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Cancer Immunology Research Dec 2023Tumor-specific neoepitopes are promising targets in cancer immunotherapy. However, the identification of functional tumor-specific neoepitopes remains challenging. In...
Tumor-specific neoepitopes are promising targets in cancer immunotherapy. However, the identification of functional tumor-specific neoepitopes remains challenging. In addition to the most common source, single-nucleotide variants (SNV), alternative splicing (AS) represents another rich source of neoepitopes and can be utilized in cancers with low SNVs such as uveal melanoma (UM). UM, the most prevalent adult ocular malignancy, has poor clinical outcomes due to a lack of effective therapies. Recent studies have revealed the promise of harnessing tumor neoepitopes to treat UM. Previous studies have focused on neoepitope targets associated with mutations in splicing factor 3b subunit 1 (SF3B1), a key splicing factor; however, little is known about the neoepitopes that are commonly shared by patients independent of SF3B1 status. To identify the AS-derived neoepitopes regardless of SF3B1 status, we herein used a comprehensive nanopore long-read-sequencing approach to elucidate the landscape of AS and novel isoforms in UM. We also performed high-resolution mass spectrometry to further validate the presence of neoepitope candidates and analyzed their structures using the AlphaFold2 algorithm. We experimentally evaluated the antitumor effects of these neoepitopes and found they induced robust immune responses by stimulating interferon (IFN)γ production and activating T cell-based UM tumor killing. These results provide novel insights into UM-specific neoepitopes independent of SF3B1 and lay the foundation for developing therapies by targeting these actionable neoepitopes.
Topics: Adult; Humans; Alternative Splicing; Melanoma; Uveal Neoplasms; RNA Splicing Factors; Phosphoproteins
PubMed: 37756564
DOI: 10.1158/2326-6066.CIR-23-0083 -
European Radiology Nov 2023To compare neuroimaging characteristics of three types of histiocytoses, namely Langerhans cell histiocytosis (LCH), Erdheim-Chester disease (ECD), and Rosai-Dorfman...
OBJECTIVES
To compare neuroimaging characteristics of three types of histiocytoses, namely Langerhans cell histiocytosis (LCH), Erdheim-Chester disease (ECD), and Rosai-Dorfman disease (RDD), with central nervous system (CNS) involvement.
METHODS
A total of 121 adult patients with histiocytoses (77 LCH, 37 ECD, and 7 RDD) and CNS involvement were retrospectively included. Histiocytoses were diagnosed based on histopathological findings combined with suggestive clinical and imaging features. Brain and dedicated pituitary MRIs were systematically analyzed for tumorous, vascular, degenerative lesions, sinus, and orbital involvement and for hypothalamic pituitary axis involvement.
RESULTS
Endocrine disorders, including diabetes insipidus and central hypogonadism, were more common in LCH patients than in ECD and RDD patients (p < 0.001). In LCH, tumorous lesions were mostly solitary (85.7%), located in the hypothalamic pituitary region (92.9%), and without peritumoral edema (92.9%), while in ECD and RDD, tumorous lesions were often multiple (ECD: 81.3%, RDD: 85.7%), their distribution was more widespread with meninges mostly involved (ECD: 75%, RDD: 71.4%), and they most likely presented with peritumoral edema (ECD: 50%, RDD: 57.1%; all p ≤ 0.020). Vascular involvement was an exclusive imaging characteristic of ECD (17.2%), which was not observed in LCH or RDD; this was also associated with a higher risk of death (p = 0.013, hazard ratio = 11.09).
CONCLUSION
The typical characteristic of adult CNS-LCH was endocrine disorders with radiological findings limited to the hypothalamic pituitary axis. The pattern of multiple tumorous lesions with predominant involvement of meninges was the main manifestation of CNS-ECD and CNS-RDD, while vascular involvement was pathognomonic for ECD and associated with poor prognosis.
CLINICAL RELEVANCE STATEMENT
Involvement of the hypothalamic-pituitary axis is the typical imaging characteristic of Langerhans cell histiocytosis. Multiple tumorous lesions, predominantly involving but not limited to meninges, occur in most Erdheim-Chester disease and Rosai-Dorfman disease patients. Vascular involvement occurs only in Erdheim-Chester disease patients.
KEY POINTS
• The different distribution patterns of brain tumorous lesions can help differentiate among LCH, ECD, and RDD. • Vascular involvement was an exclusive imaging finding of ECD and was associated with high mortality. • Some cases with atypical imaging manifestations were reported to further expand the knowledge on these diseases.
