-
Pathology, Research and Practice Aug 2023Amplification of the epidermal growth factor receptor gene (EGFR) and its variants are the most commonly detected pathogenic gene alterations in glioblastoma. Herein, we...
Amplification of the epidermal growth factor receptor gene (EGFR) and its variants are the most commonly detected pathogenic gene alterations in glioblastoma. Herein, we report a case of molecularly defined glioblastoma harboring an EGFR variant III (EGFRvIII) without EGFR amplification. The initial histological diagnosis was isocitrate dehydrogenase (IDH)-wildtype low-grade glioma, due to an absence of anaplasia, necrosis, and microvascular proliferation, and a low Ki-67 labeling index. DNA-based next-generation sequencing (NGS) panel analysis revealed a TERTp promoter mutation but no EGFR mutation or amplification, supporting the diagnosis of "molecular glioblastoma." However, RNA-based NGS panel analysis revealed mRNA expression of EGFRvIII. Therefore, the final integrative diagnosis was glioblastoma with non-amplified EGFRvIII. Our report suggests that non-amplified EGFRvIII might be an early molecular event in glioblastoma tumorigenesis. In addition to the usual DNA-based analysis, RNA-based analysis is required to identify exon-skipping EGFR variants without EGFR amplification.
Topics: Humans; Glioblastoma; Brain Neoplasms; Glioma; Mutation; ErbB Receptors
PubMed: 37499520
DOI: 10.1016/j.prp.2023.154712 -
Journal of Neuro-oncology Aug 2023Chemotherapy is commonly used for treatment in children over three years old with high-risk medulloblastoma(MB). However, little is currently known about the therapeutic...
PURPOSE
Chemotherapy is commonly used for treatment in children over three years old with high-risk medulloblastoma(MB). However, little is currently known about the therapeutic benefits and side effects of intrathecal methotrexate(MTX), warranting further research.
METHODS
In this retrospective study, patients who received intrathecal MTX during chemotherapy were included in the MTX group (n = 32), and patients that only underwent cerebrospinal fluid (CSF) cytology analysis were assigned to the control group (n = 14).
RESULTS
In the MTX group, 27(84.38%) patients had metastatic disease, 3(9.38%) had diffuse anaplasia, and 3(9.38%) had residual disease greater than 1.5 cm. Molecular subgroup classification was available for 28(87.5%) patients. In the control group, 8(57.14%) patients had metastatic disease, 3(27.27%) had diffuse anaplasia, and 6(42.86%) had residual disease greater than 1.5 cm. Molecular subgroup classification was available for 6(42.86%) patients. The 5-year progression-free survival was 70.99% and the 5-year overall survival was 72.99% for the MTX group, and the corresponding values were 41.67% and 50% for the control group, respectively. 6 (18.75%) patients in the MTX group with group 4 disease developed MTX-related acute leukoencephalopathy and one of them died.
CONCLUSIONS
Our findings support the addition of intrathecal MTX during chemotherapy as the optimal management for children with group 3 and SHH high-risk MB. However, it is not recommended for group 4 MB patients, especially in resource-limited regions.
TRIAL REGISTRATION NUMBER
Retrospective registered No.(2020 - 117).
Topics: Child; Humans; Child, Preschool; Methotrexate; Medulloblastoma; Retrospective Studies; Anaplasia; Antineoplastic Combined Chemotherapy Protocols; Cerebellar Neoplasms
PubMed: 37474745
DOI: 10.1007/s11060-023-04388-2 -
Frontiers in Oncology 2023Treatment of children with medulloblastoma (MB) includes surgery, radiation therapy (RT) and chemotherapy (CT). Several treatment protocols and clinical trials have been...
INTRODUCTION
Treatment of children with medulloblastoma (MB) includes surgery, radiation therapy (RT) and chemotherapy (CT). Several treatment protocols and clinical trials have been developed over the time to maximize survival and minimize side effects.
