Int J Radiat Oncol Biol Phys. 2024 Mar 31:S0360-3016(24)00447-4. doi: 10.1016/j.ijrobp.2024.03.033. Online ahead of print.

ABSTRACT

OBJECTIVE: We aimed to investigate the safety and efficacy of HL301, a standardized combination product of seven medicinal plants, in radiation pneumonitis in patients with unresectable non-small cell lung cancer (NSCLC) undergoing curative concurrent chemoradiotherapy.

METHODS: The target accrual was 87 and a total of 63 patients were enrolled due to poor accrual rate. We randomly assigned the 63 patients to receive a placebo (arm A), or 1200 mg HL301 (arm B), or 1800 mg HL301 (arm C). Patients received weekly paclitaxel and carboplatin concurrently with intensity-modulated radiotherapy at 60-66 Gy in conventional fractionation. Durvalumab was administered as maintenance treatment according to standard clinical practice. HL301 was administered orally, daily for 12 weeks. The primary endpoint was incidence of grade ≥2 radiation pneumonitis at 24 weeks post-chemoradiotherapy.

RESULTS: The baseline characteristics of the patients were well balanced. The drug was tolerable with a compliance rate of 86.6%, 86.2%, and 88.8% in arms A, B, and C, respectively (P = 0.874). None of the patients experienced severe drug-related adverse events. No significant difference in the rate of adverse events were observed between the treatment arms. The incidence of grade ≥2 radiation pneumonitis at 24 weeks post-chemoradiotherapy was 37.5% (95% CI, 18.5-61.4%), 55.6% (95% CI, 33.7-75.4%), and 52.4% (95% CI, 32.4-71.7%) in arms A, B, and C, respectively (P=0.535).

CONCLUSION: This is the first exploratory clinical trial to test the safety and efficacy of HL301 in patients with NSCLC. Safety and feasibility of HL301 were established but no signals of efficacy in reducing RP was observed in this dose level.

PMID:38565405 | DOI:10.1016/j.ijrobp.2024.03.033

Am J Respir Crit Care Med. 2024 Apr 2. doi: 10.1164/rccm.202311-2004OC. Online ahead of print.

ABSTRACT

RATIONALE: Observational studies suggest that high-dose isoniazid may be efficacious in treating multidrug-resistant tuberculosis (MDR-TB). However, its activity against Mycobacterium tuberculosis (M.tb) with katG mutations (which typically confer high-level resistance) is not established.

OBJECTIVE: To characterize early bactericidal activity (EBA) of high-dose isoniazid in patients with tuberculosis caused by katG-mutated M.tb.

METHODS: A5312 was a Phase 2A randomized, open-label trial. Participants with tuberculosis caused by katG-mutated M.tb were randomized to receive 15 or 20 mg/kg isoniazid daily for 7 days. Daily sputum samples were collected for quantitative culture. Intensive PK sampling was performed on day 6. Data were pooled across all A5312 participants for analysis (drug-sensitive, inhA-mutated, and katG-mutated M.tb). EBA was determined using nonlinear mixed-effects modelling.

RESULTS: Of 80 treated participants, 21 had katG-mutated M.tb. Isoniazid PK was best described by a two-compartment model with an effect of NAT2 acetylator phenotype on clearance. Model-derived Cmax and AUC in the 15 and 20 mg/kg groups were 15.0 and 22.1 mg/L and 57.6 and 76.8 mg∙h/L, respectively. Isoniazid bacterial kill was described using an effect compartment and a sigmoidal Emax relationship. Isoniazid potency against katG-mutated M.tb was approximately 10-fold lower than against inhA-mutated M.tb. The highest dose (20 mg/kg) did not demonstrate measurable EBA, except in a subset of slow NAT2 acetylators (who experienced the highest concentrations). There were no grade 3 or higher drug-related adverse events.

CONCLUSIONS: This study found negligible bactericidal activity of high-dose isoniazid (15-20 mg/kg) in the majority of participants with tuberculosis caused by katG-mutated M.tb. Clinical trial registration available at www.

CLINICALTRIALS: gov, ID: NCT01936831.

PMID:38564365 | DOI:10.1164/rccm.202311-2004OC

Front Psychiatry. 2024 Mar 18;15:1349816. doi: 10.3389/fpsyt.2024.1349816. eCollection 2024.