Topics: Humans; Adult; Erdheim-Chester Disease; Retrospective Studies; Histiocytosis, Sinus; Histiocytosis, Langerhans-Cell; Neuroimaging; Brain; Hematologic Neoplasms; Edema
PubMed: 37191919
DOI: 10.1007/s00330-023-09724-8 -
Journal of Cranio-maxillo-facial... Jun 2024The orbital cavity is a subject of interest for various specialists, and achieving optimal outcomes requires comprehensive, multidisciplinary management. This study aims...
The orbital cavity is a subject of interest for various specialists, and achieving optimal outcomes requires comprehensive, multidisciplinary management. This study aims to report 10 years of experience in the preoperative, surgical, and postoperative care of patients with orbital lesions, examining their clinical, radiological, and anatomopathological features and outcomes. A retrospective review of 125 patients who underwent surgical treatment for intraorbital masses between January 2012 and December 2021 was performed. Outcome measures included postoperative diplopia, exophthalmos, decimal visual acuity, eyeball position, ocular motility, operative time, complications, and aesthetic results. A total of 107 patients were included. All cases were discussed with a neuroradiologist to determine the best therapeutic approach based on preoperative imaging. Preoperative diplopia was linked to extraconal (p = 0.03) and anterior (p = 0.001) lesions, and exophthalmos and visual acuity deterioration were associated with intraconal (p = 0.02; p = 0.03) and retrobulbar (p = 0.001; p = 0.02) lesions. Complications (11.2%) included diplopia, worsened visual acuity, postoperative blepharoptosis, and postoperative ectropion. Of the patients, 80.4% reported an "excellent" aesthetic outcome. This study underscores the importance of a multidisciplinary approach based on a thorough analysis of preoperative imaging. Periorbital approaches tailored to the lesion's three-dimensional location enables safe access to most intraorbital lesions, resulting in minimal complications and good aesthetic results.
PubMed: 38876957
DOI: 10.1016/j.jcms.2024.06.019 -
Current Eye Research Dec 2023The purpose of this study was to develop artificial intelligence algorithms that can distinguish between orbital and conjunctival mucosa-associated lymphoid tissue...
Machine Learning Model with Texture Analysis for Automatic Classification of Histopathological Images of Ocular Adnexal Mucosa-associated Lymphoid Tissue Lymphoma of Two Different Origins.
PURPOSE
The purpose of this study was to develop artificial intelligence algorithms that can distinguish between orbital and conjunctival mucosa-associated lymphoid tissue (MALT) lymphomas in pathological images.
METHODS
Tissue blocks with residual MALT lymphoma and data from histological and flow cytometric studies and molecular genetic analyses such as gene rearrangement were procured for 129 patients treated between April 2008 and April 2020. We collected pathological hematoxylin and eosin-stained (HE) images of lymphoma from these patients and cropped 10 different image patches at a resolution of 2048 × 2048 from pathological images from each patient. A total of 990 images from 99 patients were used to create and evaluate machine-learning models. Each image patch of three different magnification rates at ×4, ×20, and ×40 underwent texture analysis to extract features, and then seven different machine-learning algorithms were applied to the results to create models. Cross-validation on a patient-by-patient basis was used to create and evaluate models, and then 300 images from the remaining 30 cases were used to evaluate the average accuracy rate.
RESULTS
Ten-fold cross-validation using the support vector machine with linear kernel algorithm was identified as the best algorithm for discriminating between conjunctival mucosa-associated lymphoid tissue and orbital MALT lymphomas, with an average accuracy rate under cross-validation of 85%. There were ×20 magnification HE images that were more accurate in distinguishing orbital and conjunctival MALT lymphomas among ×4, ×20, and ×40.
CONCLUSION
Artificial intelligence algorithms can successfully distinguish HE images between orbital and conjunctival MALT lymphomas.
Topics: Humans; Lymphoma, B-Cell, Marginal Zone; Artificial Intelligence; Eye Neoplasms; Conjunctival Neoplasms; Machine Learning
PubMed: 37566457
DOI: 10.1080/02713683.2023.2246696 -
The American Journal of Case Reports Dec 2023BACKGROUND Although screening for uterine cervical cancer (UCC) and vaccination programs for human papilloma virus (HPV) have been implemented in many countries, women...
