Expert Opin Drug Saf. 2024 Dec 4. doi: 10.1080/14740338.2024.2438752. Online ahead of print.

ABSTRACT

BACKGROUND: Reactivation of the hepatitis B virus (HBV) induced by drugs is a commonly overlooked but clinically significant complication, posing risks of treatment interruptions, hepatitis exacerbation, liver failure, and even mortality. This study aims to identify potential drugs that may lead to HBV reactivation (HBV-R) through the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS) database.

METHODS: Disproportionality analyses were conducted on the FAERS database data spanning from January 2017 to December 2023 to detect drugs posing a risk of HBV-R. HBV-R cases were identified using the Medical Dictionary for Regulatory Activities (MedDRA), and drug generic names were ascertained from the DrugBank database.

RESULTS: A total of 2596 adverse event reports (AERs) were found to be related to drug-induced HBV-R. Among them, rituximab (231 cases) was associated with the highest number of cases of HBV-R. According to the disproportionality analysis, the top five drugs with the highest ROR and PRR were daklinza, vocabria, doxorubicin, sovaldi, and ribavirin. The top 40 drugs causing drug-induced HBV-R can be roughly divided into three categories: anti-tumor drugs, immunosuppressive drugs, and antiviral drugs. Among them, 23 drugs do not explicitly mention the risk of HBV-R in their drug instructions.

CONCLUSIONS: Through an analysis of the FAERS database, it was observed that some pharmaceuticals do not adequately address the risk of HBV-R in their drug documentation. These findings could assist healthcare providers in promptly recognizing drug-induced HBV-R.

PMID:39630586 | DOI:10.1080/14740338.2024.2438752

Thyroid. 2024 Dec 4. doi: 10.1089/thy.2024.0495. Online ahead of print.

ABSTRACT

Background: Two selective RET inhibitors (RETis) are effective in treating REarranged during Transfection (RET)-altered medullary thyroid carcinoma (MTC), but clinical trials did not distinguish responses between hereditary MTC (hMTC) and sporadic MTC (sMTC) cases. We reviewed our single-center experience using a RETi to treat advanced hMTC. Methods: We conducted a retrospective cohort study of patients with hMTC treated with a selective RETi at a tertiary cancer center. The primary outcome was overall response rate using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Secondary end points included overall survival (OS), progression-free survival (PFS), biochemical response rate, and safety. Results: We identified 23 evaluable patients as follows: 15 (65%) multiple endocrine neoplasia (MEN)2A and 8 (35%) MEN2B. Median age at start of RETi was 51 years (range, 15-79). All patients had distant metastases, and 52% (12/23) had received prior systemic therapy (median = 1, range, 0-3). Patients were treated with selpercatinib (n = 13) or pralsetinib (n = 10), 57% (13/23) within a clinical trial. Median duration of RETi was 25 months (range, 3-72) with 11/23 (48%) patients remaining on drug at data cutoff due to an ongoing response. Median duration of follow-up was 49 months (range, 9-72). Best radiographical response was partial response in 18 (78%) and stable disease in 5 (22%) patients. Median OS was 51 months (confidence interval, 40.5-61.3); median PFS was not reached. Most common adverse events (AEs) were increased alanine aminotransferase (ALT) (48%) and aspartate aminotransferase (26%), dry mouth (39%), QT interval prolongation (39%), fatigue (35%), and hypertension (26%). AEs led to dose reductions in eight (35%) patients. No grade 5 treatment-related AEs occurred. While the germline nature of the RET pathogenic variant in hMTC could hypothetically result in increased drug-related toxicity, the incidence of most AEs, other than grade 1-2 ALT elevation and QT interval prolongation, was comparable to published clinical trials. Conclusions: In patients with advanced hMTC, selective RETis appear safe and effective with outcomes similar to clinical trial cohorts, which mostly comprised patients with sMTC. Duration of response and AE profile was similar to sMTC, although longer follow-up and larger patient numbers are needed to confirm this.

PMID:39630530 | DOI:10.1089/thy.2024.0495

Inn Med (Heidelb). 2024 Dec 4. doi: 10.1007/s00108-024-01817-w. Online ahead of print.

ABSTRACT

We report the case of a patient with trigeminal neuralgia who developed cholestatic liver injury with systemic inflammation and polyserositis after starting oxcarbazepine therapy. No other causes could be identified. After discontinuation of the drug, there was a complete remission. This case shows that the more modern oxcarbazepine can also cause idiosyncratic liver damage and underlines the importance of high vigilance concerning drug reactions in clinical practice.