ABSTRACT

INTRODUCTION: Major Depressive Disorder (MDD) is a chronic, recurrent, and highly prevalent disease that is associated with significant functional disability. During pregnancy, the prevalence of the disease is approximately 20%, with 12% of these, requiring treatment to avoid important negative consequences for the mother-baby binomial. Risk-benefit assessment of the use of antidepressants during pregnancy is mandatory, in addition to knowledge of the long-term effects of prenatal exposure to these drugs in the offspring. In this study, we will perform an updated systematic review and meta-analysis to explore the treatment of depression during pregnancy, along with its effectiveness, safety, and possible harm to women and children.

MATERIALS AND METHODS: We will search for publications in the following databases: Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, Web of Science, Scopus, Lilacs, and PsycINFO. The reference lists of the included studies will be manually reviewed to identify potentially relevant studies. There will be no restrictions on language or date of publication. Quality assessment of the included studies will be performed independently according to the Cochrane Risk of Bias (RoB2) instrument. To assess the certainty of the findings' body of evidence, we will use the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology. This study aimed to ascertain the efficacy and safety of antidepressants in pregnant women and children.

ETHICS AND DISSEMINATION: Ethical approval was not required as individual patient data were not collected. Dissemination: Plan to publish a systematic review in an open-access medical journal at the end of the process.

SYSTEMATIC REVIEW REGISTRATION: PROSPERO, CRD42023447694.

PMID:38563023 | PMC:PMC10982487 | DOI:10.3389/fpsyt.2024.1349816

Am J Psychiatry. 2024 Apr 1;181(4):342-345. doi: 10.1176/appi.ajp.20230553.

NO ABSTRACT

PMID:38557140 | DOI:10.1176/appi.ajp.20230553

Open Forum Infect Dis. 2024 Feb 23;11(4):ofae102. doi: 10.1093/ofid/ofae102. eCollection 2024 Apr.

ABSTRACT

BACKGROUND: Omalizumab is an anti-immunoglobulin E monoclonal antibody used to treat moderate to severe chronic idiopathic urticaria, asthma, and nasal polyps. Recent research suggested that omalizumab may enhance the innate antiviral response and have anti-inflammatory properties.

OBJECTIVE: We aimed to investigate the efficacy and safety of omalizumab in adults hospitalized for coronavirus disease 2019 (COVID-19) pneumonia.

METHODS: This was a phase II randomized, double blind, placebo-controlled trial comparing omalizumab with placebo (in addition to standard of care) in hospitalized patients with COVID-19. The primary endpoint was the composite of mechanical ventilation and/or death at day 14. Secondary endpoints included all-cause mortality at day 28, time to clinical improvement, and duration of hospitalization.

RESULTS: Of 41 patients recruited, 40 were randomized (20 received the study drug and 20 placebo). The median age of the patients was 74 years and 55.0% were male. Omalizumab was associated with a 92.6% posterior probability of a reduction in mechanical ventilation and death on day 14 with an adjusted odds ratio of 0.11 (95% credible interval 0.002-2.05). Omalizumab was also associated with a 75.9% posterior probability of reduced all-cause mortality on day 28 with an adjusted odds ratio of 0.49 (95% credible interval, 0.06-3.90). No statistically significant differences were found for the time to clinical improvement and duration of hospitalization. Numerically fewer adverse events were reported in the omalizumab group and there were no drug-related serious adverse events.

CONCLUSIONS: These results suggest that omalizumab could prove protective against death and mechanical ventilation in hospitalized patients with COVID-19. This study could also support the development of a phase III trial program investigating the antiviral and anti-inflammatory effect of omalizumab for severe respiratory viral illnesses requiring hospital admission. ClinicalTrials.gov ID: NCT04720612.

PMID:38560604 | PMC:PMC10977629 | DOI:10.1093/ofid/ofae102

Cureus. 2024 Mar 1;16(3):e55324. doi: 10.7759/cureus.55324. eCollection 2024 Mar.

ABSTRACT

We report the case of a 76-year-old female who presented with a new onset of petechial rash in her lower extremities after the introduction of a new agent, semaglutide. She started taking this medication three months before her presentation at an initial dosage of 0.5 mg subcutaneously every week. She noticed a 15-pound weight loss and debilitating fatigue within that timeframe. She stopped taking the medication due to nontolerance and GI upset (nausea and vomiting) about a week before her hospitalization. She denied the use of any other agents. Initial lab work revealed elevated transaminases, alkaline phosphatase, total bilirubin, and inflammatory markers. A CT of the abdomen revealed mild cirrhosis and hepatosplenomegaly. Other causes for cirrhosis were effectively ruled out with negative viral hepatitis, ceruloplasmin levels, and the HFE gene. An autoimmune panel was conducted, yielding positive antinuclear antibody (ANA), anti-histone antibodies, elevated double-stranded DNA, as well as low complement levels supporting evidence of drug-induced lupus (DIL). Anti-mitochondrial M2 and anti-smooth antibodies were also detected, indicating a possible overlap syndrome with autoimmune hepatitis. Perinuclear anti-neutrophil cytoplasmic antibodies (P-ANCA) and anti-neutrophil cytoplasmic autoantibodies (C-ANCA) were negative and ruled out the possibility of ANCA-associated vasculitis. The patient's condition improved with pulse-dose steroids, leading to an improvement in liver function tests. Consequently, the decision to perform skin and liver biopsies was deferred. She was discharged with a tapering dose of steroids and scheduled for outpatient follow-up to monitor her progress. This case report can offer insights to healthcare providers regarding the potential side effects of GLP-1 RAs in their patient population.

