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Trastuzumab deruxtecan (T‐DXd: DS‐8201a) is an anti‐human epidermal growth factor receptor 2 (HER2) Ab–drug conjugated with deruxtecan (DXd), a derivative of exatecan. The objective of this study was to characterize T‐DXd‐induced lung toxicity in cynomolgus monkeys. Trastuzumab deruxtecan was injected i.v. into monkeys once every 3 weeks for 6 weeks (10, 30, and 78.8 mg/kg) or for 3 months (3, 10, and 30 mg/kg). To evaluate the involvement of DXd alone in T‐DXd‐induced toxicity, DXd monohydrate was given i.v. to monkeys once a week for 4 weeks (1, 3, and 12 mg/kg). Interstitial pneumonitis was observed in monkeys given T‐DXd at 30 mg/kg or more. The histopathological features of diffuse lymphocytic infiltrates and slight fibrosis were similar to interstitial lung diseases (ILD)/pneumonitis related to anticancer drugs in patients, with an incidence that was dose‐dependent and dose‐frequency‐dependent. Monkeys receiving DXd monohydrate did not suffer lung toxicity, although the DXd exposure level was higher than that of DXd in the monkeys given T‐DXd. The HER2 expression in monkey lungs was limited to the bronchial level, although the lesions were found at the alveolar level. Immunohistochemical analysis confirmed that T‐DXd localization was mainly in alveolar macrophages, but not pulmonary epithelial cells. These findings indicate that monkeys are an appropriate model for investigating T‐DXd‐related ILD/pneumonitis. The results are also valuable for hypothesis generation regarding the possible mechanism of T‐DXd‐induced ILD/pneumonitis in which target‐independent uptake of T‐DXd into alveolar macrophages could be involved. Further evaluation is necessary to clarify the mechanism of ILD/pneumonitis in patients with T‐DXd therapy. Trastuzumab deruxtecan (T‐DXd; DS‐8201a), an anti‐human epidermal growth factor receptor 2 Ab–drug conjugate with a derivative of exatecan (DXd), has been associated with interstitial lung diseases (ILD)/pneumonitis in clinical trials. This work indicates that the histopathological features of T‐DXd‐induced lung toxicity in monkeys are similar to ILD/pneumonitis associated with anticancer drugs in patients.

We aimed to develop a model to predict visual field (VF) in the central 10 degrees in patients with glaucoma, by training a convolutional neural network (CNN) with optical coherence tomography (OCT) images and adjusting the values with Humphrey Field Analyzer (HFA) 24–2 test. The training dataset included 558 eyes from 312 glaucoma patients and 90 eyes from 46 normal subjects. The testing dataset included 105 eyes from 72 glaucoma patients. All eyes were analyzed by the HFA 10-2 test and OCT; eyes in the testing dataset were additionally analyzed by the HFA 24-2 test. During CNN model training, the total deviation (TD) values of the HFA 10-2 test point were predicted from the combined OCT-measured macular retinal layers’ thicknesses. Then, the predicted TD values were corrected using the TD values of the innermost four points from the HFA 24-2 test. Mean absolute error derived from the CNN models ranged between 9.4 and 9.5 B. These values reduced to 5.5 dB on average, when the data were corrected using the HFA 24-2 test. In conclusion, HFA 10-2 test results can be predicted with a OCT images using a trained CNN model with adjustment using HFA 24-2 test.

BackgroundThe good short-term and oncological outcomes of robot-assisted radical esophagectomy have been demonstrated, although its impact on long-term health-related quality of life (HRQoL) remains to be investigated. This study aimed to assess long-term HRQoL in patients after robot-assisted radical transmediastinal esophagectomy (TME), which is characterized as non-transthoracic esophagectomy comprising a robotic transhiatal approach and a video-assisted cervical approach, and transthoracic esophagectomy (TTE).MethodsThe European Organization for Research and Treatment of Cancer generic and disease-specific modules (QLQ-C30 and QLQ-OES18), nutritional status and body composition data were prospectively collected in patients undergoing TME or TTE before and at 3, 6, 12, 18, and 24 months after surgery. The results of long-term (≥ 2 years) survivors without recurrence were compared between the two groups.ResultsA total of 37 patients (TME; n = 18, TTE; n = 19) were included for analysis. Longitudinal survey of function scales revealed scores of physical, role, social, and emotional function to be significantly better in the TME group than in the TTE group at many points postoperatively. Markedly, the symptoms of general pain, esophageal pain, and dry mouth greatly worsened after surgery in the TTE group, but did not deteriorate in the TME group. In contrast, symptoms relating to eating difficulties, body composition data, and nutritional status did not differ between the groups over time. At 24 months after surgery, TME provided significantly higher scores of global QOL (P = 0.01) and emotional function (P = 0.01) and also resulted in significantly fewer problems of fatigue (P = 0.04), general pain (P = 0.04), insomnia (P = 0.02), and dry mouth (P = 0.03), as compared to TTE.ConclusionThis study indicates that TME can provide better long-term HRQoL outcomes than TTE.