PMID:39630227 | DOI:10.1007/s00108-024-01817-w

BMC Cancer. 2024 Dec 3;24(1):1486. doi: 10.1186/s12885-024-13250-1.

ABSTRACT

BACKGROUND: Selpercatinib, a highly selective tyrosine kinase inhibitor, has emerged as an excellent treatment option for patients with rearranged during transfection-altered cancer. However, there is limited comprehensive safety information available for selpercatinib through large-scale post-marketing monitoring.

METHODS: This study conducted a comprehensive analysis of selpercatinib-related adverse events (AEs) using the FDA Adverse Event Reporting System database. Four disproportionality methods were employed to identify potential AEs associated with selpercatinib. Specifically, this study investigated the differences in AEs of selpercatinib with respect to reporter continent, indication, sex, age, weight, dose, frequency, and onset time.

RESULTS: A total of 464 reports and 1,007 selpercatinib-related AEs were identified. Three new significant AEs were discovered, including dysphagia, pericardial effusion, and hemiparesis. Notably, Asia reported hepatic function abnormal more frequently, especially in patient administered doses exceeding 160 mg. Furthermore, hypersensitivity was reported more frequently by Asia and in individuals weighing less than 50 kg.

CONCLUSIONS: It is paramount to stay vigilant concerning the potential emergence of three newly identified AEs. Significant differences were found in selpercatinib-related AEs concerning reporter continent, sex, weight, dose, frequency, and onset time, which deserved clinical attention. These findings contribute to a broader understanding of the AE profiles of selpercatinib.

PMID:39627756 | DOI:10.1186/s12885-024-13250-1

Sci Rep. 2024 Dec 3;14(1):30155. doi: 10.1038/s41598-024-81903-z.

ABSTRACT

Indocyanine green (ICG) is a diagnostic dye commonly used in medical imaging and liver function monitoring. Given its widespread use, there is a need for detailed evaluations of its adverse drug reactions in real-world settings. As the comprehensive overview of its safety profile is very limited, this study aimed to analyze the adverse events (AEs) associated with ICG using data from the Food and Drug Administration Adverse Event Reporting System (FAERS). Data between 2004Q1 and 2023Q4 were extracted from the FAERS database. Signal detection was performed using various disproportionality analysis algorithms, including reporting odds ratio (ROR), proportional reporting ratio, Bayesian confidence propagation neural network, and multiitem gamma Poisson shrinker. During the study period, a total of 62 ICG-related AEs were reported in the FAERS database. Significant clinical adverse reactions included anaphylactic shock (ROR: 92.10, 95% confidence interval (CI): 37.71-224.96), procedural hypotension (ROR: 1397.27, 95% CI: 443.31-4404.08), and urticaria (ROR: 10.88, 95% CI: 4.02-29.42). This study provides valuable insights into the safety profile of ICG, highlighting the need for further monitoring to ensure its safe clinical use in clinical practice. Ongoing pharmacovigilance and large-scale studies are warranted to fully understand the potential risks associated with ICG.

PMID:39627439 | DOI:10.1038/s41598-024-81903-z

Sci Rep. 2024 Dec 3;14(1):30072. doi: 10.1038/s41598-024-81698-z.

ABSTRACT

Sodium-glucose co-transporter 2 (SGLT2) inhibitors are a class of drugs used in the clinical management of patients with type 2 diabetes, and their prescriptions have been increasing in recent years. Herein, we performed a retrospective analysis of seasonal variation in SGLT2 inhibitor-associated adverse events recorded in the Japanese Adverse Drug Event Report (JADER) database, an adverse event reporting database which reflects real-world clinical practice. To this end, seasonal variations in SGLT2 inhibitor-related dehydration, cerebral infarction, urinary tract infection, and ketoacidosis were analyzed. Six SGLT2 inhibitors prescribed in Japan (ipragliflozin, empagliflozin, luseogliflozin, canagliflozin, dapagliflozin, and tofogliflozin) were included. The reporting ratio (RR) for SGLT2 inhibitor adverse events per month in the JADER database from April 2014 to December 2023 was determined. The RR for dehydration-related adverse events was highest in the summer months of July and August, as well as in the winter months of December, January, and February. The highest RR for cerebral infarction was in February. No association with seasonal variations in the occurrence of ketoacidosis related to dehydration was observed. Healthcare providers should take adequate precautions against dehydration caused by SGLT2 inhibitors, not only in summer but also in winter. These findings are instructive and informational for health care professionals involved in diabetes care.

PMID:39627353 | DOI:10.1038/s41598-024-81698-z

BMJ Open. 2024 Dec 3;14(12):e091708. doi: 10.1136/bmjopen-2024-091708.