PMID:38559525 | PMC:PMC10981839 | DOI:10.7759/cureus.55324

Cureus. 2024 Feb 27;16(2):e55095. doi: 10.7759/cureus.55095. eCollection 2024 Feb.

ABSTRACT

Daptomycin-induced eosinophilic pneumonia (DIEP) is a rare but serious complication associated with the use of this broad-spectrum antibiotic. We present the case of a teenager with a history of nasopharyngeal cancer who developed DIEP while receiving daptomycin to treat an infection associated with an implanted chamber catheter. Symptoms included recurrent dyspnea and peripheral eosinophilia, with radiological findings consistent with DIEP. The pathophysiology involves an immune response triggered by daptomycin, resulting in eosinophilic pulmonary inflammation. Diagnosis requires a thorough evaluation of medical history, clinical laboratory tests, and radiological findings. The main treatment involves discontinuation of daptomycin and, in severe cases, the use of steroids. It is essential to consider DIEP in patients with respiratory failure and bilateral pulmonary opacities who have used daptomycin and to suspect it in those with blood eosinophilia or in bronchoalveolar lavage.

PMID:38558746 | PMC:PMC10978459 | DOI:10.7759/cureus.55095

J Toxicol Sci. 2024;49(4):175-191. doi: 10.2131/jts.49.175.

ABSTRACT

The Hippo pathway plays an important role in the growth, development, and regeneration of cells and organs. Transcriptional enhanced associate domain (TEAD), a transcription activator of the Hippo pathway, forms the complex with a transcriptional coactivator yes-associated protein (YAP) or a transcriptional coactivator PDZ-binding motif (TAZ). Their excessive activations are involved in carcinogenesis such as malignant pleural mesothelioma (MPM), and thus inhibition of the TEAD complex is expected to have potent anticancer activity against MPM. On the other hand, YAP or TAZ conditional knockout mice have been reported to show abnormal findings in various tissues, including the kidney, liver, and lung. In the present study, we evaluated the systemic toxicity of K-975, a novel TEAD inhibitor, in rats. When K-975 was administered orally to rats for 1 week, proteinuria suggestive of nephrotoxicity was observed. Electron microscopy revealed that K-975 at 300 mg/kg induced glomerular podocyte foot process effacement. After a 2-week recovery period, proteinuria with foot process effacement was recovered completely. Urinalysis and urinary biomarker evaluation suggested that the urinary albumin index (urinary albumin/urinary creatinine) was the most sensitive marker for detecting K-975-induced nephrotoxicity. After 3 cycles of 1-week administration followed by 2-week recovery periods, nephrotoxicity was reversible; however, incomplete reversibility was observed in rats with severe proteinuria. In conclusion, this study revealed that in rats, oral K-975 treatment induced severe proteinuria by podocyte foot process effacement, which was reversible and monitorable by the urinary albumin index, suggesting important information for developing K-975 as an anticancer drug.

PMID:38556354 | DOI:10.2131/jts.49.175

Sci Rep. 2024 Mar 29;14(1):7489. doi: 10.1038/s41598-024-57909-y.

