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Cancers May 2024This retrospective multicenter study examines therapy-induced orbital and ocular MRI findings in retinoblastoma patients following selective intra-arterial chemotherapy...
This retrospective multicenter study examines therapy-induced orbital and ocular MRI findings in retinoblastoma patients following selective intra-arterial chemotherapy (SIAC) and quantifies the impact of SIAC on ocular and optic nerve growth. Patients were selected based on medical chart review, with inclusion criteria requiring the availability of posttreatment MR imaging encompassing T2-weighted and T1-weighted images (pre- and post-intravenous gadolinium administration). Qualitative features and quantitative measurements were independently scored by experienced radiologists, with deep learning segmentation aiding total eye volume assessment. Eyes were categorized into three groups: eyes receiving SIAC (Rb-SIAC), eyes treated with other eye-saving methods (Rb-control), and healthy eyes. The most prevalent adverse effects post-SIAC were inflammatory and vascular features, with therapy-induced contrast enhancement observed in the intraorbital optic nerve segment in 6% of patients. Quantitative analysis revealed significant growth arrest in Rb-SIAC eyes, particularly when treatment commenced ≤ 12 months of age. Optic nerve atrophy was a significant complication in Rb-SIAC eyes. In conclusion, this study highlights the vascular and inflammatory adverse effects observed post-SIAC in retinoblastoma patients and demonstrates a negative impact on eye and optic nerve growth, particularly in children treated ≤ 12 months of age, providing crucial insights for clinical management and future research.
PubMed: 38791976
DOI: 10.3390/cancers16101899 -
Cancers May 2024French Guiana is a French territory in South America. The exposome of persons living there is quite different from that in mainland France and the ethnic make-up of the...
French Guiana is a French territory in South America. The exposome of persons living there is quite different from that in mainland France and the ethnic make-up of the population is also quite different. Poverty is also widespread with difficulties in accessing care magnified by the low medical-professional density. In this singular context, we aimed to measure the incidence of pediatric cancers and to compare it with other continents. We used French Guiana's certified cancer registry to study this between 2003 and 2017. Incidences were standardized using the world population with three strata: 0-4 years, 5-9 years, and 10-14 years. There were 164 solid tumors or hematologic malignancies diagnosed in children under the age of 15 (92 in boys and 72 in girls). Over the study period, the standardized incidence rate was 14.1 per 100,000 among children aged under 15 years. There was no significant trend during the study period. The three most common causes of cancer were leukemias-mostly lymphoblastic-CNS tumors, and sarcoma. The standardized incidence of pediatric cancers in French Guiana was similar to those in Western Europe and North America. As others have discovered, we found that males tended to be more likely to develop cancer, notably leukemia, CNS tumors, sarcoma, and retinoblastoma. As elsewhere, the predominant cancer types changed with age. Our initial assumption was that given the singular context of French Guiana, there may have been differences in pediatric cancer incidences. Here we showed that overall, contrary to our assumption and to trends in tropical countries, the incidence of pediatric cancers was in a range between Western Europe and North America with some apparent but non-significant differences in the main types of cancers observed in global statistics. Quality cancer registry data in this tropical region confirm the suspicion that lower incidences in tropical low- and middle-income countries are likely to result from incomplete diagnosis and data collection.
PubMed: 38791908
DOI: 10.3390/cancers16101829 -
Nature Communications May 2024Histone deacetylases (HDACs) play a crucial role in transcriptional regulation and are implicated in various diseases, including cancer. They are involved in histone...
Histone deacetylases (HDACs) play a crucial role in transcriptional regulation and are implicated in various diseases, including cancer. They are involved in histone tail deacetylation and canonically linked to transcriptional repression. Previous studies suggested that HDAC recruitment to cell-cycle gene promoters via the retinoblastoma (RB) protein or the DREAM complex through SIN3B is essential for G1/S and G2/M gene repression during cell-cycle arrest and exit. Here we investigate the interplay among DREAM, RB, SIN3 proteins, and HDACs in the context of cell-cycle gene repression. Knockout of SIN3B does not globally derepress cell-cycle genes in non-proliferating HCT116 and C2C12 cells. Loss of SIN3A/B moderately upregulates several cell-cycle genes in HCT116 cells but does so independently of DREAM/RB. HDAC inhibition does not induce general upregulation of RB/DREAM target genes in arrested transformed or non-transformed cells. Our findings suggest that E2F:RB and DREAM complexes can repress cell-cycle genes without relying on HDAC activity.