ABSTRACT

OBJECTIVES: Limited information is available on the safety of a rechallenge with an immune checkpoint inhibitor (ICI) after occurrence of an immune-related adverse event (irAE). We aim to identify potential emergent safety signals.

DESIGN: This is an update of our observational pharmacovigilance cohort study.

SETTING: We exanimated individual case safety reports from the WHO database VigiBase.

PARTICIPANTS: We included all individual case safety reports with ICI and rechallenged ICI.

INTERVENTIONS: We identified that incident irAE cases using the Medical Dictionary for Regulatory Activities V.26.1 related with at least one ICI administration were systematically collected until 1 March 2024.

PRIMARY AND SECONDARY OUTCOME MEASURES: The primary outcome was the recurrence rate (expressed as a percentage with its 95% CI) of the initial irAE postrechallenge with the same ICI.

RESULTS: We identified 1016 irAEs cases from ICI rechallenges. Of these, 323 irAEs recurrences occurred (31.8%, 95% CI 28.1 to 34.0). The most common postrechallenge irAEs were nephritis (recurrence rate: 50%, 95% CI 25 to 75), skin irAEs (44%, 95% CI 31 to 58) and colitis (39%, 95% CI 33 to 44).

CONCLUSIONS: In this updated, largest cohort study on rechallenge (NCT04696250), we observed a 31.8% recurrence rate of the same irAE postrechallenge with the same ICI, building on our previous findings.

TRIAL REGISTRATION NUMBER: NCT04696250.

PMID:39627133 | DOI:10.1136/bmjopen-2024-091708

Eur J Neurol. 2024 Dec 3:e16463. doi: 10.1111/ene.16463. Online ahead of print.

ABSTRACT

BACKGROUND: Generalized myasthenia gravis (gMG) is characterized by fluctuating muscle weakness. Exacerbation frequency, adverse events (AEs) related to immunosuppressant therapy and healthcare resource utilization (HCRU) are not well understood. Our study aimed to describe long-term clinical outcomes, drug-related AEs and estimated HCRU in gMG patients.

METHODS: This was a retrospective cohort analysis of clinical data from patients with gMG followed-up over eight consecutive years in a Spanish referral unit. Myasthenia Gravis Foundation of America (MGFA) clinical classification, MGFA post-interventional status (MGFA-PIS), Myasthenia Gravis Activities of Daily Living (MG-ADL) score, exacerbations, MG crises, therapies, AEs reported, specialist consultations and emergency room visits were studied biannually. An estimation of HRCU was made based on these data.

RESULTS: Some 220 patients newly diagnosed with gMG were included. Ninety percent were seropositive (84.5% anti-acetylcholine receptor [AChR], 5.9% anti-muscle-specific kinase [MuSK]). Baseline mean MG-ADL score was 5.04 points (SD 3.17), improving to 0.7 points (SD 1.40) after 8 years. Exacerbations were more frequent in years 1-2 (30.1%) but still occurred in years 7-8 (20.2%). Myasthenic crisis frequency remained 1% in years 7-8. Eighty-nine percent achieved MGFA-PIS minimal manifestations or better at 8 years. Fifty-one percent of patients reported at least one AE during the study period, leading to drug withdrawal in approximately 20% of cases. HCRU decreased between years 1-2 to years 7-8 with an estimated cost of MG from 8074.19 € per patient/year to 1679.46 €, respectively.

CONCLUSIONS: There is a group of MG patients that suffers from persistent symptoms and exacerbations (11%-20%) or MG crises, and drug AEs, which may increase disease burden and impact on the healthcare system.

PMID:39624955 | DOI:10.1111/ene.16463

Int Forum Allergy Rhinol. 2024 Dec 3. doi: 10.1002/alr.23498. Online ahead of print.

NO ABSTRACT

PMID:39624912 | DOI:10.1002/alr.23498

Exp Ther Med. 2024 Nov 18;29(1):15. doi: 10.3892/etm.2024.12765. eCollection 2025 Jan.

