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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 -
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 -
Journal of Contemporary Brachytherapy Oct 2023The study aimed to review the long-term outcomes of ruthenium brachytherapy for iris and iridociliary melanoma.
PURPOSE
The study aimed to review the long-term outcomes of ruthenium brachytherapy for iris and iridociliary melanoma.
MATERIAL AND METHODS
Medical records of patients who underwent ruthenium plaque treatment for iris and iridociliary melanoma at the Department of Ophthalmology, Poznań University of Medical Sciences, between 1999 and 2021 were retrospectively reviewed.
RESULTS
We identified 24 patients, including 17 women and 7 men, with a median age of 61.5 years (range, 35-84 years). Median observation time before treatment was 3 months (range, 0-68 months). Nineteen (79%) patients received a treatment with 20 mm CCB plaque, 5 (21%) with 15 mm CCA plaque and 2 (8%) patients received total irradiation to the entire iridocorneal angle. Median follow-up was 67.5 months (range, 24-265 months). We noted one (4%) recurrence managed by irradiating the anterior segment. Twelve (50%) patients developed post-operative cataracts in a median time of 38 months following treatment, 5 (21%) required topical medications to control intraocular pressure, and one (4%) developed chronic macular edema (CME) that was managed with anti-VEGF therapy. Final visual acuity between 1.0 and 0.5 was observed for 16 (67%) patients, between 0.49-0.1 for 5 (21%) patients, and below 0.09 for 3 (12%) patients. Nine (37%) patients maintained final visual acuity stable; in 4 (17%) patients, it dropped more than 3 lines, and improved in 6 (25%) patients.
CONCLUSIONS
Ruthenium brachytherapy with standard applicators is an effective and safe way of treatment for iris and iridociliary melanoma. We observed no significant post-operative complications in a long-term observation.
PubMed: 38026074
DOI: 10.5114/jcb.2023.132401 -
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 -
Current Oncology (Toronto, Ont.) Dec 2023The purpose of this guideline update is to reassess and update recommendations in the prior guideline from 2016 on the appropriate management of patients with uveal... (Review)
Review
OBJECTIVE
The purpose of this guideline update is to reassess and update recommendations in the prior guideline from 2016 on the appropriate management of patients with uveal melanoma.
METHODS
In 2021, a multidisciplinary working group from the Provincial Cutaneous Tumour Team, Cancer Care Alberta, Alberta Health Services was convened to update the guideline. A comprehensive review of new research evidence in PubMed as well as new clinical practice guidelines from prominent oncology groups informed the update. An enhancement in methodology included adding levels of evidence and strength of recommendations. The updated guideline was circulated to all members of the Provincial Cutaneous Tumour Team for review and endorsement.
RESULTS
New and modified recommendations address provider training requirements, diagnostic imaging for the detection of metastases, neo-adjuvant pre-enucleation radiotherapy, intravitreal anti-vascular endothelial growth factor agents for radiation retinopathy, genetic prognostic testing, surveillance following definitive local therapy, and systemic therapy for patients with metastatic uveal melanoma.
DISCUSSION
The recommendations represent evidence-based standards of care agreed to by a large multidisciplinary group of healthcare professionals.
Topics: Humans; Alberta; Melanoma; Skin Neoplasms; Uveal Neoplasms
PubMed: 38275828
DOI: 10.3390/curroncol31010002 -
American Journal of Ophthalmology Case... Dec 2023To report a patient with a unilateral presentation of glaucoma, pain, and acute iris transillumination syndrome simulating iris melanoma.
PURPOSE
To report a patient with a unilateral presentation of glaucoma, pain, and acute iris transillumination syndrome simulating iris melanoma.
OBSERVATIONS
A 53-year-old male presented with blurred vision and pain in his right eye several weeks following a respiratory sinus infection managed by oral azithromycin. Examination of the right eye was notable for elevated intraocular pressure of 46 mm Hg, an irregular mid-dilated pupil, and diffuse iris transillumination with pigmentary seeding on the iris surface, in the anterior chamber angle, and on the sclera, suspicious for diffuse iris melanoma with glaucoma and extrascleral extension. Ultrasound biomicroscopy (UBM) of the right eye revealed circumferential anterior chamber angle and trabecular meshwork involvement by an infiltrative process corresponding to the pigmented cells noted clinically, while the ciliary body was unremarkable. Following enucleation, histopathology showed extensive necrosis of the iris pigment epithelium, sphincter, and dilator muscles with melanophagic infiltration in the anterior chamber angle and episclera, mild chronic non-granulomatous iridocyclitis, and no evidence of a melanocytic neoplasm. Although immunohistochemical studies for herpes simplex virus (HSV) types 1 and 2, varicella-zoster virus, and cytomegalovirus were negative, qualitative real-time polymerase chain reaction on paraffin-embedded tissue detected HSV-1 DNA. The combined clinical, pathologic, and molecular findings were compatible with unilateral acute iris transillumination syndrome, likely HSV-1 associated.
CONCLUSION AND IMPORTANCE
Unilateral acute iris transillumination syndrome with diffuse iris pigment epithelial loss can simulate iris melanoma. Prompt herpes viral studies may be informative.
PubMed: 37680309
DOI: 10.1016/j.ajoc.2023.101912 -
European Radiology Dec 2023Early, accurate diagnosis is crucial for the prognosis of patients with soft tissue sarcomas. To this end, standardization of imaging algorithms, technical requirements,... (Review)
Review
OBJECTIVES
Early, accurate diagnosis is crucial for the prognosis of patients with soft tissue sarcomas. To this end, standardization of imaging algorithms, technical requirements, and reporting is therefore a prerequisite. Since the first European Society of Musculoskeletal Radiology (ESSR) consensus in 2015, technical achievements, further insights into specific entities, and the revised WHO-classification (2020) and AJCC staging system (2017) made an update necessary. The guidelines are intended to support radiologists in their decision-making and contribute to interdisciplinary tumor board discussions.