BACKGROUND Although screening for uterine cervical cancer (UCC) and vaccination programs for human papilloma virus (HPV) have been implemented in many countries, women >65 years may not have access to or comply with cervical cancer screening. Women >65 years may present with advanced-stage cervical carcinoma with a poor outcome. Metastatic UCC is often diagnosed, and there are 2 types of metastases related to different treatments and survival rate: hematogenous metastasis and lymphatic metastasis. Hematogenous metastasis is relatively unusual, and it most commonly involves lung and bone locations. Orbital metastasis is an extremely rare hematogenous metastasis in patients with UCC. CASE REPORT A 70-year-old woman receiving dialysis presented to a local hospital due to general fatigue for 5 months. She was diagnosed with locally advanced UCC and underwent radiation therapy (RT). Twenty days after RT, skin masses appeared, and 34 days after RT, right exophthalmos induced by an orbital mass appeared. We diagnosed skin and orbital masses as metastases from UCC, and performed RT to the orbital tumor. The tumor shrank and the visual symptoms disappeared. Regrettably, the patient died of cancer 7 months after the orbital RT; however, no eye symptoms recurred until her death. CONCLUSIONS This report describes a rare presentation of UCC with metastasis to the orbit, and highlights that cervical cancer may still present at an advanced stage, particularly in older women. In this case, RT to the orbital metastasis from UCC was effective and contributed to the patient's quality of life.
Topics: Aged; Female; Humans; Early Detection of Cancer; Neoplasm Recurrence, Local; Orbital Neoplasms; Quality of Life; Renal Dialysis; Uterine Cervical Neoplasms; Neoplasm Metastasis
PubMed: 38096131
DOI: 10.12659/AJCR.941076 -
Journal of Clinical Medicine Sep 2023The purpose of this study was to assess the overall survival (OS) and disease-free survival (DFS) of patients who underwent orbital exenteration for periorbital,...
INTRODUCTION
The purpose of this study was to assess the overall survival (OS) and disease-free survival (DFS) of patients who underwent orbital exenteration for periorbital, conjunctival, and primary intraorbital carcinomas. Additionally, we assessed the outcomes of anterior retrograde temporalis muscle flap restoration.
METHODS
For all patients who had orbital exenteration in the previous five years, a non-comparative retrospective assessment of their medical records, histology, and radiographic imaging was carried out. We investigated the relationships between the various qualitative factors using Cramer's V Kaplan-Meier (KM) analysis. For each of the patient's categorical factors that were of relevance, estimates of the survival distribution were displayed, and log-rank tests were used to determine whether the survival distributions were equal.
RESULTS
This study looks at 19 participants. The sample is made up of 13 men (68%) and 6 women (32%). The degree of relationship (Cramer's V index) between lymph node metastases (N) and the existence of distant metastases (M) is high, at 64%, and is statistically significant because the -value is 0.0034 < 0.005. Lymph node metastases had a statistically significant impact on overall survival ( = 0.04 < 0.05). Thirteen of the nineteen patients tested had no palsy (68%). There was no one presenting a CSF leak.
CONCLUSION
Our findings show how crucial it is to identify any lymph node involvement that orbital neoplasms may have. In patients who have received many treatments, sentinel lymph node biopsy (SLNB) may be used to determine the stage and spread of the cancer. To determine whether additional tumor characteristics may be explored, more expertise in the SLNB field for patients with orbital cancer who have received many treatments may be helpful. To prevent additional scarring and to be comparable to previous techniques for facial nerve lesions, the anterior retrograde approach and the transorbital procedure for temporal muscle flap in-setting are both effective methods.
PubMed: 37834824
DOI: 10.3390/jcm12196180 -
Asia-Pacific Journal of Ophthalmology... 2024
Topics: Humans; Orbital Neoplasms; Eye Neoplasms
PubMed: 38621648
DOI: 10.1016/j.apjo.2024.100059 -
Seminars in Ophthalmology Jul 2024To examine whether children treated for Retinoblastoma (Rb) have impaired orbital development.
PURPOSE
To examine whether children treated for Retinoblastoma (Rb) have impaired orbital development.
METHODS
A retrospective case series was performed among children with Rb treated at a single medical center from 2004 to 2020. Orbital volumes and measurements were assessed by 3-dimensional image processing software. The main outcome measures were differences in orbital growth between Rb and non-Rb eyes assessed at last follow-up.