ABSTRACT

Superficial mucoceles (SM) are small, benign, translucent vesicles, which develop in the oral mucosa, mainly on the lower lip, due to a rupture of minor salivary gland ducts and the extravasation of saliva. The use of immune checkpoint blockade treatment may lead to dermatologic immune-related adverse events in 40-50% of patients and with severe dermatologic immune adverse events of Common Terminology Criteria for Adverse Events of grade G3-G4 in 1-2% of patients. The present study described the case of a patient with squamous cell carcinoma treated with cemiplimab with the adverse effect of Stevens-Johnson syndrome. The patient developed multiple SM, which made it challenging for the patient to speak and eat. Ablative treatment using a plasma device (Plasma IQ) and electrocoagulation were used to remove all lesions, which achieved a precise and timely therapeutic effect without any remainder of scarring. Through the publication of the present case report and literature review, the present article aimed to enhance the understanding of this condition, providing valuable diagnostic and therapeutic information about the spectrum of mucosal involvement among drug-related toxicities of current oncological treatment.

PMID:39624595 | PMC:PMC11609618 | DOI:10.3892/etm.2024.12765

Front Pharmacol. 2024 Nov 15;15:1478234. doi: 10.3389/fphar.2024.1478234. eCollection 2024.

ABSTRACT

INTRODUCTION: Amdizalisib (HMPL-689) is an ATP-competitive PI3Kδ inhibitor currently under investigation for treating Hodgkin's lymphoma. This study aimed to evaluate the metabolism, excretion, pharmacokinetics, and safety profile of amdizalisib in healthy human subjects to support its clinical application.

METHODS: This Phase I clinical trial included six healthy Chinese male volunteers who received a single oral dose of 30 mg/100 µCi [14C]amdizalisib suspension. Blood, urine, and fecal samples were collected to analyze pharmacokinetics, metabolic pathways, and excretion patterns.

RESULTS: Amdizalisib was rapidly absorbed, with a median Tmax of 2.5 h. The Cmax of 244 ± 48.9 ng/mL, and AUC0-t was 1870 ± 474 h ng/mL after a single oral dose. The blood-to-plasma total radioactivity ratio ranged from 0.561 to 0.645, indicating no significant affinity of [14C]amdizalisib and its metabolites to blood cells and the radioactive material is mainly distributed in plasma. Excretion was primarily via feces and urine, with 62.08% ± 3.00% and 37.15% ± 2.84% of the dose recovered, respectively, and over 94% of the drug excreted within 96 h. The parent drug was the main radioactive component in plasma (51.45% of total radioactivity). Additionally, 11 metabolites were identified, and the metabolic pathways include oxidation on the benzene or pyrimidine rings and conjugation with cysteine or glucuronic acid. The major metabolites in plasma were the di-oxidized and hydrogenated product (M424) and the mono-oxidized product (M406-2), accounting for 16.67% and 20.91%, respectively. Both of them are also the major radioactive components in urine and feces, among of which M424 accounted for 21.01% and 14.26%, M406-2 accounted for 8.08% and 11.30%, of the administered dose in urine and feces, respectively. In addition, the di-oxidized and methylated product (M436) was one of the major metabolites in feces accounting for 17.7% of the administered dose. Few of the parent drug was found in urine and feces, suggesting primary metabolized in the liver. No serious adverse events or drug-related deaths occured, with diarrhea as the most common adverse event.

DISCUSSION: These findings demonstrate that amdizalisib is rapidly absorbed, extensively metabolized, and primarily excreted via feces and urine, supporting its continued development as a potential therapeutic for Hodgkin's lymphoma.

SYSTEMATIC REVIEW REGISTRATION: https://www.chinadrugtrials.org.cn/, identifier CTR20212448.

PMID:39619614 | PMC:PMC11605291 | DOI:10.3389/fphar.2024.1478234

Pharmacoepidemiol Drug Saf. 2024 Dec;33(12):e70034. doi: 10.1002/pds.70034.

ABSTRACT

PURPOSE: Assess the regulatory impact of selected FDA postmarketing safety registries on drug product labeling updates.

METHODS: Postmarketing safety studies were identified in internal record repositories for the Center for Drug Evaluation and Research, U.S. FDA, in March and September 2021. Studies eligible for review included prospectively enrolling patient registry studies conducted to assess the safety of drug products used to treat inflammatory or autoimmune conditions. These studies were requested between 1999 and 2011.

RESULTS: This paper analyzed 10 safety (non-pregnancy) registries and four pregnancy registries (n = 14). Only four safety registry studies were successful in reaching their targets for both patient enrollment and patient follow-up or drug exposure. These registries were either multi-center, multinational studies or studies using participants from a health insurance or health maintenance organization. None of the safety registries led to safety labeling updates, regardless of targets' achievement for study enrollment and follow-up: six did not detect a new safety signal and four provided inconclusive results. Two pregnancy registries reached their targets for patient enrollment, and all four resulted in safety labeling updates, as required by the Pregnancy and Lactation Labeling Rule guidance.