MATERIALS AND METHODS
A validated Delphi method based on peer-reviewed literature was used to derive consensus among a panel of 46 specialized musculoskeletal radiologists from 12 European countries. Statements were scored online by level of agreement (0 to 10) during two iterative rounds. Either "group consensus," "group agreement," or "lack of agreement" was achieved.
RESULTS
Eight sections were defined that finally contained 145 statements with comments. Overall, group consensus was reached in 95.9%, and group agreement in 4.1%. This communication contains the first part consisting of the imaging algorithm for suspected soft tissue tumors, methods for local imaging, and the role of tumor centers.
CONCLUSION
Ultrasound represents the initial triage imaging modality for accessible and small tumors. MRI is the modality of choice for the characterization and local staging of most soft tissue tumors. CT is indicated in special situations. In suspicious or likely malignant tumors, a specialist tumor center should be contacted for referral or teleradiologic second opinion. This should be done before performing a biopsy, without exception.
CLINICAL RELEVANCE
The updated ESSR soft tissue tumor imaging guidelines aim to provide best practice expert consensus for standardized imaging, to support radiologists in their decision-making, and to improve examination comparability both in individual patients and in future studies on individualized strategies.
KEY POINTS
• Ultrasound remains the best initial triage imaging modality for accessible and small suspected soft tissue tumors. • MRI is the modality of choice for the characterization and local staging of soft tissue tumors in most cases; CT is indicated in special situations. Suspicious or likely malignant tumors should undergo biopsy. • In patients with large, indeterminate or suspicious tumors, a tumor reference center should be contacted for referral or teleradiologic second opinion; this must be done before a biopsy.
PubMed: 38062268
DOI: 10.1007/s00330-023-10425-5 -
Nature Communications Oct 2023Cytokine therapy, involving interleukin-15 (IL-15), is a promising strategy for cancer immunotherapy. However, clinical application has been limited due to severe...
Cytokine therapy, involving interleukin-15 (IL-15), is a promising strategy for cancer immunotherapy. However, clinical application has been limited due to severe toxicity and the relatively low immune response rate, caused by wide distribution of cytokine receptors, systemic immune activation and short half-life of IL-15. Here we show that a biomimetic nanovaccine, developed to co-deliver IL-15 and an antigen/major histocompatibility complex (MHC) selectively targets IL-15 to antigen-specific cytotoxic T lymphocytes (CTL), thereby reducing off-target toxicity. The biomimetic nanovaccine is composed of cytomembrane vesicles, derived from genetically engineered dendritic cells (DC), onto which IL-15/IL-15 receptor α (IL-15Rα), tumor-associated antigenic (TAA) peptide/MHC-I, and relevant costimulatory molecules are simultaneously anchored. We demonstrate that, in contrast to conventional IL-15 therapy, the biomimetic nanovaccine with multivalent IL-15 self-transpresentation (biNV-IL-15) prolonged blood circulation of the cytokine with an 8.2-fold longer half-life than free IL-15 and improved the therapeutic window. This dual targeting strategy allows for spatiotemporal manipulation of therapeutic T cells, elicits broad spectrum antigen-specific T cell responses, and promotes cures in multiple syngeneic tumor models with minimal systemic side effects.
Topics: Humans; Interleukin-15; Biomimetics; Cytokines; Immunotherapy; Receptors, Interleukin-15; Neoplasms; Dendritic Cells; Cancer Vaccines
PubMed: 37875481
DOI: 10.1038/s41467-023-42155-z -
Indian Journal of Ophthalmology Oct 2023The most common cause of intraocular mass is metastasis from other tumors. Renal malignancies, though rare, have a substantial number of cases with ocular metastasis,... (Review)
Review
The most common cause of intraocular mass is metastasis from other tumors. Renal malignancies, though rare, have a substantial number of cases with ocular metastasis, few of which were misdiagnosed. Many a times renal malignancies present with ocular manifestations before the primary diagnosis. Here in this article, we comprehensively reviewed 106 cases of ocular metastasis from renal malignancies published till date to the best of our knowledge. The eye is a rare site for distant metastasis because of the lack of a lymphatic system. The most common ocular structures to get involved in distant metastasis are the uveal tract, i.e., choroid, iris, and ciliary body. The most common renal tumor which metastasizes to eyes is renal cell carcinoma (RCC). RCC accounts for less than 2% of all ophthalmic metastases. Out of total 106 cases, the type of renal malignancy was known in 95 cases only, of which 92 had RCC, 1 Wilm's tumor, 1 rhabdoid tumor, and 1 medullary carcinoma. The age ranged widely from 2 weeks old to 81 years old. The male to female ratio was 3.4:1. In total, 67.4% of cases had a previous history of RCC, while the rest 32.6% primarily presented with ophthalmic manifestations first. Treatment modalities included enucleation of the eye, debulking surgery followed by radiotherapy and/or chemotherapy and/or immunotherapy.
Topics: Humans; Male; Female; Infant, Newborn; Carcinoma, Renal Cell; Uveal Neoplasms; Kidney Neoplasms; Eye Neoplasms; Ciliary Body
PubMed: 37787223
DOI: 10.4103/IJO.IJO_3073_22