ABSTRACT

This study aims to evaluate the safety of Alprazolam by analyzing the FAERS database, provide data analysis for monitoring adverse drug reactions. This research encompasses adverse event (AE) reports related to Alprazolam from the first quarter of 2004 to the second quarter of 2023. Four signal mining and analysis methods were utilized, including Reporting Odds Ratio (ROR), Proportional Reporting Ratio (PRR), Bayesian Confidence Propagation Neural Network (BCPNN), and Empirical Bayesian Geometric Mean (EBGM). Further exploration was conducted regarding patient characteristics and types of AEs. A total of 23,575 AE reports in which Alprazolam was the primary suspect drug were collected, identifying 347 Preferred Term (PT) signals and 27 System Organ Classes (SOCs). The number of AE reports increased annually, especially in 2015, 2018, 2019, and 2020. The main affected groups were females and the age range of 18 to 45. Psychiatric disorders, Nervous system disorders, and Gastrointestinal disorders were the most common the organ system in which the AEs occurred. There is a certain risk of drug abuse and suicide with Alprazolam. Most notably, several AEs not recorded in the Alprazolam leaflet appeared among the top 30 PTs in signal strength, including but not limited to Benzodiazepine drug level abnormal, Acquired amegakaryocytic thrombocytopenia, Cutaneous T-cell dyscrasia, and Coronary No-reflow Phenomenon. For the first time, AEs related to the cardiovascular system and platelet function were unveiled. The severe AE reports that resulted in "hospitalization" and "death" accounted for 30.96% and 21.86%. This study highlights the risks of suicide and misuse of Alprazolam. Other potential severe or fatal AEs, such as those related to the cardiovascular system, platelet function, and others, require further research to determine their precise mechanisms and risk factors.

PMID:38553504 | PMC:PMC10980721 | DOI:10.1038/s41598-024-57909-y

Endocrinol Diabetes Nutr (Engl Ed). 2024 Mar;71(3):124-132. doi: 10.1016/j.endien.2024.03.012.

ABSTRACT

OBJECTIVES: Some concerns persist regarding the safety of semaglutide. The objective of this updated meta-analysis is to assess the risk of acute pancreatitis with the use of semaglutide, assessing the results according to the different administration regimens.

METHODS: We performed an updated meta-analysis of randomised, placebo-controlled studies of semaglutide therapy that report acute pancreatitis. This meta-analysis was performed in line with PRISMA guidelines. A global and stratified analysis according to the therapeutic scheme used was performed using the fixed-effects model.

RESULTS: Twenty-one eligible trials of semaglutide, including 34,721 patients, were identified and considered eligible for the analyses. Globally, semaglutide therapy was not associated with an increased risk of acute pancreatitis (OR 0.7; 95% CI 0.5-1.2, I2 0%). When we analysed the studies according to the different schemes used, the results were similar (group with oral semaglutide: OR 0.40; 95% CI 0.10-1.60, I2 0%; group with low subcutaneous doses of semaglutide: OR 0.80; 95% CI 0.40-1.90, I2 0%; group with high subcutaneous doses of semaglutide: OR 0.70; 95% CI 0.50-1.20, I2 0%; interaction p-value=0.689).

CONCLUSION: This updated meta-analysis demonstrates that the use of semaglutide is not associated with an increased risk of acute pancreatitis compared to placebo. In the stratified analysis, the results were similar with the different semaglutide regimens analysed.

PMID:38555109 | DOI:10.1016/j.endien.2024.03.012

Lung Cancer. 2024 Mar 15;191:107535. doi: 10.1016/j.lungcan.2024.107535. Online ahead of print.

ABSTRACT

Lorlatinib is a brain-penetrant, third-generation tyrosine kinase inhibitor (TKI) indicated for the treatment of anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC). In clinical trials, lorlatinib has shown durable efficacy and a manageable safety profile in treatment-naive patients and in those who have experienced progression while receiving first- and/or second-generation ALK TKIs. Lorlatinib has a distinct safety profile from other ALK TKIs, including hyperlipidemia and central nervous system effects. Clinical trial data showed that most adverse events (AEs) can be managed effectively or reversed with dose modifications (such as dose interruptions or reductions) or with concomitant medications without compromising clinical efficacy or quality of life for patients. A pragmatic approach to managing AEs related to lorlatinib is required. We present patient-focused recommendations for the evaluation and management of select AEs associated with lorlatinib developed by clinicians and nurses with extensive lorlatinib expertise in routine clinical practice. The recommendations follow the general framework of "prepare, monitor, manage, reassess" to streamline AE management and assist in practical, actionable, and personalized patient care.

PMID:38554546 | DOI:10.1016/j.lungcan.2024.107535

Acta Derm Venereol. 2024 Mar 29;104:adv36122. doi: 10.2340/actadv.v104.36122.