RESULTS
Among 44 patients included (mean age 16.09 ± 18.01 months), a positive correlation between age and orbital volume was observed only in the uninvolved, healthy eyes ( = .03). In unilateral cases, orbital growth in the horizontal, vertical, and depth planes was smaller on the affected side compared to the healthy eyes ( < .05). Orbits that underwent enucleation showed decreased growth over time compared to those treated conservatively ( = .017).
CONCLUSIONS
Orbital growth rate is slower in the orbits of children treated for Rb compared to healthy orbits. Enucleation negatively affects orbital growth.
Topics: Humans; Retinoblastoma; Retrospective Studies; Male; Female; Retinal Neoplasms; Orbit; Infant; Child, Preschool; Tomography, X-Ray Computed; Eye Enucleation; Imaging, Three-Dimensional; Follow-Up Studies; Magnetic Resonance Imaging
PubMed: 38329101
DOI: 10.1080/08820538.2024.2312968 -
Indian Journal of Ophthalmology Jul 2024This study aimed to determine the clinical indications for orbital exenteration, demographic profile of these patients, and clinicopathologic correlations in the current...
PURPOSE
This study aimed to determine the clinical indications for orbital exenteration, demographic profile of these patients, and clinicopathologic correlations in the current times and to compare these results with previous published data.
METHODS
It was a retrospective study. All exenterations performed at a tertiary eye care center over a period of 20 years (from January 2001 to June 2020) were retrospectively evaluated. Patient records were reviewed to obtain demographic data, presenting symptoms and their duration, laterality, and clinical and histopathologic diagnosis.
RESULTS
A total of 352 cases (males:females = 222:130) who underwent exenteration were identified. Patients age ranged from 11 months to 87 years (mean: 43.86 years, median: 50 years). The most common indication for exenteration was found to be eyelid malignancy in 54.36%, followed by retinoblastoma in 18.75% and primary orbital tumors in 14.49%. Out of 156 cases of eyelid malignancies requiring exenteration, squamous cell carcinoma (SCC) was the most common histologic subtype ( n = 94, 60.26%), followed by sebaceous gland carcinoma ( n = 40, 25.64%) and basal cell carcinoma ( n = 20, 12.82%). The most common primary orbital tumors requiring exenteration were adenocystic carcinoma of the lacrimal gland in adults and rhabdomyosarcoma in the pediatric age group. Benign conditions requiring exenteration included fulminant fungal orbital infections and lymphangioma among others.
CONCLUSION
The number of exenterations performed have significantly increased in terms of absolute numbers. However, the ratio of exenteration to other tumor-related surgeries, mainly excision biopsy, has reduced compared to that reported from a previous study. The most common indication in our study remains eyelid malignancy followed by intraocular malignancy. However, SCC has emerged as the most common tumor histologic subtype requiring exenterations.
Topics: Humans; Retrospective Studies; Male; Female; Child; Middle Aged; Orbit Evisceration; Infant; Child, Preschool; Adult; Adolescent; Tertiary Care Centers; Aged; Aged, 80 and over; Young Adult; Orbital Neoplasms; Follow-Up Studies; Incidence
PubMed: 38454866
DOI: 10.4103/IJO.IJO_2716_23 -
Neoplasia (New York, N.Y.) Mar 2024F-box only protein 38 (FBXO38) is a member of the F-box family that mediates the ubiquitination and proteasome degradation of programmed death 1 (PD-1), and thus has...
F-box only protein 38 (FBXO38) is a member of the F-box family that mediates the ubiquitination and proteasome degradation of programmed death 1 (PD-1), and thus has important effects on T cell-related immunity. While its powerful role in adaptive immunity has attracted much attention, its regulatory roles in innate immune pathways remain unknown. The cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway is an important innate immune pathway that regulates type I interferons. STING protein is the core component of this pathway. In this study, we identified that FBXO38 deficiency enhanced tumor proliferation and reduced tumor CD8 T cells infiltration. Loss of FBXO38 resulted in reduced STING protein levels in vitro and in vivo, further leading to preventing cGAS-STING pathway activation, and decreased downstream product IFNA1 and CCL5. The mechanism of reduced STING protein was associated with lysosome-mediated degradation rather than proteasomal function. Our results demonstrate a critical role for FBXO38 in the cGAS-STING pathway.
Topics: Humans; Signal Transduction; CD8-Positive T-Lymphocytes; Nucleotidyltransferases; Neoplasms; Lysosomes; Immunity, Innate
PubMed: 38277817
DOI: 10.1016/j.neo.2024.100973