CONCLUSIONS: While six non-pregnancy registries did not detect a new safety signal, four did not produce safety results considered sufficiently robust to warrant specific regulatory action including safety-related labeling updates. The lack of safety signal detection in these observational studies should not imply the absence of safety signals. Appropriately designed, prospective, randomized controlled safety studies are the most reliable way to obtain interpretable safety data.

PMID:39617731 | DOI:10.1002/pds.70034

J Tradit Chin Med. 2024 Dec;44(6):1254-1267. doi: 10.19852/j.cnki.jtcm.20240806.005.

ABSTRACT

OBJECTIVE: To evaluate the clinical efficacy and safety of Buzhongyiqi pills (BZYQP, ) in improving the appetite of patients with colorectal cancer (CRC) receiving chemotherapy.

TRIAL DESIGN: A pilot, randomized, single-blind cross-over clinical trial was conducted on diagnosed stage II-IV CRC patients receiving chemotherapy.

METHODS: Patients were randomly assigned to either the BZYQP-placebo or placebo-BZYQP groups. The BZYQP-placebo group received BZYQP for 1-2 d before the first cycle of chemotherapy and continued until the end of the third cycle. A 7-day washout followed, after which they received a placebo until the end of the sixth cycle. The placebo-BZYQP group followed the opposite treatment order. The oral dose of BZYQP and placebo was ten pills three times daily. A total of 12 visit points were scheduled in this study, with each visit point carried out before and after each of the six cycles of chemotherapy. The Simplified Nutrition Appetite Questionnaire (SNAQ), the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30, version 3.0), and the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE, V5.0) were used to evaluate patient appetite, quality of life, and drug safety.

RESULTS: Totally 62 patients completed the study, and baseline characteristics were balanced between the BZYQP-placebo and placebo-BZYQP groups. The primary outcome, as assessed by SNAQ scores, demonstrates a statistically significant difference between the two groups during the first three cycles of chemotherapy, with the mean SNAQ score of the BZYQP-placebo group consistently higher than that of the placebo-BZYQP group from V1 (P < 0.001). After the washout period, the SNAQ score of the BZYQP-placebo group decreased from V7, and the difference in SNAQ scores between the two groups gradually became more significant after the intersection at V9. Secondary outcomes showed that during the first three cycles of chemotherapy, the BZYQP-placebo group had significantly lower scores in physical, role, emotional, cognitive, and social functioning domains, as well as in fatigue, loss of appetite, and diarrhea symptoms, compared to the placebo-BZYQP group (P < 0.001). Scores for physical, role, emotional, cognitive, and social functioning in the BZYQP-placebo group remained lower (P < 0.05) at V11. The chemotherapy-induced adverse events (AEs) in the BZYQP-placebo group were significantly lower than those in the placebo-BZYQP group at V5, mainly in nausea and vomiting (9.1% vs 62.1%, P < 0.001), diarrhea (12.1% vs 44.8%, P = 0.004), and anemia (15.2% vs 41.4%, P = 0.021). No drug-related events were reported in this study.

CONCLUSION: BZYQP is feasible and safe to effectively improve the appetite of patients with CRC receiving chemotherapy and help them with better quality of life.

PMID:39617711 | DOI:10.19852/j.cnki.jtcm.20240806.005

J Thorac Oncol. 2024 Nov 29:S1556-0864(24)02488-2. doi: 10.1016/j.jtho.2024.11.025. Online ahead of print.

ABSTRACT

INTRODUCTION: Alectinib, a small-molecule kinase inhibitor, is used as first-line treatment for anaplastic lymphoma kinase-positive (ALK+) non-small cell lung cancer (NSCLC). Albeit generally well-tolerated, a considerable subset of patients requires dose adjustments due to drug-related toxicity. Single-nucleotide polymorphisms (SNPs) in genes related to the metabolism of alectinib may upfront identify patients at risk for toxicity.

METHODS: In this multicenter observational cohort study in patients with advanced ALK+ NSCLC receiving alectinib treatment, we investigated the association between toxicity, pharmacokinetics, and key genetic variants in ABCB1, CYP3A4, PPAR-α, POR, and CYP3A5. Data on demographics, adverse events, and alectinib trough levels were collected from five hospitals.

RESULTS: Among 215 patients, 47% experienced severe toxicity. Women experienced more severe toxicity (female versus male: 56% versus 34%; p=0.001) and also had +35% higher alectinib trough levels (p<0.001). Homozygous carriers of the PPAR-α 209G>A variant exhibited a higher incidence of grade ≥ 3 toxicity (38%) compared to patients who carried at least one wild-type allele (11%) (p=0.004). This remained significant after Bonferroni correction. Patients who experienced severe toxicity had +18.5% (95%CI: 2.9-36.6%; p=0.019) higher trough levels.