ABSTRACT

The impact of chronic urticaria on work has been scarcely reported, whereas its peak incidence is between the ages of 20 and 40. The aim of this study was to assess the occupational impact of chronic urticaria and its treatment, by combining objective and patient-reported data. A monocentric observational study was performed using questionnaires over a 1-year period from 2021 to 2022 in chronic urticaria patients who were in a period of professional activity and agreed to participate. Of the 88 patients included, 55.7% assessed the occupational impact of their chronic urticaria as significant, and even more severe when chronic urticaria was poorly controlled. Some 86% of patients had symptoms at work, in a third of cases aggravated by work. However, occupational physical factors were not associated with an aggravation of inducible chronic urticaria. A total of 20% reported treatment-related adverse effects affecting their work. Despite low absenteeism, presenteeism and reduced productivity were important (> 20%). Six patients (6.8%) had difficulties keeping their work. For 72.7% of the patients, the occupational physician was not informed. The occupational impact of chronic urticaria should be discussed during consultations, particularly when it is insufficiently controlled. The occupational physician should be informed in order to support patients' professional project.

PMID:38551378 | DOI:10.2340/actadv.v104.36122

Expert Rev Anticancer Ther. 2024 Mar 29. doi: 10.1080/14737140.2024.2337266. Online ahead of print.

ABSTRACT

OBJECTIVES: To provide a more comprehensive understanding of the efficacy and safety profile of cabozantinib versus placebo in malignant tumors, we conducted a systematic review and meta-analysis. This involved analyzing a collection of published randomized controlled trials to assess the outcomes.

METHODS: We used RevMan5.3 software to evaluate the outcomes of the collected studies. The primary outcome we focused on was progression-free survival (PFS), and the secondary outcomes included overall survival (OS) and disease control rate (DCR).

RESULTS: Our findings revealed that compared to placebo, cabozantinib significantly extended the PFS of patients [hazard ratios (HR) 0.37, 95% confidence intervals (CI): 0.32, 0.43, p < 0.00001]. Additionally, cabozantinib improved the OS of patients [HR 0.78, 95%CI: 0.68, 0.91, p = 0.002]. While it is important to note that cabozantinib was associated with a higher likelihood of causing digestive, cutaneous, and cardiovascular related adverse events [relative risk (RR) 4.40, 95% CI: 3.10, 6.25, p < 0.00001].

CONCLUSION: Based on our analysis, cabozantinib significantly prolonged the PFS and OS of patients with malignant tumors (p < 0.01). We recommend the use of cabozantinib in treating advanced malignant tumors. However, it is important to continuously monitor and manage the drug-related adverse events.

REGISTRATION: PROSPERO (No. CRD42023449261).

PMID:38551185 | DOI:10.1080/14737140.2024.2337266

Cureus. 2024 Feb 27;16(2):e55035. doi: 10.7759/cureus.55035. eCollection 2024 Feb.

ABSTRACT

Acute interstitial nephritis (AIN) is characterized by an inflammatory infiltrate of the interstitium of the kidney, typically causing a decline in kidney function. Drug-induced AIN (also called allergic AIN) is a type of AIN. Common drugs associated with AIN are antibiotics, non-steroidal anti-inflammatory drugs (NSAIDs), and proton pump inhibitors (PPIs). A 59-year-old male with a history of recent laparoscopic robotic sleeve gastrectomy presented to the emergency department with five weeks of progressively worsening fatigue, nausea, and lightheadedness. Postoperatively, he was prescribed omeprazole 20 mg daily for gastric ulcer prophylaxis. His other home medications were amlodipine, atorvastatin, ursodiol, and budesonide-formoterol fumarate nebulizer. His physical examination was normal. Laboratory studies revealed elevated creatinine of 4.19 mg/dL from a baseline of 0.9 mg/dL two months ago and the presence of urine eosinophils. The etiology of this elevated creatinine was unclear, prompting CT-guided left renal biopsy. The biopsy showed diffuse interstitial inflammatory infiltration with numerous lymphocytes, a large number of neutrophils, and scattered eosinophils, consistent with the allergic type of AIN. Omeprazole was discontinued and the patient received a seven-day course of prednisone. Despite treatment, permanent renal damage occurred, and the patient's new baseline creatinine was 2.3 mg/dL. AIN caused by PPIs should be considered in the differential diagnosis of acute kidney injury (AKI). AIN can be difficult to diagnose, presenting with nonspecific symptoms, such as oliguria, malaise, nausea, and vomiting. An accurate and timely diagnosis can help prevent and treat worsening renal failure.

PMID:38550437 | PMC:PMC10974950 | DOI:10.7759/cureus.55035

Arh Hig Rada Toksikol. 2024 Mar 29;75(1):1-14. doi: 10.2478/aiht-2024-75-3807. eCollection 2024 Mar 1.