MAS-related G protein coupled receptor-X2 (MRGPRX2), expressed in human mast cells, is associated with drug-induced pseudo-allergic reactions. Dogs are highly susceptible to drug-induced anaphylactoid reactions caused by various drugs; however, the distribution and physiological function of canine MRGPR family genes, including MRGPRX2, remain largely unknown. In the present study, we clarified the distribution of dog MRGPR family genes by real-time quantitative PCR and in situ hybridisation. We also investigated the stimulatory effects of various histamine-releasing agents, including fluoroquinolones, on HEK293 cells transiently transfected with dog MRGPR family genes to identify their physiological function. Dog MRGPRX2 and MRGPRG were distributed in a limited number of tissues, including the skin (from the eyelid, abdomen, and cheek), whereas MRGPRD and MRGPRF were extensively expressed in almost all tissues examined. Histochemical and in situ hybridisation analyses revealed that MRGPRX2 was expressed in dog connective tissue-type mast cells in the skin. Intracellular Ca 2+ mobilisation assay revealed that HEK293 cells, expressing dog MRGPRX2 or human MRGPRX2, but not dog MRGPRD, MRGPRF, and MRGPRG, responded to histamine-releasing agents. Our results suggest that dog MRGPRX2 is the functional orthologue of human MRGPRX2 and plays an essential role in drug-induced anaphylactoid reactions in dogs.

The PreserFlo MicroShunt (PMS) is a minimally invasive surgical device for glaucoma management. However, postoperative hypotony remains a significant complication. This retrospective cohort study analyzed 471 eyes to evaluate the efficacy of PMS implantation in reducing intraocular pressure (IOP) and medication dependency, as well as to identify risk factors associated with hypotony. The median IOP decreased significantly from 19 mmHg preoperatively to 10 mmHg three months postoperatively, with the median medications score dropping to zero. Postoperative hypotony occurred in 18.7% of the cases. Multivariate analysis identified preoperative IOP ≥ 25 mmHg (odds ratio (OR): 2.01, 95% confidence interval (CI): 1.00–4.02, p  = 0.049) and medication scores ≥ 5 (OR: 2.12, 95% CI: 1.13–3.96, p  = 0.019) as significant risk factors for hypotony, while axial length ≥ 25.5 mm (OR: 0.19, 95% CI: 0.09–0.39, p  < 0.001) and intraluminal suture stenting (OR: 0.08, 95% CI: 0.03–0.25, p  < 0.001) were significantly protective. Importantly, intraluminal suture stenting mitigated the risk of hypotony without compromising the short-term surgical outcomes. These findings emphasize the need for careful patient selection and the potential of intraluminal suture stenting as an effective intraoperative strategy to improve the safety and outcomes of PMS implantation.

MAS-related G protein-coupled receptor X2 (MRGPRX2), expressed in human mast cells, is associated with drug-induced pseudo-allergic reactions. Dogs are highly sensitive to the anaphylactoid reactions induced by certain drugs including fluoroquinolones. Recently, dog MRGPRX2 was identified as a functional ortholog of human MRGPRX2, with dog MRGPRX2 being particularly sensitive to fluoroquinolones. The aim of this study was to determine key residues responsible for the enhanced activity of fluoroquinolone-induced histamine release associated with MRGPRX2. Firstly, a structure model of human and dog MRGPRX2 was built by homology modeling, and docking simulations with fluoroquinolones were conducted. This model indicated that E164 and D184, conserved between human and dog, are essential for the binding to fluoroquinolones. In contrast, F78 (dog: Y) and M109 (dog: W) are unconserved residues, to which the species difference in fluoroquinolone sensitivity is attributable. Intracellular calcium mobilisation assay with human MRGPRX2 mutants, in which residues at positions 78 and 109 were substituted to those of dog MRGPRX2, revealed that M109 and F78 of human MRGPRX2 are crucial residues for enhancing the fluoroquinolone-induced histamine release. In conclusion, these key residues have important clinical implications for revealing the mechanisms and predicting the risks of fluoroquinolone-mediated pseudo-allergic reactions in humans.

Purpose To assess the risk factors for intraocular pressure (IOP) elevation during the early period post cataract surgery. Study design Retrospective study. Methods This study involved 1587 eyes that underwent cataract surgery at the Baptist Eye Institute, Kyoto, Japan between April 2020 and May 2021. In all subjects, risk factors for early postoperative IOP elevation (i.e., an increase of IOP of 10 mmHg or more at 1-day postoperative compared with that at baseline, or a postoperative IOP of 28 mmHg or more) were analyzed by multivariate logistic regression analysis. Results Of the 1587 treated eyes in this study, 100 (6.3%) experienced early-postoperative IOP elevation. Of those 100 eyes, 78.0% were men, 27.0% had an axial length (AL) of ≥ 26.5 mm, 23.0% had a history of glaucoma treatment, 11.0% had poor mydriasis and 10.0% had intraoperative floppy iris syndrome (IFIS). Multivariate analysis findings revealed that male [odds ratio (OR) 4.36; 95% confidence interval (CI) 2.63–7.23; P < 0.001], AL of ≥ 26.5 mm (3.11; 1.83–5.30; P < 0.001), a history of glaucoma treatment (2.83; 1.63–4.91; P < 0.001), poorly mydriasis (2.63; 1.16–6.01; P = 0.02), IFIS (4.37; 1.78–10.74; P = 0.001) and baseline high IOP (1.09; 1.01–1.18; P = 0.03) were associated with increased IOP during the early period post cataract surgery. Conclusions The findings in this study reveal that male sex, high myopia, a history of glaucoma treatment, poor mydriasis, IFIS and baseline high IOP are risk factors for IOP elevation during the early period post cataract surgery.