CONCLUSIONS: Female patients encounter more severe toxicity due to higher alectinib exposure, which warrants further exploration. PPAR-α 209G>A significantly increased relevant alectinib-induced toxicity, most likely due to an increase in alectinib exposure. Pre-treatment testing for genetic variants with a subsequent dose reduction could provide a viable approach to reduce alectinib-related toxicity.

PMID:39617342 | DOI:10.1016/j.jtho.2024.11.025

An Bras Dermatol. 2024 Nov 29:S0365-0596(24)00208-3. doi: 10.1016/j.abd.2024.04.007. Online ahead of print.

ABSTRACT

OBJECTIVE: To evaluate the adverse effects of facial aesthetic treatments using botulinum toxin and biomaterial implants.

METHODS: The bibliographic research for this narrative review considered articles published in journals from the Medline, Pubmed, Embase and Lilacs databases with the following terms: "dermal fillers AND complications, vascular complications AND dermal fillers, adverse reaction, AND toxin botulinum and adverse reaction AND dermal fillers". Inclusion criteria were articles available in English on adverse events with the aesthetic use of botulinum toxin and dermal fillers/biostimulators.

RESULTS: The demonstration of complications increases simultaneously with the progressive performance of facial aesthetic procedures. Quantitative statistics of the procedures and the countries that use them are skillfully classified, as well as the prosperity trends of these procedures. Complications do not receive the same relevance. There is a deficiency in dissemination of the information by the scientific community, or in other words, there is a publication bias in favor of successful results as opposed to adverse events.

CONCLUSION: The lack of knowledge about complications arising from so widely publicized and performed procedures prevents the development of evidence-based guidelines. Complications in aesthetic procedures have become a public health problem, an epidemic that occurs under the supervision of health authorities. Mandatory reporting of adverse events occurring in aesthetic procedures that require medical care aims to fill this gap. With reliable and technical data, it will be possible to identify the causes and perform interventions capable of minimizing irreversible sequelae and deaths. Complications should be promptly recognized by the dermatologist so that, when possible, they can be reversed or adequately managed.

PMID:39616095 | DOI:10.1016/j.abd.2024.04.007

J Transl Med. 2024 Nov 29;22(1):1087. doi: 10.1186/s12967-024-05772-w.

ABSTRACT

BACKGROUND: B-cell maturation antigen (BCMA)-targeted chimeric antigen receptor T-cell (CAR T-cell) therapy has exhibited remarkable efficacy in refractory or relapsed multiple myeloma (R/R MM), but recurrence and rapid progression of disease are still observed within a short time after treatment. Long-term pomalidomide therapy, which potentiates T-cell functionality, might enhance the efficacy of BCMA CAR T-cell therapy.

METHODS: We performed a single-center retrospective clinical study. Patients with relapsed or refractory multiple myeloma who received BCMA CAR T-cell infusion were enrolled in our study, and were followed by long-term pomalidomide treatment (4 mg/day) or not one month after infusion. The response and adverse events were assessed after infusion. The effect of pomalidomide on BCMA CAR T-cells was assessed in vitro.

RESULTS: The objective response rate (ORR) of BCMA-CART was 100%. Three months following CAR T-cell infusion, of the 8 patients receiving pomalidomide, except for 2 patients who stopped maintenance therapy and were lost to follow-up, all patients (6/6) achieved VGPR (very good partial response) or CR (complete response), while only 5 patients (5/8) who did not receive pomalidomide treatment achieved VGPR or better. At a median follow-up of 27 months, for the 8 patients who did not receive pomalidomide administration, the median TTP (time to progression) was 5.85 (1-14) months, while the OS (overall survival) was 10.7 (1.2-16) months. Of the 8 patients who received pomalidomide therapy after CAR T-cell infusion, the median TTP was 13 (7-13) months, while the OS was not reached. Moreover, neither long-term hematological toxicity nor drug-induced liver damage was observed during the follow-up period. Mechanistically, pomalidomide promotes antimyeloma efficacy of BCMA CAR T-cells by inhibiting cell apoptosis and enhancing cytoxicity.

CONCLUSIONS: Our results confirmed that BCMA CAR T-cell therapy combined with long-term pomalidomide had a low recurrence rate and manageable therapy-related side effects, providing a promising option for treating R/R MM.