Topics: Humans; Histone Deacetylases; HCT116 Cells; Repressor Proteins; E2F Transcription Factors; Retinoblastoma Protein; Mice; Animals; Sin3 Histone Deacetylase and Corepressor Complex; Kv Channel-Interacting Proteins; Cell Cycle; Promoter Regions, Genetic; Gene Expression Regulation; Genes, cdc
PubMed: 38789411
DOI: 10.1038/s41467-024-48724-0 -
Asia-Pacific Journal of Ophthalmology... 2024Retinoblastoma (RB), originating from the developing retina, is an aggressive intraocular malignant neoplasm in childhood. Biallelic loss of RB1 is conventionally... (Review)
Review
Retinoblastoma (RB), originating from the developing retina, is an aggressive intraocular malignant neoplasm in childhood. Biallelic loss of RB1 is conventionally considered a prerequisite for initiating RB development in most RB cases. Additional genetic mutations arising from genome instability following RB1 mutations are proposed to be required to promote RB development. Recent advancements in high throughput sequencing technologies allow a deeper and more comprehensive understanding of the etiology of RB that additional genetic alterations following RB1 biallelic loss are rare, yet epigenetic changes driven by RB1 loss emerge as a critical contributor promoting RB tumorigenesis. Multiple epigenetic regulators have been found to be dysregulated and to contribute to RB development, including noncoding RNAs, DNA methylations, RNA modifications, chromatin conformations, and histone modifications. A full understanding of the roles of genetic and epigenetic alterations in RB formation is crucial in facilitating the translation of these findings into effective treatment strategies for RB. In this review, we summarize current knowledge concerning genetic defects and epigenetic dysregulations in RB, aiming to help understand their links and roles in RB tumorigenesis.
Topics: Retinoblastoma; Humans; Retinal Neoplasms; Epigenesis, Genetic; Mutation; DNA Methylation; Retinoblastoma Binding Proteins; Ubiquitin-Protein Ligases
PubMed: 38789041
DOI: 10.1016/j.apjo.2024.100072 -
Science Advances May 2024Resistance to therapy commonly develops in patients with high-grade serous ovarian carcinoma (HGSC) and triple-negative breast cancer (TNBC), urging the search for...
Resistance to therapy commonly develops in patients with high-grade serous ovarian carcinoma (HGSC) and triple-negative breast cancer (TNBC), urging the search for improved therapeutic combinations and their predictive biomarkers. Starting from a CRISPR knockout screen, we identified that loss of RB1 in TNBC or HGSC cells generates a synthetic lethal dependency on casein kinase 2 (CK2) for surviving the treatment with replication-perturbing therapeutics such as carboplatin, gemcitabine, or PARP inhibitors. CK2 inhibition in RB1-deficient cells resulted in the degradation of another RB family cell cycle regulator, p130, which led to S phase accumulation, micronuclei formation, and accelerated PARP inhibition-induced aneuploidy and mitotic cell death. CK2 inhibition was also effective in primary patient-derived cells. It selectively prevented the regrowth of RB1-deficient patient HGSC organoids after treatment with carboplatin or niraparib. As about 25% of HGSCs and 40% of TNBCs have lost RB1 expression, CK2 inhibition is a promising approach to overcome resistance to standard therapeutics in large strata of patients.
Topics: Humans; Casein Kinase II; Retinoblastoma Binding Proteins; Female; Cell Line, Tumor; Triple Negative Breast Neoplasms; Ovarian Neoplasms; Ubiquitin-Protein Ligases; Carboplatin; Synthetic Lethal Mutations; DNA Replication; Drug Resistance, Neoplasm; Poly(ADP-ribose) Polymerase Inhibitors; Antineoplastic Agents
PubMed: 38781347
DOI: 10.1126/sciadv.adj1564 -
International Journal of Molecular... Jul 2024Following the publication of the above paper, it has been drawn to the Editors' attention by a concerned reader that certain of the lumen formation assay data shown in...