Drug-induced interstitial lung disease (DILD) occurs when drug exposure causes inflammation of the lung interstitium. DILD can be caused by different types of drugs, and some DILD patterns results in a high mortality rate; hence, DILD poses a serious problem in clinical practice as well as drug development, and strategies to diagnose and distinguish DILD from other lung diseases are necessary. We aimed to identify novel biomarkers for DILD by performing lipidomics analysis on plasma samples from patients with acute and recovery phase DILD. Having identified lysophosphatidylcholines (LPCs) as candidate biomarkers for DILD, we determined their concentrations using validated liquid chromatography/mass spectrometry biomarker assays. In addition, we evaluated the ability of LPCs to discriminate patients with acute phase DILD from those with recovery phase DILD, DILD-tolerant, or other lung diseases, and characterized their association with clinical characteristics. Lipidomics analysis revealed a clear decrease in LPC concentrations in the plasma of patients with acute phase DILD. In particular, LPC(14:0) had the highest discriminative index against recovery phase and DILD-tolerant patients. LPC(14:0) displayed no clear association with causal drugs, or subjects’ backgrounds, but was associated with disease severity. Furthermore, LPC(14:0) was able to discriminate between patients with DILD and other lung diseases, including idiopathic interstitial pneumonia and lung disease associated with connective tissue disease. LPC(14:0) is a promising biomarker for DILD that could improve the diagnosis of DILD and help to differentiate DILD from other lung diseases, such as idiopathic interstitial pneumonia and connective tissue disease.

Purpose To assess the effectiveness of switching from the concomitant use of brinzolamide 1% (BZM) and brimonidine 0.1% (BMD) to a BZM/BMD fixed-dose combination (BBFC) for the reduction of corneal epithelial damage. Study Design Retrospective cohort study. Methods This study involved 52 eyes of 52 glaucoma patients (26 women, 26 men; mean age: 67.0 ± 14.0 years) followed for more than 3 months after being switched from concomitant BZM and BMD to BBFC. Superficial punctate keratitis (SPK) was assessed by fluorescein staining according to the National Eye Institute classification, with the cornea divided into 5 areas: center, superior, nasal, temporal, and inferior. SPK density was graded as 0 (no SPK), 1 (separate SPK), 2 (moderately dense SPK), and 3 (high SPK with overlapping lesions). SPK scores and intraocular pressure (IOP) at pre switching to BBFC (pre-BBFC) and at 3-months post switching to BBFC (post-BBFC) were then compared using the Wilcoxon signed-rank test. Results At pre-BBFC and post-BBFC, respectively, mean IOP was 12.4 ± 2.5 and 12.4 ± 2.7 mmHg, thus illustrating no significant difference in IOP between pre and post switch ( p  = 0.924), and the mean SPK score for center, superior, nasal, temporal, and inferior was 0.06 ± 0.24, 0.04 ± 0.19, 0.52 ± 0.67, 0.15 ± 0.36, and 0.92 ± 0.74, and 0.04 ± 0.19, 0.02 ± 0.14, 0.37 ± 0.56, 0.04 ± 0.19, and 0.75 ± 0.62, thus clearly showing a significant reduction in SPK scores for the nasal, temporal, and inferior areas at post-BBFC compared to those at pre-BBFC ( p  < 0.05). Conclusion Our findings reveal that compared with the concomitant use of BZM and BMD, BBFC is effective in reducing corneal epithelial damage.

Among the various histopathological patterns of drug-induced interstitial lung disease (DILD), diffuse alveolar damage (DAD) is associated with poor prognosis. However, there is no reliable biomarker for its accurate diagnosis. Here, we show stratifin/14-3-3σ (SFN) as a biomarker candidate found in a proteomic analysis. The study includes two independent cohorts (including totally 26 patients with DAD) and controls (total 432 samples). SFN is specifically elevated in DILD patients with DAD, and is superior to the known biomarkers, KL-6 and SP-D, in discrimination of DILD patients with DAD from patients with other DILD patterns or other lung diseases. SFN is also increased in serum from patients with idiopathic DAD, and in lung tissues and bronchoalveolar lavage fluid of patients with DAD. In vitro analysis using cultured lung epithelial cells suggests that extracellular release of SFN occurs via p53-dependent apoptosis. We conclude that serum SFN is a promising biomarker for DAD diagnosis. No reliable serum biomarker for diffuse alveolar damage, a poor prognosis subtype of drug-induced interstitial lung disease, is currently available. Here, the authors show stratifin/14-3-3σ in serum is a promising biomarker for diagnosis of this type of disease.