METHODS
We performed a systematic literature search in May 2023 using PubMed. We selected all clinical trials articles and multicenter studies focusing on MB. We excluded studies focusing exclusively on infants, adults, supratentorial PNETs or refractory/relapsed tumors, studies involving different tumors or different types of PNETs without differentiating survival, studies including <10 cases of MB, solely retrospective studies and those without reference to outcome and/or side effects after a defined treatment.
RESULTS
1. The main poor-prognosis factors are: metastatic disease, anaplasia, MYC amplification, age younger than 36 months and some molecular subgroups. The postoperative residual tumor size is controversial.2. MB is a collection of diseases.3. MB is a curable disease at diagnosis, but survival is scarce upon relapse.4. Children should be treated by experienced neurosurgeons and in advanced centers.5. RT is an essential treatment for MB. It should be administered craniospinal, early and without interruptions.6. Craniospinal RT dose could be lowered in some low-risk patients, but these reductions should be done with caution to avoid relapses.7. Irradiation of the tumor area instead of the entire posterior fossa is safe enough.8. Hyperfractionated RT is not superior to conventional RT9. Both photon and proton RT are effective.10. CT increases survival, especially in high-risk patients.11. There are multiple drugs effective in MB. The combination of different drugs is appropriate management.12. CT should be administered after RT.13. The specific benefit of concomitant CT to RT is unknown.14. Intensified CT with stem cell rescue has no benefit compared to standard CT regimens.15. The efficacy of intraventricular/intrathecal CT is controversial.16. We should start to think about incorporating targeted therapies in front-line treatment.17. Survivors of MB still have significant side effects.
CONCLUSION
Survival rates of MB improved greatly from 1940-1970, but since then the improvement has been smaller. We should consider introducing targeted therapy as front-line therapy.
PubMed: 37456257
DOI: 10.3389/fonc.2023.1229853 -
Annals of Medicine and Surgery (2012) Jul 2023The most common malignant tumors of the uterus are endometrioid adenocarcinomas (EA). Their prognosis depends on the qualitative characteristics of the neoplastic cells...
UNLABELLED
The most common malignant tumors of the uterus are endometrioid adenocarcinomas (EA). Their prognosis depends on the qualitative characteristics of the neoplastic cells and their stroma. The neovascularization of EA tissues and level of microvascular density (MVD) influence tumor progression. Our study aims to establish the relationship between MVD in EA tissue and the histological and immunohistochemical features of tumors.
MATERIALS AND METHODS
The authors studied 30 cases of endometrial ЕА and compared their histological and immunohistochemical characteristics with the MVD of tumor tissues.
RESULTS
Our study indicated that MVD in EA tissue depends on the grade of the tumors and their FIGO stage. Increased MVD was correlated with a depression of E-cadherin and PR expression and enhanced expression of VEGF and Ki-67. MVD enhancement during VEGF overexpression is a manifestation of the functional activity of these proteins. The increase in MVD was accompanied by more frequent metastasis of the EA to the lymph nodes.
CONCLUSION
EA progression is accompanied by qualitative and quantitative variations of parenchymal and stromal patterns of tumors. Dedifferentiation of EA leads to overexpression of VEGF, which becomes diffuse in tumors cells, resulting in an increase of adenocarcinomas' MVD and their metastatic potential. Correlations between histological and immunohistochemical features of EAs indicate the synchronicity of the occurrence and progression of morphological and immunological anaplasia, which can be used in predicting the course of the disease.
PubMed: 37427185
DOI: 10.1097/MS9.0000000000000939 -
Pediatric Blood & Cancer May 2023Rhabdomyosarcoma (RMS) is a well-described cancer in Li-Fraumeni syndrome, resulting from germline TP53 pathogenic variants (PVs). RMS exhibiting anaplasia (anRMS) are...