Following the publication of the above paper, it has been drawn to the Editors' attention by a concerned reader that certain of the lumen formation assay data shown in Fig. 5A on p. 112 were strikingly similar to data appearing in different form in another article written by different authors at different research institute, which had already been published in the journal prior to the submission of this paper to , and which has also subsequently been retracted. In view of the fact that the contentious data had already apparently been published previously, the Editor of has decided that this paper should be retracted from the Journal. After having been in contact with the authors, they agreed with the decision to retract the paper. The Editor apologizes to the readership for any inconvenience caused. [International Journal of Molecular Medicine 44: 103‑114, 2019; DOI: 10.3892/ijmm.2019.4183].
PubMed: 38757359
DOI: 10.3892/ijmm.2024.5382 -
Ocular Oncology and Pathology Apr 2024Retinoblastoma, although rare, is one of the most common intraocular malignancies worldwide. Its prognosis has improved significantly in the past few decades, thanks to... (Review)
Review
BACKGROUND
Retinoblastoma, although rare, is one of the most common intraocular malignancies worldwide. Its prognosis has improved significantly in the past few decades, thanks to modern treatments, like systemic, intra-arterial, and intravitreal chemotherapy. However, regarding survival, there are significant differences between high- and low-income countries, eye salvage is still a challenge worldwide, and treatment-related toxicity needs to be carefully and sufficiently managed.
SUMMARY
To appraise the strength of supporting evidence, we performed a systematic review of randomized controlled trials investigating any therapeutic protocol for retinoblastoma. Four trials with 174 participants (188 eyes) were eligible, all pertaining to different intravenous chemotherapy regimens. Vincristine, etoposide, and carboplatin (VEC) appear superior to a 5-drug combination for stage III retinoblastoma. Moreover, etoposide and carboplatin as neoadjuvant chemotherapy followed by thermochemotherapy seem to offer better local control than vincristine and carboplatin. However, increasing carboplatin dose in the VEC protocol failed to improve treatment efficacy.
KEY MESSAGES
Retinoblastoma is a success story of modern medicine. However, only intravenous chemotherapy has been studied through randomized trials, while evidence for the most novel retinoblastoma treatments has mainly stemmed from observational studies. International collaborations for multicenter randomized trials could overcome difficulties and increase certainty and precision in the field.
PubMed: 38751498
DOI: 10.1159/000536410 -
Ocular Oncology and Pathology Apr 2024The objective of this study was to report the clinicopathologic features of three cases of -amplified retinoblastoma identified genetically by aqueous humor sampling.
INTRODUCTION
The objective of this study was to report the clinicopathologic features of three cases of -amplified retinoblastoma identified genetically by aqueous humor sampling.
METHODS
Whole-genome sequencing was performed using isolated cell-free DNA (cfDNA) from aqueous humor of 3 retinoblastoma patients. We analyzed genomic copy number and mutational alterations, histologic and pathologic features, and clinical data.
RESULTS
The most common genetic alteration identified in these three retinoblastoma cases was a focal amplification on 2p. All tumors showed an early age of diagnosis with a median of 9 months. The tumor histopathologic features included neovascularization and subretinal seeding in case 1, diffuse nature with choroidal and prelaminar optic nerve invasion in case 2, and complete vitreous seeding in case 3. Case 1 expressed RB protein and had no mutation, case 2 did not express RB protein and had an mutation, and case 3 did not express RB protein and likely had an epigenetic effect on RB expression.
CONCLUSIONS
Our report shows 3 cases of unilateral retinoblastomas diagnosed in patients ranging from 4 months to 18 months old. Genomic analysis from AH cfDNA revealed amplification with intact RB protein staining in case 1 and lack of RB staining in cases 2 and 3. mutational analysis in the AH confirmed a pathogenic variant in case 2. Clinical pathology showed features requiring aggressive treatment, specifically enucleation.
IMPORTANCE
-amplified retinoblastomas demonstrate unique pathogenesis and aggressive behavior, regardless if is a primary or secondary driver of disease. Genomic analysis from aqueous humor may be useful when deciding to enucleate as opposed to treating conservatively. Focal amplification on 2p might be relevant for tumor growth in this subset of the retinoblastoma population in terms of targeted therapeutics.
