-
The Indian Journal of Radiology &... Jul 2024: Despite documented correlation between glioma grades and dynamic contrast-enhanced (DCE) magnetic resonance (MR) perfusion-derived parameters, and its inherent...
Diagnostic Utility of Integration of Dynamic Contrast-Enhanced and Dynamic Susceptibility Contrast MR Perfusion Employing Split Bolus Technique in Differentiating High-Grade Glioma.
: Despite documented correlation between glioma grades and dynamic contrast-enhanced (DCE) magnetic resonance (MR) perfusion-derived parameters, and its inherent advantages over dynamic susceptibility contrast (DSC) perfusion, the former remains underutilized in clinical practice. Given the inherent spatial heterogeneity in high-grade diffuse glioma (HGG) and assessment of different perfusion parameters by DCE (extravascular extracellular space volume [Ve] and volume transfer constant in unit time [k-trans]) and DSC (rCBV), integration of the two into a protocol could provide a holistic assessment. Considering therapeutic and prognostic implications of differentiating WHO grade 3 from 4, we analyzed the two grades based on a combined DCE and DSC perfusion. : Perfusion sequences were performed on 3-T MR. Cumulative dose of 0.1 mmol/kg of gadodiamide, split into two equal boluses, was administered with an interval of 6 minutes between the DCE and DSC sequences. DCE data were analyzed utilizing commercially available GenIQ software. : Of the 41 cases of diffuse gliomas analyzed, 24 were WHO grade III and 17 grade IV gliomas (2016 WHO classification). To differentiate grade III and IV gliomas, Ve cut-off value of 0.178 provided the best combination of sensitivity (88.24%) and specificity (87.50%; AUC: 0.920; < 0.001). A relative cerebral blood volume (rCBV) of value 3.64 yielded a sensitivity of 70.59% and specificity of 62.50% ( = 0.018). The k-trans value, although higher in grade III than in grade IV gliomas, did not reach statistical significance ( = 0.108). : Uniqueness of employed combined perfusion technique, treatment naïve patients at imaging, user-friendly postprocessing software utilization, and ability of Ve and rCBV to differentiate between grade III and IV gliomas ( < 0.05) are the strengths of the present study, contributing to the existing literature and moving a step closer to achieving accurate MR perfusion-based glioma grading.
PubMed: 38912247
DOI: 10.1055/s-0043-1777742 -
The Indian Journal of Radiology &... Jul 2024Constitutional mismatch repair deficiency (CMMRD) is a rare childhood cancer predisposition syndrome that results from biallelic germline mutations in one of the four...
Constitutional mismatch repair deficiency (CMMRD) is a rare childhood cancer predisposition syndrome that results from biallelic germline mutations in one of the four MMR genes, MLH1, MSH2, MSH6, or PMS2. This syndrome is characterized by a broad spectrum of early-onset malignancies, including hematologic malignancies, colorectal malignancies, brain tumors, and other malignancies. It is common to have more than one malignancy in an individual diagnosed with CMMRD. In addition to malignancies, primary immunodeficiency in the form of low or absent immunoglobulin levels can also be seen in CMMRD. Congenital abnormalities such as agenesis of the corpus callosum (ACC), cavernous hemangioma, and other non-neoplastic diseases can also be linked to it. In this case report, we discussed the case of a girl born out of consanguineous marriage initially identified as having T-cell acute lymphoblastic lymphoma and later found to have selective immunoglobulin A (IgA) deficiency. Her younger sibling with a pontine cavernous hemangioma was also diagnosed with lymphoma. The girl exhibited brain lesions on magnetic resonance imaging (MRI), which were initially diagnosed as posterior reversible encephalopathy syndrome (PRES) related changes; however, one of the lesions persisted and remained stable over a period of 2 years and more in favor of diffuse glioma. The younger sibling also showed a solitary lesion in the brain. Based on the clinical and radiological findings, a diagnosis of CMMRD was suspected. Next-generation sequence (NGS) analysis of her blood sample was done. The results showed a homozygous mutation in the MSH6 gene was diagnostic of CMMRD.
PubMed: 38912246
DOI: 10.1055/s-0044-1779586 -
Frontiers in Oncology 2024Pediatric low-grade gliomas (pLGG) are the most common brain tumor in children and encompass a wide range of histologies. Treatment may pose challenges, especially in...
INTRODUCTION
Pediatric low-grade gliomas (pLGG) are the most common brain tumor in children and encompass a wide range of histologies. Treatment may pose challenges, especially in those incompletely resected or those with multiple recurrence or progression.