Rhabdomyosarcoma (RMS) is a well-described cancer in Li-Fraumeni syndrome, resulting from germline TP53 pathogenic variants (PVs). RMS exhibiting anaplasia (anRMS) are associated with a high rate of germline TP53 PVs. This study provides updated estimates of the prevalence of TP53 germline PVs in RMS (3%) and anRMS (11%) from a large cohort (n = 239) enrolled in five Children's Oncology Group (COG) clinical trials. Although the prevalence of germline TP53 PVs in patients with anRMS in this series is much lower than previously reported, this prevalence remains elevated. Germline evaluation for TP53 PVs should be strongly considered in patients with anRMS.
PubMed: 37194615
DOI: 10.1002/pbc.30413 -
Clinical Cancer Research : An Official... Jul 2023While patients with intermediate-risk (IR) Wilms tumors now have an overall survival (OS) rate of almost 90%, those affected by high-stage tumors with diffuse anaplasia...
PURPOSE
While patients with intermediate-risk (IR) Wilms tumors now have an overall survival (OS) rate of almost 90%, those affected by high-stage tumors with diffuse anaplasia have an OS of only around 50%. We here identify key events in the pathogenesis of diffuse anaplasia by mapping cancer cell evolution over anatomic space in Wilms tumors.
EXPERIMENTAL DESIGN
We spatially mapped subclonal landscapes in a retrospective cohort of 20 Wilms tumors using high-resolution copy-number profiling and TP53 mutation analysis followed by clonal deconvolution and phylogenetic reconstruction. Tumor whole-mount sections (WMS) were utilized to characterize the distribution of subclones across anatomically distinct tumor compartments.
RESULTS
Compared with non-diffuse anaplasia Wilms tumors, tumors with diffuse anaplasia showed a significantly higher number of genetically distinct tumor cell subpopulations and more complex phylogenetic trees, including high levels of phylogenetic species richness, divergence, and irregularity. All regions with classical anaplasia showed TP53 alterations. TP53 mutations were frequently followed by saltatory evolution and parallel loss of the remaining wild-type (WT) allele in different regions. Morphologic features of anaplasia increased with copy-number aberration (CNA) burden and regressive features. Compartments demarcated by fibrous septae or necrosis/regression were frequently (73%) associated with the emergence of new clonal CNAs, although clonal sweeps were rare within these compartments.
CONCLUSIONS
Wilms tumors with diffuse anaplasia display significantly more complex phylogenies compared with non-diffuse anaplasia Wilms tumors, including features of saltatory and parallel evolution. The subclonal landscape of individual tumors was constrained by anatomic compartments, which should be considered when sampling tissue for precision diagnostics.
Topics: Humans; Kidney Neoplasms; Anaplasia; Retrospective Studies; Phylogeny; Wilms Tumor
PubMed: 37140929
DOI: 10.1158/1078-0432.CCR-23-0311 -
Journal of Neuro-oncology Apr 2023Data on differences in overall survival and molecular characteristics between incidental (iLGG) and symptomatic lower grade Glioma (sLGG) are limited. The aim of this...
PURPOSE
Data on differences in overall survival and molecular characteristics between incidental (iLGG) and symptomatic lower grade Glioma (sLGG) are limited. The aim of this study was to investigate differences between patients with iLGG and sLGG.
METHODS
All adult patients with a histologically proven diffuse (WHO°II) or anaplastic (WHO°III) glioma who underwent their first surgery at the authors' institution between 2010 and 2019 were retrospectively included. Tumor volume on pre- and postoperative MRI scans was determined. Clinical and routine neuropathological data were gained from patients' charts. If IDH1, ATRX and EGFR were not routinely assessed, they were re-determined.
