Grade Of Malignancy Research Articles

Apoptosis-related factors are relevant to progression of pancreatic neuroendocrine tumors

BackgroundMultidisciplinary therapy centered on antitumor drugs is indicated in patients with unresectable pancreatic neuroendocrine tumors (PanNET). However, the criteria for selection of optimal therapeutic agents is controversial. The aim of this study was to assess the malignancy of PanNET for optimal therapeutic drug selection.MethodsForty-seven patients with PanNET who underwent surgery were reviewed retrospectively, and immunohistochemical characteristics, including expression of GLUT1, SSTR2a, SSTR5, Survivin, X-chromosome-linked inhibitor of apoptosis protein (XIAP), and Caspase3 in the resected specimens, were investigated. Relapse-free survival (RFS) and overall survival (OS) were evaluated with regard to the characteristics using the Kaplan–Meier method and compared with the log-rank test.ResultsGLUT1 expression showed significant correlation with sex (p = 0.036) and mitotic rate (p = 0.048). Survivin and XIAP expression showed significant correlation with T-stage (p = 0.014 and 0.009), p-Stage (p = 0.028 and 0.045), and mitotic rate (p = 0.023 and 0.007). XIAP expression also significantly influenced OS (p = 0.044).ConclusionsSurvivin and XIAP correlated with grade of malignancy, and expression of XIAP in particular was associated with a poor prognosis. Expression of these proteins may be a useful indicator to select optimal therapeutic agents in PanNET.

Evaluation of the presence of Th1 response through T-bet and IFN-gamma immunohistochemical expression in lower lip and oral tongue squamous cell carcinomas

IntroductionEvaluate the immunohistochemical expression of T-bet and IFN-γ in lower lip (LLSCC) and oral tongue squamous cell carcinoma (OTSCC), verifying the presence of Th1 responses in lesions with different clinical conditions. Methods and materialsThirty OTSCC and 30 LLSCC were analyzed by immunohistochemistry. T-bet was quantitatively assessed by parenchyma cell and stroma quantification, and IFN-γ was semi-quantitatively analyzed: 1:0–25%; 2:26–50%; 3:51–75%; 4:> 75% immunopositive cells. Histological differentiation degrees were categorized as well differentiated (WD), moderately differentiated (MD), or poorly differentiated (PD). ResultsOTSCC presented the highest number of T-bet+, parenchyma (p: 0.006), stroma (p: 0.156), parenchyma/stroma (p: 0.015), with no relationship to histological malignancy grade. IFN-γ higher concentrations in LLSCC were detected in parenchyma, stroma and in parenchyma/stroma (p: 0.000), as well as greater immunoreactivity in WD and MD (p: 0.001). In OTSCC, a positive and statistically significant correlation was observed between T-bet+ in parenchyma and IFN-γ in stroma(r: 0.388; p: 0.034), in addition to a statistically significant positive correlation between T-bet in parenchyma compared to stroma(r: 0.411; p: 0.024) and for IFN-γ in both parenchyma and stroma(r: 0.775; p: 0.000) in LLSCC. Higher T-bet+ was observed in OTSCCs, although higher IFN-γ was detected in LLSCCs. ConclusionThus, we suggest that, even though LLSCC presented lower T-bet+, the favorable microenvironment in these lesions led to an expressive activation of IFN-γ by T-bet+, considerably acting on Th1 differentiation and in antitumor activity, which, admittedly, present less aggressive behavior, reinforcing once again the important role of this cytokine and its use in strategy to fight cancer.

