effective at stimulating a systemic immune response.

PMID:38372596 | DOI:10.1093/jleuko/qiae031

Cureus. 2024 Jan 19;16(1):e52587. doi: 10.7759/cureus.52587. eCollection 2024 Jan.

ABSTRACT

Mesalamine is a first-line drug used in the treatment of inflammatory bowel disease (IBD), specifically ulcerative colitis (UC), with side effects ranging from gastrointestinal effects to cardiotoxicity. We present a rare case of mesalamine-induced myopericarditis in a patient with IBD, who presented with epigastric pain and was found to have elevated an c-reactive protein (CRP) in the absence of chest pain and any other gastrointestinal symptoms. This case highlights the importance of including myopericarditis as a differential for IBD patients on mesalamine with an isolated elevated CRP, especially within the first month of initiating this medication, as drug cessation usually leads to immediate clinical improvement.

PMID:38370999 | PMC:PMC10874644 | DOI:10.7759/cureus.52587

BMJ Open. 2024 Feb 17;14(2):e074956. doi: 10.1136/bmjopen-2023-074956.

ABSTRACT

INTRODUCTION: The development of oral anticancer agents (OAA) has profoundly changed cancer care, leading patients to manage their chemotherapy treatment on an outpatient basis. The prevention of iatrogenic effects of OAA remains a major concern, especially since their side effects are not less serious than those of intravenous chemotherapy. The ONCORAL programme was set up to secure the management of OAA in cancer patients followed at the Lyon University Hospital. This multidisciplinary programme involves hospital pharmacists, nurses, oncologists, and haematologists, as well as community health professionals. Given the economic stakes that this programme entails for the health system, a medico-economic study was designed.

METHODS AND ANALYSIS: This is a prospective controlled study, with individual open-label randomisation. A total of 216 outpatients treated with OAA and at risk of developing a drug-related iatrogenic event, will be randomised (2:1) to undergo follow-up in the ONCORAL programme or usual care. The primary outcome will be the estimation of the incremental cost-effectiveness ratio (difference in total costs per quality adjusted life years gained) at 12 months between the two groups. The secondary outcomes will be evaluation of OAA management consequences (relative-dose intensity, adherence, adverse drug events, drug-drug interactions, and proven medication errors), evaluation of overall survival and cancer-related quality of life, and patient-reported outcomes in relation to the treatment. A budget impact analysis will be implemented. Patient and health professional satisfaction regarding the ONCORAL programme will be measured.

ETHICS AND DISSEMINATION: Approval to conduct this study was obtained from an Ethics Committee (Comité de Protection des Personnes Ile-de-France VI) in October 2019, and from the French data protection agency (Commission Nationale de l'Informatique et des Libertés), according to the French Law. Trial results will be disseminated at clinical conferences and published in peer-reviewed journals.

TRIAL REGISTRATION: NCT03660670.

PMID:38367968 | DOI:10.1136/bmjopen-2023-074956

Oncologist. 2024 Feb 16:oyae005. doi: 10.1093/oncolo/oyae005. Online ahead of print.

ABSTRACT

BACKGROUND: This study aimed to assess the activity of apatinib plus toripalimab in the second line for patients with advanced gastric or esophagogastric junction cancer (GC/EGJC).

METHODS: In this open-label, phase II, randomized trial, patients with advanced GC/EGJC who progressed after first-line chemotherapy were enrolled and received 250 mg apatinib per day plus 240 mg toripalimab on day 1 per 3 weeks (arm A) or physician's choice of chemotherapy (PC, arm B). The primary endpoint of this study was the 1-year survival rate. Progression-free survival (PFS), overall survival (OS), overall response rate (ORR), and safety were assessed as secondary endpoints.

RESULTS: Twenty-five patients received apatinib plus toripalimab while 26 were enrolled in arm B. The 1-year survival rates of the 2 groups were 43.3% and 42.3%, respectively (P = .903). The PFS was 2.77 versus 2.33 months (P = .660). The OS was 8.30 versus 9.88 months (P = .539). An objective response was reported in 20.0% of patients in arm A compared to 26.9% in arm B (P = .368), respectively. A total of 6 (24.0%) patients experienced adverse events of grade ≥ 3 in arm A, while 9 (34.6%) patients suffered from adverse events of grade ≥ 3 in arm B. No drug-related deaths occurred in either group.

CONCLUSION: Toripalimab plus apatinib treatment in second-line therapy of advanced GC/EGJC showed manageable toxicity but did not improve clinical outcomes relative to PC treatment (ClinicalTrials.gov Identifier: NCT04190745).

PMID:38366886 | DOI:10.1093/oncolo/oyae005

BMJ Open. 2024 Feb 15;14(2):e079798. doi: 10.1136/bmjopen-2023-079798.