RESULTS
Out of 161 patients included, 23 (14%) were diagnosed as incidental findings. Main reasons for obtaining MRI were: headache(n = 12), trauma(n = 2), MRI indicated by other departments(n = 7), staging examination for cancer(n = 1), volunteering for MRI sequence testing(n = 1). The asymptomatic patients were significantly younger with a median age of 38 years (IqR28-48) vs. 50 years (IqR38-61), p = 0.011. Incidental LGG showed significantly lower preoperative tumor volumes in T1 CE (p = 0.008), FLAIR (p = 0.038) and DWI (p = 0.028). Incidental LGG demonstrated significantly lower incidence of anaplasia (p = 0.004) and lower expression of MIB-1 (p = 0.008) compared to sLGG. IDH1-mutation was significantly more common in iLGG (p = 0.024). Incidental LGG showed a significantly longer OS (mean 212 vs. 70 months, p = 0.005) and PFS (mean 201 vs. 61 months, p = 0.001) compared to sLGG.
CONCLUSION
Our study is the first to depict a significant difference in molecular characteristics between iLGG and sLGG. The findings of this study confirmed and extended the results of previous studies showing a better outcome and more favorable radiological, volumetric and neuropathological features of iLGG.
Topics: Adult; Humans; Middle Aged; Brain Neoplasms; Retrospective Studies; Glioma; Magnetic Resonance Imaging; Headache
PubMed: 37043120
DOI: 10.1007/s11060-023-04301-x -
Frontiers in Oncology 2023Wilms Tumor (WT), or nephroblastoma, is the most common pediatric kidney cancer. Most WTs display a "favorable" triphasic histology, in which the tumor is comprised of...
INTRODUCTION
Wilms Tumor (WT), or nephroblastoma, is the most common pediatric kidney cancer. Most WTs display a "favorable" triphasic histology, in which the tumor is comprised of blastemal, stromal, and epithelial cell types. Blastemal predominance after neoadjuvant chemotherapy or diffuse anaplasia ("unfavorable" histology; 5-8%) portend a worse prognosis. Blastema likely provide the putative cancer stem cells (CSCs), which retain molecular and histologic features characteristic of nephron progenitor cells (NPCs), within WTs. NPCs arise in the metanephric mesenchyme (MM) and populate the cap mesenchyme (CM) in the developing kidney. WT blastemal cells, like NPCs, similarly express markers, SIX2 and CITED1. Tumor xenotransplantation is currently the only dependable method to propagate tumor tissue for research or therapeutic screening, since efforts to culture tumors as monolayers have invariably failed. Therefore, a critical need exists to propagate WT stem cells rapidly and efficiently for high-throughput, real-time drug screening.
METHODS
Previously, our lab developed niche conditions that support the propagation of murine NPCs in culture. Applying similar conditions to WTs, we assessed our ability to maintain key NPC "stemness" markers, SIX2, NCAM, and YAP1, and CSC marker ALDHI in cells from five distinct untreated patient tumors.
RESULTS
Accordingly, our culture conditions maintained the expression of these markers in cultured WT cells through multiple passages of rapidly dividing cells.
DISCUSSION
These findings suggest that our culture conditions sustain the WT blastemal population, as previously shown for normal NPCs. As a result, we have developed new WT cell lines and a multi-passage model for studying the blastemal lineage/CSCs in WTs. Furthermore, this system supports growth of heterogeneous WT cells, upon which potential drug therapies could be tested for efficacy and resistance.
PubMed: 37007076
DOI: 10.3389/fonc.2023.1091274 -
Neoplasia (New York, N.Y.) May 2023Pediatric intracranial ependymoma has seen a recent exponential expansion of biological findings, rapidly dividing the diagnosis into several subgroups, each with...
Pediatric intracranial ependymoma has seen a recent exponential expansion of biological findings, rapidly dividing the diagnosis into several subgroups, each with specific molecular and clinical characteristics. While such subdivision may complicate clinical conclusions from historical trials, this knowledge also provides an opportunity for interrogating the major clinical and biological questions preventing near-term translation into effective therapy for children with ependymoma. In this article, we briefly review some of the most critical clinical questions facing both patient management and the construct of future trials in childhood ependymoma, as well as explore some of the current barriers to efficient translation of preclinical discovery to the clinic.
Topics: Child; Humans; Brain Neoplasms; Ependymoma; Prognosis
PubMed: 36944298
DOI: 10.1016/j.neo.2023.100895