CASE DESCRIPTION
We report the clinical course of a girl diagnosed with pilocytic astrocytoma and profound hydrocephalus at age 12 years treated with subtotal resection, vinblastine chemotherapy, and focal proton radiotherapy. After radiotherapy the tumor increased in enhancement temporarily with subsequent resolution consistent with pseudoprogression. Despite improvement in imaging and radiographic local control, the patient continues to have challenges with headaches, visual and auditory concerns, stroke-like symptoms, and poor quality of life.
CONCLUSION
pLGG have excellent long-term survival; thus, treatments should focus on maintaining disease control and limiting long-term toxicities. Various treatment options exist including surgery, chemotherapy, targeted agents, and radiation therapy. Given the morbidity associated with pLGG, individualized treatment approaches are necessary, with a multi-disciplinary approach to care focused on minimizing treatment side effects, and promoting optimal quality of life for patients.
PubMed: 38912055
DOI: 10.3389/fonc.2024.1366251 -
Journal of Cancer 2024Cancer is a destructive disease and is currently the leading cause of major threats to human health. PLBD1 is a transcription factor that regulates phospholipid...
Cancer is a destructive disease and is currently the leading cause of major threats to human health. PLBD1 is a transcription factor that regulates phospholipid metabolism, but its role in tumors is unknown. We assessed pan-cancer expression, methylation, and mutation data of PLBD1 by multiple databases to investigate its clinical prognostic value. In addition, we examined the pan-cancer immunological signature of PLBD1, particularly in gliomas. Furthermore, we assessed the impact of PLBD1 knockdown on the proliferation and invasive capacity of glioma cells by experiments. Our results suggest that PLBD1 is highly expressed in multiple types of cancers, and it can serve as an independent prognostic factor for gliomas. In addition, we found that the epigenetic alterations of PLBD1 were highly heterogeneous in a variety of cancers, including gliomas, and that its high methylation was associated with poor prognosis in a broad range of cancers. Immunological profiling demonstrated that PLBD1 was significantly associated with immune cell infiltration and multiple immune checkpoints in gliomas and is a potential biomarker for gliomas. Furthermore, cellular experiments showed that knockdown of PLBD1 significantly inhibited the proliferation and invasive ability of glioma cells. In conclusion, PLBD1 is a potential tumor prognostic biomarker and immunotherapeutic target that plays a crucial role in glioma cell proliferation, invasion and immunotherapy.
PubMed: 38911364
DOI: 10.7150/jca.96365 -
Journal of Cancer Research and Clinical... Jun 2024Glioblastoma (GBM) is a high-grade and heterogeneous subtype of glioma that presents a substantial challenge to human health, characterized by a poor prognosis and low...
BACKGROUND
Glioblastoma (GBM) is a high-grade and heterogeneous subtype of glioma that presents a substantial challenge to human health, characterized by a poor prognosis and low survival rates. Despite its known involvement in regulating leukemia and melanoma, the function and mechanism of DNAJC1 in GBM remain poorly understood.
METHODS
Utilizing data from the TCGA, CGGA, and GEO databases, we investigated the expression pattern of DNAJC1 and its correlation with clinical characteristics in GBM specimens. Loss-of-function experiments were conducted to explore the impact of DNAJC1 on GBM cell lines, with co-culture experiments assessing macrophage infiltration and functional marker expression.
RESULTS
Our analysis demonstrated frequent overexpression of DNAJC1 in GBM, significantly associated with various clinical characteristics including WHO grade, IDH status, chromosome 1p/19q codeletion, and histological type. Moreover, Kaplan‒Meier and ROC analyses revealed DNAJC1 as a negative prognostic predictor and a promising diagnostic biomarker for GBM patients. Functional studies indicated that silencing DNAJC1 impeded cell proliferation and migration, induced cell cycle arrest, and enhanced apoptosis. Mechanistically, DNAJC1 was implicated in stimulating extracellular matrix reorganization, triggering the epithelial-mesenchymal transition (EMT) process, and initiating immunosuppressive macrophage infiltration.
CONCLUSIONS
Our findings underscore the pivotal role of DNAJC1 in GBM pathogenesis, suggesting its potential as a diagnostic and therapeutic target for this challenging disease.
Topics: Humans; Glioblastoma; Brain Neoplasms; Macrophages; Disease Progression; Extracellular Matrix; Prognosis; HSP40 Heat-Shock Proteins; Cell Line, Tumor; Animals; Male; Female; Mice; Biomarkers, Tumor; Cell Proliferation; Epithelial-Mesenchymal Transition; Cell Movement; Gene Expression Regulation, Neoplastic; Apoptosis; Middle Aged
PubMed: 38909166
DOI: 10.1007/s00432-024-05823-1 -
Cell Death & Disease Jun 2024The transmembrane death receptor Fas transduces apoptotic signals upon binding its ligand, FasL. Although Fas is highly expressed in cancer cells, insufficient cell...
