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International Journal of Molecular... Mar 2023Glioblastoma multiforme (GBM) is a primary brain tumor that is very aggressive, resistant to treatment, and characterized by a high degree of anaplasia and... (Review)
Review
Glioblastoma multiforme (GBM) is a primary brain tumor that is very aggressive, resistant to treatment, and characterized by a high degree of anaplasia and proliferation. Routine treatment includes ablative surgery, chemotherapy, and radiotherapy. However, GMB rapidly relapses and develops radioresistance. Here, we briefly review the mechanisms underpinning radioresistance and discuss research to stop it and install anti-tumor defenses. Factors that participate in radioresistance are varied and include stem cells, tumor heterogeneity, tumor microenvironment, hypoxia, metabolic reprogramming, the chaperone system, non-coding RNAs, DNA repair, and extracellular vesicles (EVs). We direct our attention toward EVs because they are emerging as promising candidates as diagnostic and prognostication tools and as the basis for developing nanodevices for delivering anti-cancer agents directly into the tumor mass. EVs are relatively easy to obtain and manipulate to endow them with the desired anti-cancer properties and to administer them using minimally invasive procedures. Thus, isolating EVs from a GBM patient, supplying them with the necessary anti-cancer agent and the capability of recognizing a specified tissue-cell target, and reinjecting them into the original donor appears, at this time, as a reachable objective of personalized medicine.
Topics: Humans; Glioblastoma; Cell Line, Tumor; Brain Neoplasms; Neoplasm Recurrence, Local; Extracellular Vesicles; Tumor Microenvironment
PubMed: 36902314
DOI: 10.3390/ijms24054883 -
Brain Tumor Pathology Apr 2023Pilocytic astrocytomas (PAs) are benign tumors. However, clinically aggressive PAs despite benign histology have been reported, and histological and molecular risk...
Clinical, histopathological and molecular risk factors for recurrence of pilocytic astrocytomas: brainstem/spinal location, nestin expression and gain of 7q and 19 are associated with early tumor recurrence.
Pilocytic astrocytomas (PAs) are benign tumors. However, clinically aggressive PAs despite benign histology have been reported, and histological and molecular risk factors for prognosis have not been elucidated. 38 PAs were studied for clinical, histological, and molecular factors, including tumor location, extent of resection, post-operative treatment, glioma-associated molecules (IDH1/2, ATRX, BRAF, FGFR1, PIK3CA, H3F3A, p53, VEGF, Nestin, PD-1/PD-L1), CDKN2A/B deletion, and chromosomal number aberrations, to see if there is any correlation with patient's progression-free survival (PFS). Brainstem/spinal location, extent of resection and post-operative treatment, and VEGF-A, Nestin and PD-L1 expression, copy number gain of chromosome 7q or 19, TP53 mutation were significantly associated with shorter PFS. None of the histological parameters was associated with PFS. Multivariate analyses demonstrated that high Nestin expression, gain of 7q or 19, and extent of removal were independently predictive for early tumor recurrence. The brainstem/spinal PAs appeared distinct from those in the other sites in terms of molecular characteristics. Clinically aggressive PAs despite benign histology exhibited high Nestin expression. Brainstem/spinal location, extent of resection and some molecular factors including Nestin expression and gains of 7q and 19, rather than histological parameters, may be associated with early tumor recurrence in PAs.
Topics: Humans; B7-H1 Antigen; Brain Neoplasms; Neoplasm Recurrence, Local; Nestin; Astrocytoma; Brain Stem
PubMed: 36892668
DOI: 10.1007/s10014-023-00453-w -
Journal of Personalized Medicine Jan 2023Grade 3 meningiomas are rare malignant tumors that can originate de novo or from the progression of lower grade meningiomas. The molecular bases of anaplasia and...
Grade 3 meningiomas are rare malignant tumors that can originate de novo or from the progression of lower grade meningiomas. The molecular bases of anaplasia and progression are poorly known. We aimed to report an institutional series of grade 3 anaplastic meningiomas and to investigate the evolution of molecular profile in progressive cases. Clinical data and pathologic samples were retrospectively collected. VEGF, EGFR, EGFRvIII, PD-L1; and Sox2 expression; methylation status; and promoter mutation were assessed in paired meningioma samples collected from the same patient before and after progression using immunohistochemistry and PCR. Young age, de novo cases, origin from grade 2 in progressive cases, good clinical status, and unilateral side, were associated with more favorable outcomes. In ten progressive meningiomas, by comparing molecular profile before and after progression, we identified two subgroups of patients, one defined by Sox2 increase, suggesting a stem-like, mesenchymal phenotype, and another defined by EGFRvIII gain, suggesting a committed progenitor, epithelial phenotype. Interestingly, cases with Sox2 increase had a significantly shortened survival compared to those with EGFRvIII gain. PD-L1 increase at progression was also associated with worse prognosis, portending immune escape. We thus identified the key drivers of meningioma progression, which can be exploited for personalized treatments.