PubMed: 38751495
DOI: 10.1159/000533311 -
MedRxiv : the Preprint Server For... May 2024Retinoblastoma (RB) proteins are highly conserved transcriptional regulators that play important roles during development by regulating cell-cycle gene expression. RBL2...
Retinoblastoma (RB) proteins are highly conserved transcriptional regulators that play important roles during development by regulating cell-cycle gene expression. RBL2 dysfunction has been linked to a severe neurodevelopmental disorder. However, to date, clinical features have only been described in six individuals carrying five biallelic predicted loss of function (pLOF) variants. To define the phenotypic effects of mutations in detail, we identified and clinically characterized a cohort of 28 patients from 18 families carrying LOF variants in , including fourteen new variants that substantially broaden the molecular spectrum. The clinical presentation of affected individuals is characterized by a range of neurological and developmental abnormalities. Global developmental delay and intellectual disability were uniformly observed, ranging from moderate to profound and involving lack of acquisition of key motor and speech milestones in most patients. Frequent features included postnatal microcephaly, infantile hypotonia, aggressive behaviour, stereotypic movements and non-specific dysmorphic features. Common neuroimaging features were cerebral atrophy, white matter volume loss, corpus callosum hypoplasia and cerebellar atrophy. In parallel, we used the fruit fly, , to investigate how disruption of the conserved RBL2 orthologueue Rbf impacts nervous system function and development. We found that LOF mutants recapitulate several features of patients harboring variants, including alterations in the head and brain morphology reminiscent of microcephaly, and perturbed locomotor behaviour. Surprisingly, in addition to its known role in controlling tissue growth during development, we find that continued expression is also required in fully differentiated post-mitotic neurons for normal locomotion in , and that adult-stage neuronal re-expression of is sufficient to rescue mutant locomotor defects. Taken together, this study provides a clinical and experimental basis to understand genotype-phenotype correlations in an -linked neurodevelopmental disorder and suggests that restoring expression through gene therapy approaches may ameliorate aspects of LOF patient symptoms.
PubMed: 38746364
DOI: 10.1101/2024.05.03.24306631 -
Scientific Reports May 2024Osteosarcoma is the most common malignant bone cancer in pediatric patients. Patients who respond poorly to chemotherapy experience worse clinical outcomes with a high...
Osteosarcoma is the most common malignant bone cancer in pediatric patients. Patients who respond poorly to chemotherapy experience worse clinical outcomes with a high mortality rate. The major challenge is the lack of effective drugs for these patients. To introduce new drugs for clinical approval, preclinical studies based on in vitro models must demonstrate the potency of the tested drugs, enabling the drugs to enter phase 1 clinical trials. Patient-derived cell culture is a promising testing platform for in vitro studies, as they more accurately recapitulate cancer states and genetic profiles compared to cell lines. In the present study, we established patient-derived osteosarcoma cells (PDC) from a patient who had previously been diagnosed with retinoblastoma. We identified a new variant of a germline mutation in the RB1 gene in the tissue of the patient. The biological effects of this PDC were studied to observe whether the cryopreserved PDC retained a feature of fresh PDC. The cryopreserved PDC preserved the key biological effects, including cell growth, invasive capability, migration, and mineralization, that define the conserved phenotypes compared to fresh PDC. From whole genome sequencing analysis of osteosarcoma tissue and patient-derived cells, we found that cryopreserved PDC was a minor population in the origin tissue and was selectively grown under the culture conditions. The cryopreserved PDC has a high resistance to conventional chemotherapy. This study demonstrated that the established cryopreserved PDC has the aggressive characteristics of osteosarcoma, in particular the chemoresistance phenotype that might be used for further investigation in the chemoresistant mechanism of osteosarcoma. In conclusion, the approach we applied for primary cell culture might be a promising method to generate in vitro models for functional testing of osteosarcoma.
Topics: Humans; Osteosarcoma; Retinoblastoma; Bone Neoplasms; Cell Line, Tumor; Retinoblastoma Binding Proteins; Cell Proliferation; Germ-Line Mutation; Cryopreservation; Male; Gene Expression Profiling; Cell Movement
PubMed: 38744935
DOI: 10.1038/s41598-024-60628-z