The transmembrane death receptor Fas transduces apoptotic signals upon binding its ligand, FasL. Although Fas is highly expressed in cancer cells, insufficient cell surface Fas expression desensitizes cancer cells to Fas-induced apoptosis. Here, we show that the increase in Fas microaggregate formation on the plasma membrane in response to the inhibition of endocytosis sensitizes cancer cells to Fas-induced apoptosis. We used a clinically accessible Rho-kinase inhibitor, fasudil, that reduces endocytosis dynamics by increasing plasma membrane tension. In combination with exogenous soluble FasL (sFasL), fasudil promoted cancer cell apoptosis, but this collaborative effect was substantially weaker in nonmalignant cells. The combination of sFasL and fasudil prevented glioblastoma cell growth in embryonic stem cell-derived brain organoids and induced tumor regression in a xenograft mouse model. Our results demonstrate that sFasL has strong potential for apoptosis-directed cancer therapy when Fas microaggregate formation is augmented by mechano-inhibition of endocytosis.
Topics: Humans; Endocytosis; Apoptosis; Animals; Fas Ligand Protein; fas Receptor; Mice; Cell Line, Tumor; 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; Xenograft Model Antitumor Assays; Glioblastoma
PubMed: 38909035
DOI: 10.1038/s41419-024-06822-3 -
Medicina 2024The frontal aslant tract (FAT) connects the supplementary motor area (SMA) with the pars opercularis. Its role in language and its implications in glioma surgery remain...
The frontal aslant tract (FAT) connects the supplementary motor area (SMA) with the pars opercularis. Its role in language and its implications in glioma surgery remain under discussion. We present an anatomosurgical study of three cases with surgical resolution. Three patients with gliomas in the left frontal lobe were operated on using an awake patient protocol with cortical and subcortical mapping techniques, conducting motor and language evaluations. Tractography was performed using DSI Studio software. All three patients showed intraoperative language inhibition through subcortical stimulation of the FAT. Resection involving the FAT correlated with language deficits in all cases and movement initiation deficits in two cases. All patients recovered from their deficits at six months postoperatively. In conclusion, the tract has been successfully reconstructed, showing both anatomical and functional complexity, supporting the idea of its mapping and preservation in glioma surgery. Future interdisciplinary studies are necessary to determine the transient or permanent nature of the deficits.
Topics: Humans; Brain Neoplasms; Glioma; Male; Frontal Lobe; Middle Aged; Female; Adult; Neurosurgical Procedures; Brain Mapping; Motor Cortex; Diffusion Tensor Imaging
PubMed: 38907981
DOI: No ID Found -
Cellular and Molecular Neurobiology Jun 2024The circadian system is a conserved time-keeping machinery that regulates a wide range of processes such as sleep/wake, feeding/fasting, and activity/rest cycles to...
The circadian system is a conserved time-keeping machinery that regulates a wide range of processes such as sleep/wake, feeding/fasting, and activity/rest cycles to coordinate behavior and physiology. Circadian disruption can be a contributing factor in the development of metabolic diseases, inflammatory disorders, and higher risk of cancer. Glioblastoma (GBM) is a highly aggressive grade 4 brain tumor that is resistant to conventional therapies and has a poor prognosis after diagnosis, with a median survival of only 12-15 months. GBM cells kept in culture were shown to contain a functional circadian oscillator. In seeking more efficient therapies with lower side effects, we evaluated the pharmacological modulation of the circadian clock by targeting the cytosolic kinases glycogen synthase kinase-3 (GSK-3) and casein kinase 1 ε/δ (CK1ε/δ) with specific inhibitors (CHIR99021 and PF670462, respectively), the cryptochrome protein stabilizer (KL001), or circadian disruption after Per2 knockdown expression in GBM-derived cells. CHIR99021-treated cells had a significant effect on cell viability, clock protein expression, migration, and cell cycle distribution. Moreover, cultures exhibited higher levels of reactive oxygen species and alterations in lipid droplet content after GSK-3 inhibition compared to control cells. The combined treatment of CHIR99021 with temozolomide was found to improve the effect on cell viability compared to temozolomide therapy alone. Per2 disruption affected both GBM migration and cell cycle progression. Overall, our results suggest that pharmacological modulation or molecular clock disruption severely affects GBM cell biology.
