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Clinical Cancer Research : An Official... Jun 2023Eganelisib (IPI-549) is a first-in-class, orally administered, highly selective PI3Kγ inhibitor with antitumor activity alone and in combination with programmed cell...
PURPOSE
Eganelisib (IPI-549) is a first-in-class, orally administered, highly selective PI3Kγ inhibitor with antitumor activity alone and in combination with programmed cell death protein 1/ligand 1 (PD-1/PD-L1) inhibitors in preclinical studies. This phase 1/1b first-in-human, MAcrophage Reprogramming in Immuno-Oncology-1 (NCT02637531) study evaluated the safety and tolerability of once-daily eganelisib as monotherapy and in combination with nivolumab in patients with solid tumors.
PATIENTS AND METHODS
Dose-escalation cohorts received eganelisib 10-60 mg as monotherapy (n = 39) and 20-40 mg when combined with nivolumab (n = 180). Primary endpoints included incidence of dose-limiting toxicities (DLT) and adverse events (AE).
RESULTS
The most common treatment-related grade ≥3 toxicities with monotherapy were increased alanine aminotransferase (ALT; 18%), aspartate aminotransferase (AST; 18%), and alkaline phosphatase (5%). No DLTs occurred in the first 28 days; however, toxicities meeting DLT criteria (mostly grade 3 reversible hepatic enzyme elevations) occurred with eganelisib 60 mg in later treatment cycles. In combination, the most common treatment-related grade ≥3 toxicities were increased AST (13%) and increased ALT and rash (10%). Treatment-related serious AEs occurred in 5% of monotherapy patients (grade 4 bilirubin and hepatic enzyme increases in one patient each) and 13% in combination (pyrexia, rash, cytokine release syndrome, and infusion-related reaction in ≥2 patients each). Antitumor activity was observed in combination, including patients who had progressed on PD-1/PD-L1 inhibitors.
CONCLUSIONS
On the basis of the observed safety profile, eganelisib doses of 30 and 40 mg once daily in combination with PD-1/PD-L1 inhibitors were chosen for phase 2 study.
Topics: Humans; Nivolumab; Antibodies, Monoclonal, Humanized; Programmed Cell Death 1 Receptor; Immune Checkpoint Inhibitors; Neoplasms; Angiogenesis Inhibitors; Antineoplastic Combined Chemotherapy Protocols
PubMed: 37000164
DOI: 10.1158/1078-0432.CCR-22-3313 -
Medicina (Kaunas, Lithuania) Oct 2023: To report a case of microbial keratitis complicated by severe corneal melting and whole corneal descemetocele. : A 72-year-old male farmer presented with a right...
: To report a case of microbial keratitis complicated by severe corneal melting and whole corneal descemetocele. : A 72-year-old male farmer presented with a right corneal ulcer involving nearly the entire cornea, which was almost completely melted down with the remaining Descemet's membrane (DM). The pupil area was filled with melted necrotic material, with the intraocular lens partially protruding from the pupil and indenting the DM. Corneal optical coherence tomography (OCT) examination revealed a corneal thickness of 37 µm that was attached to its back surface, with the iris and a part of the intraocular lens (IOL) protruding through the pupil. The patient was hospitalized and treated with local and systemic antibiotics until control of the inflammation was achieved. Corneoscleral transplantation plus excision/transplantation of the corneal limbus were performed, and the entire corneal limbus was lamellarly incised. After completely suturing all around the transplanted corneoscleral graft, the anterior chamber was formed. Postoperative treatment included local antibiotics, anti-inflammatory drugs, and cycloplegic drops. : There was no recurrence of infection, and the corneal epithelium gradually regenerated and covered the whole graft. Visual acuity was light perception at 6 months after the surgery. The patient was satisfied that the globe was preserved and did not wish to undergo any further treatment. : Corneoscleral transplantation is preferred for the treatment of large-sized descemetoceles with active microbial keratitis and extensive infiltrates, especially in cases where the whole cornea has transformed into a large cyst.
Topics: Male; Humans; Aged; Corneal Transplantation; Cornea; Keratitis; Tomography, Optical Coherence; Anti-Bacterial Agents
PubMed: 37893498
DOI: 10.3390/medicina59101780 -
ESMO Open Aug 2023Trastuzumab deruxtecan (T-DXd) has been shown to benefit progression-free survival and overall survival in patients with metastatic breast cancer (mBC) after progression... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Trastuzumab deruxtecan (T-DXd) has been shown to benefit progression-free survival and overall survival in patients with metastatic breast cancer (mBC) after progression on ≥1 human epidermal growth factor receptor 2 (HER2)-targeted therapies. However, interstitial lung disease (ILD) and cardiotoxicity are the most significant toxicities associated with T-DXd. Therefore, we conducted a systematic review and meta-analysis to assess the incidence and severity of these toxicities in mBC patients treated with T-DXd.
MATERIALS AND METHODS
We searched PubMed, Cochrane, and Scopus databases, and conferences websites for randomized clinical trials and nonrandomized studies of intervention including HER2-low or HER2-positive mBC patients who received at least one dose of T-DXd. Statistical analysis was carried out using R software.