PubMed: 36836440
DOI: 10.3390/jpm13020206 -
Scientific Reports Feb 2023Distant intercellular communication in gliomas is based on the expansion of tumor microtubuli, where actin forms cytoskeleton and GAP-43 mediates the axonal conus...
Distant intercellular communication in gliomas is based on the expansion of tumor microtubuli, where actin forms cytoskeleton and GAP-43 mediates the axonal conus growth. We aimed to investigate the impact of GAP-43 and actin expression on overall survival (OS) as well as crucial prognostic factors. FFPE tissue of adult patients with diffuse and anaplastic gliomas, who underwent first surgery in our center between 2010 and 2019, were selected. GAP-43, Cx43 and actin expression was analyzed using immunohistochemistry and semi-quantitatively ranked. 118 patients with a median age of 46 years (IqR: 35-57) were evaluated. 48 (41%) presented with a diffuse glioma and 70 (59%) revealed anaplasia. Tumors with higher expression of GAP-43 (p = 0.024, HR = 1.71/rank) and actin (p < 0.001, HR = 2.28/rank) showed significantly reduced OS. IDH1 wildtype glioma demonstrated significantly more expression of all proteins: GAP-43 (p = 0.009), Cx43 (p = 0.003) and actin (p < 0.001). The same was confirmed for anaplasia (GAP-43 p = 0.028, actin p = 0.029), higher proliferation rate (GAP-43 p = 0.016, actin p = 0.038), contrast-enhancement in MRI (GAP-43 p = 0.023, actin p = 0.037) and age (GAP-43 p = 0.004, actin p < 0.001; Cx43 n.s. in all groups). The intercellular distant communication network in diffuse and anaplastic gliomas formed by actin and GAP-43 is associated with a negative impact on overall survival and with unfavorable prognostic features. Cx43 did not show relevant impact on OS.
Topics: Adult; Humans; Middle Aged; Actins; Anaplasia; Brain Neoplasms; Connexin 43; GAP-43 Protein; Glioma; Prognosis
PubMed: 36739296
DOI: 10.1038/s41598-023-29298-1 -
Journal of Zoo and Wildlife Medicine :... Jan 2023Neoplasia in porcupines is rarely reported in the literature, and the prevalence is unknown. A retrospective review of records from a private zoo diagnostic pathology...
Neoplasia in porcupines is rarely reported in the literature, and the prevalence is unknown. A retrospective review of records from a private zoo diagnostic pathology service found four cases of mammary adenocarcinoma in Indian crested porcupines () from four separate zoological institutions. All cases presented in geriatric females (14-19 yr of age) as freely movable subcutaneous masses within the mammary chain. None of the individuals had additional clinical signs, radiographic, or hematologic changes at initial presentation. All cases were managed with surgical excision in the form of either an excisional biopsy or a partial mastectomy. Histologic examination diagnosed all tumors with anaplasia and moderate to high numbers of mitotic figures. Two cases required subsequent surgeries for management of local recurrence in the years following initial diagnosis. One case is 19 months postsurgical removal without evidence of metastasis or local recurrence. Two of the cases were euthanized after diagnosis of inoperable metastases to the lungs and spinal cord, including one previously treated with an oral nonsteroidal antiestrogen medication, tamoxifen. The third case was euthanized due to degenerative mobility changes and renal dysfunction and had no evidence of metastasis. The average survival time from initial surgical excision to euthanasia for the three applicable cases was 33 months. These cases suggest that surgical excision alone may result in temporary management of mammary adenocarcinoma in this species. Metastasis can occur, and routine screening with advanced imaging may aid in early detection of these lesions.
Topics: Female; Animals; Porcupines; Mastectomy; Adenocarcinoma; Retrospective Studies; Rodent Diseases
PubMed: 36640090
DOI: 10.1638/2021-0137 -
Journal of Cancer Research and... Jan 2023Medulloblastoma (MB) is a heterogeneous disease, displaying distinct genetic profiles, with specific molecular subgroups. Various clinical, pathological and molecular...