ABSTRACT

OBJECTIVE: To investigate the prognostic impact of initial lung cancer (LC) on second primary breast cancer after LC (LC-BC) and further develop a nomogram for predicting the survival of patients.

METHODS: All patients diagnosed with LC-BC and first primary BC (BC-1) during 2000-2017 were collected from Surveillance, Epidemiology, and End Results database. Pathological features, treatment strategies and survival outcomes were compared between LC-BC and BC-1 before and after propensity score matching (PSM). Cox regression analysis was performed to identify the prognostic factors associated with LC in patients with LC-BC. Additionally, least absolute shrinkage and selection operator regression analysis was used to select clinical characteristics for nomogram construction, which were subsequently evaluated using the concordance index (C-index), calibration curve and decision curve analysis (DCA).

RESULTS: 827 429 patients with BC-1 and 1445 patients with LC-BC were included in the analysis. Before and after PSM, patients with BC-1 had a better prognosis than individuals with LC-BC in terms of both overall survival (OS) and breast cancer-specific survival (BCSS). Furthermore, characteristics such as more regional lymph node dissection, earlier stage and the lack of chemotherapy and radiation for LC were found to have a stronger predictive influence on LC-BC. The C-index values (OS, 0.748; BCSS, 0.818), calibration curves and DCA consistently demonstrated excellent predictive accuracy of the nomogram.

CONCLUSION: In conclusion, patients with LC-BC have a poorer prognosis than those with BC-1, and LC traits can assist clinicians estimate survival of patients with LC-BC more accurately.

PMID:38365292 | DOI:10.1136/bmjopen-2023-079798

Lancet Gastroenterol Hepatol. 2024 Feb 13:S2468-1253(23)00454-5. doi: 10.1016/S2468-1253(23)00454-5. Online ahead of print.

ABSTRACT

BACKGROUND: The aim of the COSMIC-312 trial was to evaluate cabozantinib plus atezolizumab versus sorafenib in patients with previously untreated advanced hepatocellular carcinoma. In the initial analysis, cabozantinib plus atezolizumab significantly prolonged progression-free survival versus sorafenib. Here, we report the pre-planned final overall survival analysis and updated safety and efficacy results following longer follow-up.

METHODS: COSMIC-312 was an open-label, randomised, phase 3 study done across 178 centres in 32 countries. Patients aged 18 years or older with previously untreated advanced hepatocellular carcinoma were eligible. Patients must have had measurable disease per Response Evaluation Criteria in Solid Tumours version 1.1 (RECIST 1.1), and adequate marrow and organ function, including Child-Pugh class A liver function; those with fibrolamellar carcinoma, sarcomatoid hepatocellular carcinoma, or combined hepatocellular cholangiocarcinoma were ineligible. Patients were randomly assigned (2:1:1) using a web-based interactive response system to a combination of oral cabozantinib 40 mg once daily plus intravenous atezolizumab 1200 mg every 3 weeks, oral sorafenib 400 mg twice daily, or oral single-agent cabozantinib 60 mg once daily. Randomisation was stratified by disease aetiology, geographical region, and presence of extrahepatic disease or macrovascular invasion. Dual primary endpoints were for cabozantinib plus atezolizumab versus sorafenib: progression-free survival per RECIST 1.1, as assessed by a blinded independent radiology committee, in the first 372 randomly assigned patients (previously reported) and overall survival in all patients randomly assigned to cabozantinib plus atezolizumab or sorafenib. The secondary endpoint was progression-free survival in all patients randomly assigned to cabozantinib versus sorafenib. Outcomes in all randomly assigned patients, including final overall survival, are presented. Safety was assessed in all randomly assigned patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, NCT03755791.