ABSTRACT

Human exposure to plastic particles has raised great concern among all relevant stakeholders involved in the protection of human health due to the contamination of the food chain, surface waters, and even drinking water as well as due to their persistence and bioaccumulation. Now more than ever, it is critical that we understand the biological fate of plastics and their interaction with different biological systems. Because of the ubiquity of plastic materials in the environment and their toxic potential, it is imperative to gain reliable, regulatory-relevant, science-based data on the effects of plastic micro- and nanoparticles (PMNPs) on human health in order to implement reliable risk assessment and management strategies in the circular economy of plastics. This review presents current knowledge of human-relevant PMNP exposure doses, pathways, and toxic effects. It addresses difficulties in properly assessing plastic exposure and current knowledge gaps and proposes steps that can be taken to underpin health risk perception, assessment, and mitigation through rigorous science-based evidence. Based on the existing scientific data on PMNP adverse health effects, this review brings recommendations on the development of PMNP-specific adverse outcome pathways (AOPs) following the AOP Users' Handbook of the Organisation for Economic Cooperation and Development (OECD).

PMID:38548377 | PMC:PMC10978163 | DOI:10.2478/aiht-2024-75-3807

Int J Mol Sci. 2024 Mar 19;25(6):3438. doi: 10.3390/ijms25063438.

ABSTRACT

Contrast-Induced Acute Kidney Injury (CI-AKI) remains a frequent iatrogenic condition since radiological procedures using intra-vascular iodinated contrast media (CM) are being widely administered for diagnostic and therapeutic purposes. Despite the improvement of the medical healthcare system worldwide, CI-AKI is still associated with direct short-term and indirect long-term outcomes including increased morbidity and mortality, especially in patients with underlying pre-existing renal function impairment, cardiovascular disease, or diabetes that could rapidly progress into Chronic Kidney Disease. Although the RIFLE (Risk, Injury, Failure, Loss, End-Stage Kidney Disease), AKIN (Acute Kidney Injury Network), and KDIGO (Kidney Disease Improving Global Outcomes) clinical criteria and recommendation guidelines are based on traditional "gold standard" biomarkers known as serum creatinine, glomerular filtration rate, and urinary output, new reliable serum and urinary biomarkers are still needed for an effective unified diagnostic strategy for AKI. Starting from previous and recent publications on the benefits and limitations of validated biomarkers responding to kidney injury, glomerular filtration, and inflammation among others, this review unravels the role of new emerging biomarkers used alone or in combination as reliable tools for early diagnosis and prognosis of CI-AKI, taking into account patients and procedures-risk factors towards a new clinical perspective.

PMID:38542410 | DOI:10.3390/ijms25063438

Lancet Oncol. 2024 Apr;25(4):439-454. doi: 10.1016/S1470-2045(24)00064-0.

ABSTRACT

BACKGROUND: DESTINY-Lung01 is a multicentre, open-label, phase 2 study evaluating the antitumour activity and safety of trastuzumab deruxtecan, a HER2-directed antibody-drug conjugate, in patients with HER2-overexpressing or HER2 (ERBB2)-mutant unresectable or metastatic non-small-cell lung cancer (NSCLC). The results of the HER2-mutant cohort (cohort 2) have been reported elsewhere. Herein, we report the primary analysis of cohorts 1 and 1A, which aimed to evaluate the activity and safety of trastuzumab deruxtecan 5·4 mg/kg and 6·4 mg/kg in patients with HER2-overexpressing NSCLC.

METHODS: Patients aged 18 years or older with unresectable or metastatic (or both unresectable and metastatic) non-squamous NSCLC who had relapsed following or were refractory to standard treatment or for whom no standard treatment was available, with an HER2 immunohistochemistry score of 3+ or 2+ (without known HER2 mutations) and an Eastern Cooperative Oncology Group performance status score of 0 or 1, were enrolled at 20 specialist hospitals in France, Japan, the Netherlands, Spain, and the USA. Patients were assigned to cohorts sequentially, first to cohort 1, to receive trastuzumab deruxtecan 6·4 mg/kg (cohort 1), then to cohort 1A, to receive trastuzumab deruxtecan 5·4 mg/kg, both administered intravenously once every 3 weeks. The primary endpoint was confirmed objective response rate by independent central review and was assessed in the full analysis set, which included all patients who signed an informed consent form and were enrolled in the study. Safety was assessed in all enrolled patients who received at least one dose of trastuzumab deruxtecan. This trial is registered with ClinicalTrials.gov, NCT03505710, and is ongoing (closed to recruitment).