BACKGROUND
Medulloblastoma (MB) is a heterogeneous disease, displaying distinct genetic profiles, with specific molecular subgroups. Various clinical, pathological and molecular variables have been associated with disease outcome and therefore utilised in risk stratification of patients.
OBJECTIVES
To perform molecular classification of medulloblastoma using surrogate immunohistochemistry (IHC) and associate molecular subgroups, histopathological types, and available clinicopathological parameters with overall survival (OS) of MB patients.
RESULTS
This study included 65 medulloblastoma patients. Immunohistochemical staining, using β-catenin YAP1 and GRB2-Associated Binding Protein 1 (GAB1) antibodies was used to classify MB cases into wingless signalling (WNT) activated, sonic hedgehog (SHH) activated, and non-WNT/non-SHH molecular subgroups. The relevant statistical analysis was done using GraphPad Prism version 9.3.0. Histological patterns included classic (40 cases, 62%), desmoplastic nodular (D/N) (14 cases, 22%), large cell/anaplastic (LC/A) (9 cases, 13%), medulloblastoma with extensive nodularity (MBEN) (1 case, 1.5%) and one special subtype, i.e., medulloblastoma with myogenic and melanotic differentiation. Molecular subgroups included WNT (4 cases, 6%), SHH (34 cases, 52%), and non-WNT/non-SHH (27 cases, 42%) subgroups. Histopathological types differed significantly according to tumor location, degree of anaplasia and molecular subgroups. Molecular subgroups differed significantly in age distribution and tumor location. The probability of survival was 78% and 68% after 1 and 2 years, respectively. Infants (<3 years of age), LC/A pattern, and TP53-mutant status among SHH subgroup conferred poor prognosis in our study. At the end of the study (at 65 months of maximum follow-up period) probability of survival was 51%.
CONCLUSIONS
Immunohistochemical analysis helps in molecular classification of medulloblastoma in majority of the cases as well as helps in predicting prognosis and treatment response.
Topics: Infant; Humans; Hedgehog Proteins; Medulloblastoma; Tertiary Care Centers; Prognosis; Cerebellar Neoplasms
PubMed: 38384024
DOI: 10.4103/jcrt.jcrt_1268_22 -
Virchows Archiv : An International... Apr 2023Corded and hyalinized endometrioid carcinoma (CHEC) typically shows low-grade features and "no specific molecular profile" (NSMP). This study aimed to perform a...
Corded and hyalinized endometrioid carcinoma (CHEC) typically shows low-grade features and "no specific molecular profile" (NSMP). This study aimed to perform a clinicopathological and molecular characterization of endometrial CHEC with high-grade features. Immunohistochemistry for cytokeratin AE1/AE3, e-cadherin, β-catenin, estrogen receptor, progesterone receptor, p53, p16, and mismatch repair proteins was performed. A next-generation sequencing kit was used to assess POLE, POLD1, APC, MLH1, MSH2, MSH6, PMS2, MUTYH, EPCAM, and CTNNB1. Molecular groups, i.e., POLE-mutant, mismatch repair deficient (MMRd), p53-abnormal, and NSMP, were assigned according to the TCGA classifier. Six high-grade endometrial CHECs were identified. The mean age was 57.5 years; 5/6 cases were uterine-confined. Five cases showed a diffusely and markedly atypical corded component and a MMRd or p53-abnormal signature; additional features included single-cell keratinization, necrosis, osteoid or myxoid/chondro-myxoid matrix, foci of anaplasia, and nuclear β-catenin expression. The remaining case showed a low mitotic count and a NSMP phenotype, with focal bizarre cells in an otherwise classical CH endometrioid carcinoma. All cases showed variably reduced expression of epithelial markers and hormone receptors in the corded component. No mutations were found in any of the analyzed genes. In conclusion, high-grade CHECs are a heterogeneous subset of biphasic endometrial carcinoma which show similarities and differences with classical CHEC and carcinosarcoma. These cases often show MMRd or p53-abnormal signatures.
Topics: Female; Humans; Carcinoma, Endometrioid; beta Catenin; Tumor Suppressor Protein p53; Endometrial Neoplasms; Endometrium; Biomarkers, Tumor
PubMed: 36550216
DOI: 10.1007/s00428-022-03472-8 -
Current Issues in Molecular Biology Dec 2022This research was aimed at investigating the features of free radical activity and the parameters of glutathione metabolism in tumor tissues and the peritumoral zone at...