FINDINGS: Between Dec 7, 2018, and Aug 27, 2020, 432 patients were randomly assigned to combination treatment, 217 to sorafenib, and 188 to single-agent cabozantinib, and included in all efficacy analyses. 704 (84%) patients were male and 133 (16%) were female. 824 of these patients received at least one dose of study treatment and were included in the safety population. Median follow-up was 22·1 months (IQR 19·3-24·8). Median overall survival was 16·5 months (96% CI 14·5-18·7) for the combination treatment group and 15·5 months (12·2-20·0) for the sorafenib group (hazard ratio [HR] 0·98 [0·78-1·24]; stratified log-rank p=0·87). Median progression-free survival was 6·9 months (99% CI 5·7-8·2) for the combination treatment group, 4·3 months (2·9-6·1) for the sorafenib group, and 5·8 months (99% CI 5·4-8·2) for the single-agent cabozantinib group (HR 0·74 [0·56-0·97] for combination treatment vs sorafenib; HR 0·78 [99% CI 0·56-1·09], p=0·05, for single-agent cabozantinib vs sorafenib). Grade 3 or 4 adverse events occurred in 281 (66%) of 429 patients in the combination treatment group, 100 (48%) of 207 patients in the sorafenib group, and 108 (57%) of 188 patients in the single-agent cabozantinib group; the most common were hypertension (37 [9%] vs 17 [8%] vs 23 [12%]), palmar-plantar erythrodysaesthesia (36 [8%] vs 18 [9%] vs 16 [9%]), aspartate aminotransferase increased (42 [10%] vs eight [4%] vs 17 [9%]), and alanine aminotransferase increased (40 [9%] vs six [3%] vs 13 [7%]). Serious adverse events occurred in 223 (52%) patients in the combination treatment group, 84 (41%) patients in the sorafenib group, and 87 (46%) patients in the single agent cabozantinib group. Treatment-related deaths occurred in six (1%) patients in the combination treatment group (encephalopathy, hepatic failure, drug-induced liver injury, oesophageal varices haemorrhage, multiple organ dysfunction syndrome, and tumour lysis syndrome), one (<1%) in the sorafenib group (general physical health deterioration), and four (2%) in the single-agent cabozantinib group (asthenia, gastrointestinal haemorrhage, sepsis, and gastric perforation).

INTERPRETATION: First-line cabozantinib plus atezolizumab did not improve overall survival versus sorafenib in patients with advanced hepatocellular carcinoma. The progression-free survival benefit of the combination versus sorafenib was maintained, with no new safety signals.

FUNDING: Exelixis and Ipsen.

PMID:38364832 | DOI:10.1016/S2468-1253(23)00454-5

JAMA. 2024 Feb 16. doi: 10.1001/jama.2024.0728. Online ahead of print.

ABSTRACT

IMPORTANCE: Angiotensinogen is the most upstream precursor of the renin-angiotensin-aldosterone system, a key pathway in blood pressure (BP) regulation. Zilebesiran, an investigational RNA interference therapeutic, targets hepatic angiotensinogen synthesis.

OBJECTIVE: To evaluate antihypertensive efficacy and safety of different zilebesiran dosing regimens.

DESIGN, SETTING, AND PARTICIPANTS: This phase 2, randomized, double-blind, dose-ranging study of zilebesiran vs placebo was performed at 78 sites across 4 countries. Screening initiation occurred in July 2021 and the last patient visit of the 6-month study occurred in June 2023. Adults with mild to moderate hypertension, defined as daytime mean ambulatory systolic BP (SBP) of 135 to 160 mm Hg following antihypertensive washout, were randomized.

INTERVENTIONS: Randomization to 1 of 4 subcutaneous zilebesiran regimens (150, 300, or 600 mg once every 6 months or 300 mg once every 3 months) or placebo (once every 3 months) for 6 months.

MAIN OUTCOMES AND MEASURES: The primary end point was between-group difference in least-squares mean (LSM) change from baseline to month 3 in 24-hour mean ambulatory SBP.

RESULTS: Of 394 randomized patients, 377 (302 receiving zilebesiran and 75 receiving placebo) comprised the full analysis set (93 Black patients [24.7%]; 167 [44.3%] women; mean [SD] age, 57 [11] years). At 3 months, 24-hour mean ambulatory SBP changes from baseline were -7.3 mm Hg (95% CI, -10.3 to -4.4) with zilebesiran, 150 mg, once every 6 months; -10.0 mm Hg (95% CI, -12.0 to -7.9) with zilebesiran, 300 mg, once every 3 months or every 6 months; -8.9 mm Hg (95% CI, -11.9 to -6.0) with zilebesiran, 600 mg, once every 6 months; and 6.8 mm Hg (95% CI, 3.6-9.9) with placebo. LSM differences vs placebo in change from baseline to month 3 were -14.1 mm Hg (95% CI, -19.2 to -9.0; P < .001) with zilebesiran, 150 mg, once every 6 months; -16.7 mm Hg (95% CI, -21.2 to -12.3; P < .001) with zilebesiran, 300 mg, once every 3 months or every 6 months; and -15.7 mm Hg (95% CI, -20.8 to -10.6; P < .001) with zilebesiran, 600 mg, once every 6 months. Over 6 months, 60.9% of patients receiving zilebesiran had adverse events vs 50.7% patients receiving placebo and 3.6% had serious adverse events vs 6.7% receiving placebo. Nonserious drug-related adverse events occurred in 16.9% of zilebesiran-treated patients (principally injection site reactions and mild hyperkalemia) and 8.0% of placebo-treated patients.

CONCLUSIONS AND RELEVANCE: In adults with mild to moderate hypertension, treatment with zilebesiran across a range of doses at 3-month or 6-month intervals significantly reduced 24-hour mean ambulatory SBP at month 3.

TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04936035.

PMID:38363577 | DOI:10.1001/jama.2024.0728