Modelling Meningioma Using Organoids: A Review of Methodologies and Applications

Meningiomas are the most common tumours of the central nervous system. According to the World Health Organization (WHO), this disease is classified into three different grades: 80% of meningioma patients present with benign grade I tumours, while less than 2% present with malignant grade III meningiomas. Despite affecting thousands of people worldwide, much remains unknown about this disease, and the development of systemic treatments is still far behind in comparison to other types of tumours. Therefore, forming 3D structures (spheroids and organoids) could facilitate research on the mechanisms of formation, proliferation, migration, and invasion of these, for the most part, benign tumours, while also helping in the process of drug development. To date, there are three published methods for the formation of meningioma organoids primarily derived from patient tissue samples. Organoids offer many advantages in the development of treatments because they recapitulate the cellular complexity within tumours. These new methodological advances could open a substantial number of possibilities for the further characterisation and treatment of meningiomas. This review includes an overview of the disease and a description and comparison of established protocols for meningioma organoid formation.

Focused ultrasound combined with radiotherapy for malignant brain tumor: a preclinical and clinical study.

Blood-brain barrier (BBB) remains to be the major obstacle to conquer in treating patients with malignant brain tumors. Radiation therapy (RT), despite being the mainstay adjuvant modality regardless of BBB, the effect of radiation induced cell death is hindered by the hypoxic microenvironment. Focused ultrasound (FUS) combined with systemic microbubbles has been shown not only to open BBB but also potentially increased regional perfusion. However, no clinical study has investigated the combination of RT with FUS-BBB opening (RT-FUS). We aimed to provide preclinical evidence of RT-FUS combination in GBM animal model, and to report an interim analysis of an ongoing single arm, prospective, pilot study (NCT01628406) of combining RT-FUS for recurrent malignant high grade glioma patients, of whom re-RT was considered for disease control. In both preclinical and clinical studies, FUS-BBB opening was conducted within 2h before RT. Treatment responses were evaluated by objective response rate (ORR) using magnetic resonance imaging, progression free survival, and overall survival, and adverse events (AE) in clinical study. Survival analysis was performed in preclinical study and descriptive analysis was performed in clinical study. In mouse GBM model, the survival analysis showed RT-FUS (2Gy) group was significantly longer than RT (2Gy) group and control, but not RT (5Gy) group. In the pilot clinical trial, an interim analysis of six recurrent malignant high grade glioma patients underwent a total of 24 RT-FUS treatments was presented. Three patients had rapid disease progression at a mean of 33days after RT-FUS, while another three patients had at least stable disease (mean 323days) after RT-FUS with or without salvage chemotherapy or target therapy. One patient had partial response after RT-FUS, making the ORR of 16.7%. There was no FUS-related AEs, but one (16.7%) re-RT-related grade three radiation necrosis. Reirradiation is becoming an option after disease recurrence for both primary and secondary malignant brain tumors since systemic therapy significantly prolongs survival in cancer patients. The mechanism behind the synergistic effect of RT-FUS in preclinical model needs further study. The clinical evidence from the interim analysis of an ongoing clinical trial (NCT01628406) showed a combination of RT-FUS was safe (no FUS-related adverse effect). A comprehensive analysis of radiation dosimetry and FUS energy distribution is expected after completing the final recruitment.

The Potential Utility of Cerebral Fluid sLR11 and sIL-2R As a Marker for CNS Involvement of Malignant Lymphoma