Topics: Glioblastoma; Humans; Cell Line, Tumor; Brain Neoplasms; Pyridines; Cell Survival; Cytosol; Glycogen Synthase Kinase 3; Pyrimidines; Cell Movement; Circadian Clocks; CLOCK Proteins; Period Circadian Proteins; Reactive Oxygen Species
PubMed: 38907776
DOI: 10.1007/s10571-024-01485-2 -
BMC Cancer Jun 2024Diffuse midline glioma (DMG), H3 K27M-mutant is a type of diffuse high-grade glioma that occurs in the brain midline carrying an extremely poor prognosis under the best...
PURPOSE
Diffuse midline glioma (DMG), H3 K27M-mutant is a type of diffuse high-grade glioma that occurs in the brain midline carrying an extremely poor prognosis under the best efforts of surgery, radiation, and other therapies. For better therapy, we explored the efficacy and toxicity of a novel therapy that combines apatinib and temozolomide in DMG.
METHODS
A retrospective analysis of 32 patients with DMG who underwent apatinib plus temozolomide treatment was performed. Apatinib was given 500 mg in adults, 250 mg in pediatric patients once daily. Temozolomide was administered at 200 mg/m/d according to the standard 5/28 days regimen. The main clinical data included basic information of patients, radiological and pathological characteristics of tumors, treatment, adverse reactions, prognosis.
RESULTS
The objective response rate was 24.1%, and the disease control rate was 79.3%. The median PFS of all patients was 5.8 months, and median OS was 10.3 months. A total of 236 cycles of treatment were available for safety assessment and the toxicity of the combination therapy was relatively well tolerated. The most common grade 3 toxicities were myelosuppression including leukopenia (5.08%), neutropenia (4.24%), lymphopenia (2.12%), thrombocytopenia (1.69%) and anemia (1.27%). Grade 4 toxicities included neutropenia (2.12%), thrombocytopenia (2.12%) and proteinuria (1.69%). All the adverse events were relieved after symptomatic treatment or dose reduction.
CONCLUSIONS
Apatinib plus temozolomide could be an effective regimen with manageable toxicities and favorable efficacy and may outperform temozolomide monotherapy, particularly in newly diagnosed adults with tumors located outside the pons. The novel therapy deserves further investigation in adult DMG patients.
Topics: Humans; Temozolomide; Female; Male; Adult; Pyridines; Glioma; Adolescent; Retrospective Studies; Child; Brain Neoplasms; Young Adult; Antineoplastic Combined Chemotherapy Protocols; Child, Preschool; Middle Aged; Treatment Outcome
PubMed: 38907215
DOI: 10.1186/s12885-024-12373-9 -
Scientific Reports Jun 2024Glioblastoma (GBM) is a highly aggressive and deadly brain cancer. Temozolomide (TMZ) is the standard chemotherapeutic agent for GBM, but the majority of patients...
Glioblastoma (GBM) is a highly aggressive and deadly brain cancer. Temozolomide (TMZ) is the standard chemotherapeutic agent for GBM, but the majority of patients experience recurrence and invasion of tumor cells. We investigated whether TMZ treatment of GBM cells regulates matrix metalloproteinases (MMPs), which have the main function to promote tumor cell invasion. TMZ effectively killed GL261, U343, and U87MG cells at a concentration of 500 µM, and surviving cells upregulated MMP9 expression and its activity but not those of MMP2. TMZ also elevated levels of MMP9 mRNA and MMP9 promoter activity. Subcutaneous graft tumors survived from TMZ treatment also exhibited increased expression of MMP9 and enhanced gelatinolytic activity. TMZ-mediated MMP9 upregulation was specifically mediated through the phosphorylation of p38 and JNK. This then stimulates AP-1 activity through the upregulation of c-Fos and c-Jun. Inhibition of the p38, JNK, or both pathways counteracted the TMZ-induced upregulation of MMP9 and AP-1. This study proposes a potential adverse effect of TMZ treatment for GBM: upregulation of MMP9 expression potentially associated with increased invasion and poor prognosis. This study also provides valuable insights into the molecular mechanisms by which TMZ treatment leads to increased MMP9 expression in GBM cells.
Topics: Temozolomide; Glioblastoma; Matrix Metalloproteinase 9; Humans; p38 Mitogen-Activated Protein Kinases; Cell Line, Tumor; Gene Expression Regulation, Neoplastic; MAP Kinase Signaling System; Antineoplastic Agents, Alkylating; Animals; Brain Neoplasms; Transcription Factor AP-1; Up-Regulation; Mice
PubMed: 38906916
DOI: 10.1038/s41598-024-65398-2