FINDINGS: Between Aug 27, 2018, and Jan 28, 2020, 49 patients were enrolled in cohort 1 (median age 63·0 years [IQR 58·0-68·0], 30 [61%] male, 19 [39%] female, and 31 [63%] White), and from June 16 to Dec 9, 2020, 41 patients were enrolled in cohort 1A (median age 62·0 years [IQR 56·0-66·0], 22 [54%] male, 19 [46%] female, and 31 [76%] White). As of data cutoff (Dec 3, 2021), the median treatment duration was 4·1 months (IQR 1·4-7·1) in cohort 1 and 5·5 months (1·4-8·7) in cohort 1A, and median follow-up was 12·0 months (5·4-22·4) in cohort 1 and 10·6 months (4·5-13·5) in cohort 1A. Confirmed objective response rate by independent central review was 26·5% (95% CI 15·0-41·1; 13 of 49, all partial responses) in cohort 1 and 34·1% (20·1-50·6; 14 of 41; two complete responses and 12 partial responses) in cohort 1A. The most common treatment-emergent adverse events of grade 3 or worse were neutropenia (12 [24%] of 49 in cohort 1, none in cohort 1A), pneumonia (six [12%] and two [5%], respectively), fatigue (six [12%] and three [7%], respectively), and disease progression (six [12%] and four [10%], respectively). Drug-related treatment-emergent adverse events of grade 3 or worse occurred in 26 (53%) of 41 patients in cohort 1 and nine (22%) of 49 patients in cohort 1A. Drug-related serious adverse events were reported in ten (20%) patients and three (7%) patients, respectively. Deaths due to treatment-emergent adverse events occurred in ten (20%) patients in cohort 1 (disease progression in six (12%) patients and bronchospasm, hydrocephalus, respiratory failure, and pneumonitis in one [2%] patient each), and in seven (17%) patients in cohort 1A (due to disease progression in four (10%) patients and dyspnoea, malignant neoplasm, and sepsis in one (2%) patient each). One death due to a treatment-emergent adverse event was determined to be due to study treatment by the investigator, which was in cohort 1 (pneumonitis). Independent adjudication of interstitial lung disease or pneumonitis found that drug-related interstitial lung disease or pneumonitis occurred in ten (20%) patients in cohort 1 (two [4%] grade 1, five [10%] grade 2, and three [6%] grade 5) and two (5%) patients in cohort 1A (one [2%] grade 2 and one [2%] grade 5). An additional patient in cohort 1A had grade 4 pneumonitis after the data cutoff, which was subsequently adjudicated as drug-related grade 5 interstitial lung disease or pneumonitis.

INTERPRETATION: Given the low antitumour activity of existing treatment options in this patient population, trastuzumab deruxtecan might have the potential to fill a large unmet need in HER2-overexpressing NSCLC. Our findings support further investigation of trastuzumab deruxtecan in patients with HER2-overexpressing NSCLC.

FUNDING: Daiichi Sankyo and AstraZeneca.

PMID:38547891 | DOI:10.1016/S1470-2045(24)00064-0

Target Oncol. 2024 Mar 28. doi: 10.1007/s11523-024-01051-2. Online ahead of print.

ABSTRACT

BACKGROUND: Recurrent or refractory solid and central nervous system (CNS) tumours in paediatric patients have limited treatment options and carry a poor prognosis. The EnGeneIC Dream Vector (EDV) is a novel nanocell designed to deliver cytotoxic medication directly to the tumour. The epidermal growth factor receptor is expressed in several CNS and solid tumours and is the target for bispecific antibodies attached to the EDV.

OBJECTIVE: To assess the safety and tolerability of EGFR-Erbitux receptor EnGeneIC Dream Vector with mitoxantrone (EEDVsMit) in children with recurrent / refractory solid or CNS tumours expressing EGFR.

PATIENTS AND METHODS: Patients aged 2-21 years with relapsed or refractory CNS and solid tumours, or radiologically diagnosed diffuse intrinsic pontine glioma (DIPG), were treated in this phase I open-label study of single agent EEDVsMit. Thirty-seven patients' tumours were screened for EGFR expression. EEDVsMit was administered twice weekly in the first cycle and weekly thereafter. Standard dose escalation with a rolling 6 design was employed. Dosing commenced at 5 × 108 EEDVsMit per dose and escalated to 5 × 109 EEDVsMit per dose.

RESULTS: EGFR expression was detected in 12 (32%) of the paediatric tumours tested. Nine patients were enrolled and treated on the trial, including three patients with diffuse midline glioma. Overall, EEDVsMit was well tolerated, with no dose-limiting toxicities observed. The most common drug-related adverse events were grade 1-2 fever, nausea and vomiting, rash, lymphopaenia, and mildly deranged liver function tests. All patients had disease progression, including one patient who achieved a mixed response as the best response.