This research was aimed at investigating the features of free radical activity and the parameters of glutathione metabolism in tumor tissues and the peritumoral zone at different degrees of glial tumor anaplasia. We analyzed postoperative material from 20 patients with gliomas of different degrees of anaplasia. The greatest differences compared to adjacent noncancerous tissues were found in the tumor tissue: an increased amount of glutathione and glutathione-related enzymes at Grades I and II, and a decrease of these parameters at Grades III and IV. For the peritumoral zone of Grades I and II, the indices changed in different directions, while for Grades III and IV, they occurred synchronously with the tumor tissue changes. For Low Grade and High Grade gliomas, opposite trends were revealed regarding changes in the level of glutathione and the enzymes involved in its metabolism and in the free radical activity in the peritumoral zone. The content of glutathione and the enzymes involved in its metabolism decreased with the increasing degree of glioma anaplasia. In contrast, free radical activity increased. The glutathione system is an active participant in the antioxidant defense of the body and can be used to characterize the cell condition of gliomas at different stages of tumor development.
PubMed: 36547100
DOI: 10.3390/cimb44120439 -
Journal of Indian Association of... 2022Rhabdomyosarcoma is an aggressive malignant striated muscle neoplasm commonly seen in children involving orbit, paranasal sinuses, cheek, tongue, and rarely upper lip....
Rhabdomyosarcoma is an aggressive malignant striated muscle neoplasm commonly seen in children involving orbit, paranasal sinuses, cheek, tongue, and rarely upper lip. The anaplastic subtype is further rare and associated with poor prognosis. Herein, we report a 3-year-old female with this uncommon variant at an uncommon site.
PubMed: 36530822
DOI: 10.4103/jiaps.jiaps_242_21 -
Neurosurgical Focus Dec 2022The authors aimed to assess the frequency of homozygous CDKN2A deletion in isocitrate dehydrogenase (IDH)-mutant diffuse astrocytomas (grade 2/3) and to narrow down the...
OBJECTIVE
The authors aimed to assess the frequency of homozygous CDKN2A deletion in isocitrate dehydrogenase (IDH)-mutant diffuse astrocytomas (grade 2/3) and to narrow down the clinicopathological indications in which the CDKN2A fluorescence in situ hybridization (FISH) assay is cost-effective in resource-constrained settings.
METHODS
IDH-mutant astrocytomas were analyzed for ATRX, p53, MIB1-LI, and p16 expression using immunohistochemistry. The FISH assay was used to evaluate CDKN2A deletion and 1p/19q codeletion. Survival outcomes were assessed according to the different molecular markers.
RESULTS
A total of 150 adult patients with IDH-mutant grade 2 (n = 95) and grade 3 (n = 55) astrocytomas (145 primary and 5 recurrent) were analyzed. Using a cutoff value of 30% for defining significant homozygous CDKN2A deletion, none of the grade 2 and 10.9% (6/55) of grade 3 astrocytomas showed this deletion (4 primary and 2 recurrent grade 3 tumors) and were reclassified as grade 4. This mutation was more frequent in recurrent (40%, 2/5) than primary (2.76%, 4/145) gliomas. Half (3/6, 50%) of the CDKN2A-deleted cases demonstrated poor outcomes; 2 of these cases experienced recurrence at 12 and 36 months after surgery, and 1 died at 5 months. The majority of CDKN2A-deleted cases showed marked cellularity (100%), pleomorphism (100%), brisk mitosis (83.3%), and tumor giant cell formation (83.4%). None of the cases with retained p16 expression harbored this deletion. Both overall survival (p = 0.039) and progression-free survival (p = 0.0045) were found to be worse in cases with p16 loss. Selectively performing CDKN2A FISH only in high-risk cases with histomorphological features of anaplasia, p16 loss, or recurrent tumors achieved a sensitivity and negative predictive value of 100%. This approach would have resulted in saving 41.1% of the original expenditure ($6900 US per 150 samples) and 27.6 person-minutes per sample without compromising the identification of deleted cases.
CONCLUSIONS
Homozygous CDKN2A deletion is conspicuously absent in grade 2 and rare in primary grade 3 IDH-mutant astrocytomas. The authors propose that restricting use of the FISH assay to cases showing histomorphological features of anaplasia, p16 loss, or recurrent tumors will help this platform to be utilized in the most cost-effective manner in resource-constrained settings.
Topics: Humans; Anaplasia; In Situ Hybridization, Fluorescence; Astrocytoma; Glioma; Progression-Free Survival; Cyclin-Dependent Kinase Inhibitor p16
PubMed: 36455270
DOI: 10.3171/2022.9.FOCUS22427