PMID:39614361 | DOI:10.1186/s12967-024-05772-w

BMC Geriatr. 2024 Nov 29;24(1):980. doi: 10.1186/s12877-024-05557-2.

ABSTRACT

BACKGROUND: The association between fall risk-increasing drugs (FRIDs, medications known to be associated with falls) and the number of falls among generally healthy and active community-dwelling older adults is understudied. Prior studies have focused on individual medication classes or have predominantly relied on retrospective assessments of falls. The aim of this study was to investigate the association between FRID use at baseline and the prospective incidence rates of total, injurious and recurrent falls in community-dwelling older adults.

METHODS: This is a 3-year observational analysis of DO-HEALTH, a randomized controlled trial, among community-dwelling adults aged ≥ 70 years without major diseases at baseline. The main exposures were use of at least one FRID and multiple FRIDs (≥ 2 FRIDs) at baseline. The number of total falls (including high- and low-trauma falls, as well as injurious falls) over 3 years of follow-up was defined as the primary outcome, and the number of injurious and the number of recurrent total falls (≥ 2 falls), as the two separate secondary outcomes. To examine these associations, separate negative binomial regression models controlled for the fixed effects of treatment allocation in the DO-HEALTH trial, study site, fall in the last year, age, sex, BMI, and walking aid were used. Additionally, an offset of the logarithm of each participant's time in the study was included in the models.

RESULTS: A total of 2157 participants were included, with a baseline median age of 74.0 years, 61.7% of whom were women, and 41.9% having experienced a prior fall in the year preceding enrolment. At baseline, 908 (42.1%) participants used at least one FRID, and 351 (16.3%) reported multiple FRIDs use. Prospectively, over 3 years of follow-up, 3333 falls were reported by 1311 (60.8%) out of the 2157 participants. Baseline use of at least one FRID was significantly associated with increased incidence rates of total falls (incidence rate ratio (IRR) [95% Confidence Interval (CI)] = 1.13 [1.01-1.27]), injurious falls (IRR = 1.15 [1.02-1.29]), and recurrent falls (IRR = 1.12 [1.01-1.23]) over 3 years. These associations were most pronounced among users of multiple FRIDs, with increased incidence rates of total falls (IRR = 1.22 [1.05-1.42]), injurious falls (IRR = 1.33 [1.14-1.54]) and recurrent falls (IRR = 1.14 [1.02-1.29]).

CONCLUSION: Our results suggest that FRID use is associated with increased prospective incidence rates of total, injurious, and recurrent falls even among generally healthy older adults.

TRIAL REGISTRATION: DO-HEALTH is registered as NCT01745263 on clinicaltrials.gov, with a registration date of 2012-12-06.

PMID:39614147 | DOI:10.1186/s12877-024-05557-2

Sci Rep. 2024 Nov 29;14(1):29739. doi: 10.1038/s41598-024-81342-w.

ABSTRACT

It's well known that sex is a risk factor for the occurrence of adverse events (AEs), most of which have found sex differences. Real-world data studies on the sex differences of fall-risk-increasing drugs (FRIDs) are few and far between, with most small-scale retrospective studies based on FRID classes. To establish a list of FRIDs and describe their sex differences, we used preferred terms from the Medical Dictionary for Regulatory Activities to search for AEs in the FDA Adverse Event Reporting System (FAERS), and then perform disproportionality analyses and female/male ratio analyses. During January 2004 to March 2023, 101,746 fall-related AEs were reported in FAERS from patients aged 50 to 100, with 68,492 (67.3%) females and 32,547 (32.0%) males. We found 261 signals for females while 284 for males. For females, the top 3 signals with the highest reporting odds ratio (ROR) were anethole trithione, clopenthixol, nikethamide (ROR: 388.88, 212.10, 113.94), while the top 3 signals with the highest lower limit of information component (IC025) were nikethamide, anethole trithione, benzbromarone (IC025: 3.91, 3.15, 2.49). For males, the top 3 signals with the highest ROR were fluprednidene acetate, potassium hydroxide, ketazolam (ROR: 216.86, 108.43, 108.43), while the top 3 signals with the highest IC025 were clomethiazole, piribedil, melperone (IC025: 3.31, 3.24, 2.99). Moreover, among the 119 shared signals found between males and females, 33 were positively correlated with falls in females and 38 with falls in males. Signals showing significant sex differences were mainly concentrated on agents of the immune, nervous, musculo-skeletal, and cardiovascular systems. We offered a series of FRIDs and suggested their sex differences in falls through the FAERS. In the future, it is essential to balance the inclusion of women and men, and analyse sex-stratified for FRIDs.