CONCLUSIONS: EGFR-Erbitux receptor targeted EnGeneIC Dream Vector with mitoxantrone can be safely delivered in paediatric patients aged 2-21 years with solid or CNS tumours harbouring EGFR expression. The discovery of EGFR expression in a high proportion of paediatric gliomas means that EGFR may be useful as a target for other treatment strategies. Targeted therapeutic-loaded EDVs may be worth exploring further for their role in stimulating an anti-tumour immune response.

GOV IDENTIFIER: NCT02687386.

PMID:38546944 | DOI:10.1007/s11523-024-01051-2

Front Public Health. 2024 Mar 13;12:1348015. doi: 10.3389/fpubh.2024.1348015. eCollection 2024.

ABSTRACT

INTRODUCTION: There are different types of COVID-19 vaccines approved worldwide. Since no national studies focus on vaccine-related adverse reactions and breakthrough cases, this study aimed to investigate the rate of adverse events and COVID-19 infection in medical students in Iran.

METHODS: This retrospective cohort study included Iranian medical students who received two doses of COVID-19 vaccines. The medical team gathered the demographic characteristics, comorbidities, type of vaccine, adverse events following vaccination, and history of COVID-19 infection data through a phone interview. The frequency of adverse events and breakthrough infection was stratified by vaccine type (ChAdOx1-S, Gam-COVID-Vac, and BIBP-CorV).

RESULTS: A total of 3,591 medical students enrolled in this study, of which 57.02% were females, with a mean age of 23.31 + 4.87. A PCR-confirmed and suspicious-for-COVID-19 breakthrough infection rate of 4.51 and 7.02% was detected, respectively. There was no significant relation between breakthrough infection and gender, BMI, blood groups, and comorbidities. However, there was a significant difference in breakthrough infection rate among different types of vaccines (p = 0.001) and history of COVID-19 infection (p = 0.001). A total of 16 participants were hospitalized due to COVID-19 infection after vaccination for reasons such as dyspnea, abnormal imaging, or decreased oxygen saturation. No severe infection or death was observed in the studied population.

CONCLUSION: Vaccination prevented severe COVID-19 infection, although a high breakthrough infection rate was evident among Iranian medical students during the Delta variant's peak. Vaccine effectiveness may be fragile during emerging new variants and in high-exposure settings. Moreover, adverse events are rare, and the benefits of vaccination outweigh the side effects. However, many limitations challenged this study, and the results should be cautious.

PMID:38544731 | PMC:PMC10965537 | DOI:10.3389/fpubh.2024.1348015

Indian J Orthop. 2024 Mar 2;58(4):402-411. doi: 10.1007/s43465-024-01110-w. eCollection 2024 Apr.

ABSTRACT

BACKGROUND: Management outcomes of drug-resistant (DR) osteoarticular tuberculosis (OATB) is dismal as in pre-ATT era (1905). The studies documenting treatment outcome of DR-OATB are scarce; hence, present retrospective analysis was conducted to evaluate outcome of consecutive cases of DR-OATB.

METHODS: 45 consecutive patients of suspected DR-OATB were treated from 2010 onwards. Tissue samples were submitted for AFB smear, cytology/histology, liquid culture, CBNAAT/LPA besides gram's staining and aerobic/anaerobic culture. Patients were treated by individualized second-line ATT till documenting healed status by contrast MRI/PET. The changes in neurological deficit, deformities, and drug-induced adverse events were documented.

RESULTS: 37/45 patients, 15 males and 22 females, mean age 26.89 years were followed. DR was suspected observing poor clinico-radiological response/appearance of fresh lesions on ATT. All showed no growth on aerobic/anaerobic pyogenic culture. 29 (78%) had microbiologically proven drug resistance and 8 (22%) were labeled as clinical drug resistance (CDR). 18/29 had multi-drug resistance. Mean prior ATT intake was 12.03 months 15 (40%) underwent surgical decompression. Mean duration of second-line ATT was 22.5 months (9-36 months). All patients achieved healed status with 8 (21%) developed side effects, most commonly hepatotoxicity, ototoxicity, and psychiatric disturbances. Average follow-up after completion of ATT was 40.5 months.

CONCLUSION: We report a large series where patients of DR-OATB were suspected on clinical criteria, investigated by DST, and treated. Patients with proven drug resistance were treated by individualized second-line ATT. CDR cases were treated by MDR protocol. Genotypic DST (CBNAAT/LPA) improved demonstration of DR. We demonstrated healed status on MRI/PET with no recurrence at minimum 2-year follow-up.

PMID:38544531 | PMC:PMC10963675 | DOI:10.1007/s43465-024-01110-w