RESULTS
We included 15 studies comprising 1970 patients with a mean follow-up of 13.3 months. Median age ranged from 53 to 59 years, 61.9% were non-Asian, and 67.4% had hormone receptor-positive mBC. In a pooled analysis, the incidence of ILD was 11.7% [222 patients; 95% confidence interval (CI) 9.1% to 15.0%]. Patients receiving T-DXd dose of 6.4 mg/kg developed a significantly higher rate of ILD (22.7%) compared to those receiving a dose of 5.4 mg/kg (9.3%) (P < 0.01). Most cases of ILD (80.2%; 174/217 patients) were mild (grade 1 or 2). Grade 3 or 4 ILD was reported in 29 patients (13.4%), and grade 5 in 14 patients (6.4%). The incidence of decreased left ventricular ejection fraction (LVEF) was 1.95% (95% CI 0.65% to 3.73%), and the QT interval (QTi) prolongation was 7.77% (95% CI 2.74% to 20.11%). Most patients were asymptomatic, but four had LV dysfunction and heart failure (0.26%).
CONCLUSIONS
In this meta-analysis of 1970 patients with mBC, treatment with T-DXd was associated with a 11.7% incidence of ILD, 7.7% incidence of prolonged QTi, and 1.9% incidence of reduced LVEF. Early detection and management of T-DXd-related toxicity by a multidisciplinary team may ultimately improve patient outcomes.
Topics: Humans; Middle Aged; Female; Breast Neoplasms; Cardiotoxicity; Incidence; Stroke Volume; Ventricular Function, Left; Lung Diseases, Interstitial
PubMed: 37481956
DOI: 10.1016/j.esmoop.2023.101613 -
Cell Insight Jun 2024The ciliary body, located at the junction of the choroid and iris, is crucial in the development of the embryonic eye. Notch2 signalling, Wnt signalling, transforming... (Review)
Review
The ciliary body, located at the junction of the choroid and iris, is crucial in the development of the embryonic eye. Notch2 signalling, Wnt signalling, transforming growth factor β (TGF-β) signalling, and Pax6 signalling are critical for coordinating the ciliary body formation. These signalling pathways are coordinated with each other and participate in the ciliary body development, ensuring the precise formation and optimal functioning of the eye structure. Although rare, ciliary body hypoplasia, ciliary tumours, and genetic-related iritis indicate the intricate nature of ciliary body development. Given the ciliary body's important biological significance and potential medical relevance, we aim to provide a comprehensive overview of the developmental molecular mechanisms governing ciliary body formation and function. Here, we focus on the intricate signalling pathways governing ciliary body development and corresponding genetic ciliary diseases.
PubMed: 38595769
DOI: 10.1016/j.cellin.2024.100162 -
Investigative Ophthalmology & Visual... Oct 2023The worldwide incidence of ocular melanoma (OM), uveal melanoma (UM), and conjunctival melanoma has last been reported on 15 years ago. Recently, light iris color and...
PURPOSE
The worldwide incidence of ocular melanoma (OM), uveal melanoma (UM), and conjunctival melanoma has last been reported on 15 years ago. Recently, light iris color and four specific single-nucleotide-polymorphisms (SNPs) have been identified as a UM-risk factor. Furthermore, six iris color predicting SNPs have been discovered (IrisPlex). Interestingly, two of these (rs129138329 and rs12203592) are also UM-risk factors. We collected worldwide incidence data of OM and investigated its correlations with iris color, IrisPlex SNPs, and UM-risk SNPs.
METHODS
Cases of OM, as defined by the International Classification of Diseases Oncology C69 (eye), 8720/3 to 8790/3 (malignant melanoma), and 8000 to 8005 (malignant neoplasm), between 1988 and 2012, were extracted from the Cancer Incidence in Five Continents. Incidence rates were age-standardized and their trends were analyzed with joinpoint regression and age period cohort modeling. Frequencies for each country of iris color, IrisPlex SNPs, and UM-risk SNPs were collected from the literature.
RESULTS
Incidence rates were generally ≥8.0 cases per million person-years in Northern Europe, Western Europe, and Oceania; 2.0 to 7.9 in North America, Eastern Europe, and Southern Europe; and <2.0 in South America, Asia, and Africa. OM incidence correlated with latitude (r = 0.77, P ≤ 0.001) and is expressed as a north-to-south decreasing gradient in Europe. SNP rs12913832 correlated with OM incidence (r = 0.83, P ≤ 0.001), blue iris color (r = 0.56, P ≤ 0.05), green iris color (r = 0.51, P ≤ 0.05), and brown iris color (r = -0.64, P ≤ 0.01). Trends were stable for most countries (28/35).
CONCLUSIONS
OM incidence is highest in populations of European ancestry and lowest in populations of Asian and African ancestry. Overall, trends are stable, and the spatial correlation among OM incidence, iris color, and rs12913832 may support the role of pigmentation-related risk factors in OM development.
Topics: Humans; Incidence; Pigmentation; Melanoma; Uveal Neoplasms
PubMed: 37902747
DOI: 10.1167/iovs.64.13.45