PMID:39613826 | DOI:10.1038/s41598-024-81342-w

Lancet Oncol. 2024 Nov 26:S1470-2045(24)00581-3. doi: 10.1016/S1470-2045(24)00581-3. Online ahead of print.

ABSTRACT

BACKGROUND: A previous phase 2 trial showed promising outcomes for patients with HER2-positive early-stage breast cancer using neoadjuvant de-escalation chemotherapy with paclitaxel, trastuzumab, and pertuzumab. We aimed to evaluate the efficacy of weekly nab-paclitaxel compared with the standard regimen of docetaxel plus carboplatin, both with trastuzumab and pertuzumab, as neoadjuvant therapies for patients with HER2-positive breast cancer.

METHODS: HELEN-006 was a multicentre, randomised, phase 3 trial done at six hospitals in China. We enrolled patients aged 18-70 years with untreated, histologically confirmed stage II-III invasive HER2-positive breast cancer and an Eastern Cooperative Oncology Group performance status of 0 or 1. Using an interactive response system, patients were randomly assigned (1:1) under a permuted block randomisation scheme (block size of four), stratified by tumour stage, nodal status, and hormone receptor status. Patients received either intravenous nab-paclitaxel (125 mg/m2 on days 1, 8, and 15) for six 3-week cycles, or intravenous docetaxel (75 mg/m2 on day 1) plus intravenous carboplatin (area under the concentration-time curve 6 mg/mL per min on day 1) for six 3-week cycles. Both groups also received concurrent intravenous trastuzumab, with an initial loading dose of 8 mg/kg and a maintenance dose of 6 mg/kg on day 1, as well as intravenous pertuzumab with a loading dose of 840 mg and a maintenance dose of 420 mg on day 1. This report is the final analysis of the primary endpoint, pathological complete response (ypT0/is ypN0), analysed in all patients who started treatment (modified intention to treat). The trial is registered with ClinicalTrials.gov, NCT04547907, and follow-up of the adjuvant phase is ongoing.

FINDINGS: Between Sept 20, 2020, and March 1, 2023, 789 patients were screened for eligibility, 689 of whom were randomly assigned (343 to the nab-paclitaxel group and 346 to the docetaxel plus carboplatin group). All 689 patients were Asian women. 669 patients received at least one dose of the study treatment and were included in the full analysis set (332 in the nab-paclitaxel group and 337 in the docetaxel plus carboplatin group). Median age of the patients was 50 years (IQR 43-55). Median follow-up time was 26 months (IQR 19-32). 220 (66·3% [95% CI 61·2-71·4]) patients in the nab-paclitaxel group had a pathological complete response, compared with 194 (57·6% [52·3-62·9]) in the docetaxel plus carboplatin group (combined odds ratio 1·54 [95% CI 1·10-2·14]; stratified p=0·011). 100 (30%) patients in the nab-paclitaxel group and 128 (38%) in the docetaxel plus carboplatin group had grade 3-4 adverse events. The most common grade 3-4 adverse events were nausea (22 [7%] in the nab-paclitaxel group vs 76 [23%] in the docetaxel plus carboplatin group), diarrhoea (25 [8%] vs 55 [16%]), and neuropathy (43 [13%] vs eight [2%]). Serious drug-related adverse events were reported in three (1%) patients in the nab-paclitaxel group and five (2%) in the docetaxel plus carboplatin group. No treatment-related deaths were reported in either group.

INTERPRETATION: These findings might suggest a potential advantage of nab-paclitaxel combined with trastuzumab and pertuzumab compared with the standard regimen in neoadjuvant therapy for patients with HER2-positive early breast cancer, suggesting that this new combination might establish a new standard for neoadjuvant treatment in this patient population.

FUNDING: National Natural Science Foundation of China, and Science and Technology Research Projects of Henan Province, China.

TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

PMID:39612919 | DOI:10.1016/S1470-2045(24)00581-3

Arch Argent Pediatr. 2024 Dec 5:e202410510. doi: 10.5546/aap.2024-10510.eng. Online ahead of print.

ABSTRACT

High-dose methotrexate is an effective and safe therapy. It is included in the treatment regimens of various hematologic and oncologic diseases. The acute and severe toxicity of this chemotherapeutic agent is unusual. Nephrotoxicity occurs in about 2-12% of patients, associated with a slow clearance of the drug. It is usually reversible but requires an early approach. The objective was to describe the case of a patient diagnosed with lymphoblastic leukemia who presented with acute kidney injury after the administration of high doses of methotrexate.

PMID:39612347 | DOI:10.5546/aap.2024-10510.eng