Introduction: LR11 is a type I membrane protein that releases serum-soluble LR11 (sLR11) by proteolytic shedding. In the past, we reported that patients with acute leukemia and malignant lymphoma showed significantly increased serum sLR11 levels compared to those in normal controls. The diagnosis of central nervous system involvement of malignant lymphoma (CNS ML) is often difficult to diagnose by cytology. This study analyzed the potential utility of cerebral fluids (CFs) sLR11 and sIL-2R as diagnostic markers for CNS ML. Materials and Methods: We enrolled patients suspected of CNS ML and administrated intrathecal anticancer drugs from 2017 to 2023. We analyzed CFs levels of sLR11 and sIL-2R, and cytological malignant grades. Then, we analyzed the relationship between changes in these CFs markers and clinical outcomes. Results: We studied 26 patients (16 men and 10 women; mean age: 72 years old). The 20 patients were diagnosed as CNS ML in clinical conditions, and the other 6 patients were treated with prevention because of ML of the testis and adrenal glands. The sLR11 of CFs levels significantly and positively correlated with the sIL-2R of CFs levels (r = 0.6618, p = 0.0002) (Figure 1A). As shown in Figure 1B, in CNS invasion groups, only four patients showed class V in the cytology of CFs, the other patients showed negative results. There were no relations between the number of cell numbers and sLR11 and sIL-2R of CFs. As shown in Figure 2, the levels of sLR11 of CFs in diagnosis tended to be higher (p = 0.1831) in the CNS invasion group (36.5±30.0 ng/ml) than in the no-invasive group (23.9±5.8 ng/ml). The levels of sIL-2R of CFs in diagnosis were significantly higher (p = 0.0035) in the CNS invasion group (986.0±1274.3 U/ml) than in the no-invasive group (74.2±78.2 U/ml). The LR11 and sIL-2R of CFs post-treatment were lower in the remission group (n=9; 13.46±6.37 ng/ml, <50.0 U/ml) than non-remission group (n=5; 22.40±14.32 ng/ml, 78.4±41.1 U/ml), p = 0.2861, 0.0629 respectively. Conclusions: Patients diagnosed with CNS ML showed high levels of sLR11 and sIL-2R of CFs. These two may be good markers for evaluating diagnosis and treatment effects. Further examination of a large number of cases is required to elucidate these mechanisms.

Shared and malignancy-specific functional plasticity of dynamic brain properties for patients with left frontal glioma.

The time-varying brain activity may parallel the disease progression of cerebral glioma. Assessment of brain dynamics would better characterize the pathological profile of glioma and the relevant functional remodeling. This study aims to investigate the dynamic properties of functional networks based on sliding-window approach for patients with left frontal glioma. The generalized functional plasticity due to glioma was characterized by reduced dynamic amplitude of low-frequency fluctuation of somatosensory networks, reduced dynamic functional connectivity between homotopic regions mainly involving dorsal attention network and subcortical nuclei, and enhanced subcortical dynamic functional connectivity. Malignancy-specific functional remodeling featured a chaotic modification of dynamic amplitude of low-frequency fluctuation and dynamic functional connectivity for low-grade gliomas, and attenuated dynamic functional connectivity of the intrahemispheric cortico-subcortical connections and reduced dynamic amplitude of low-frequency fluctuation of the bilateral caudate for high-grade gliomas. Network dynamic activity was clustered into four distinct configuration states. The occurrence and dwell time of the weakly connected state were reduced in patients' brains. Support vector machine model combined with predictive dynamic features achieved an averaged accuracy of 87.9% in distinguishing low- and high-grade gliomas. In conclusion, dynamic network properties are highly predictive of the malignant grade of gliomas, thus could serve as new biomarkers for disease characterization.

Oxidized ATM governs stemness of breast cancer stem cell through regulating ubiquitylation and acetylation switch

Cancer stem cells (CSCs), as parts of tumor initiation cells, play a crucial role to tumorigenesis, development and recurrence. However, the complicated mechanisms of CSCs to adapt to tumor microenvironment and its stemness maintenance remains unclear. Here, we show that oxidized ATM, a hypoxia-activated cytoplasm ATM, acts a novel function to maintain CSC stemness in triple-negative breast cancer cells (BCSCs) via regulating histone H4 acetylation. Mechanistically, oxidized ATM phosphorylates TRIM21 (a E3 ubiquitin ligase) serine 80 and serine 469. Serine 80 phosphorylation of TRIM21 is essential for the ubiquitination activity of TRIM21. TRIM21 binds with SIRT1 (one of deacetylase), resulting in ubiquitylation-mediated degradation of SIRT1. The reduced SIRT1 leads to increase of histone H4 acetylation, thus facilitating CSC-related gene expression. Clinical data verify that high level of ATM in breast tumors is positively correlated with malignant grade, and is closely related with low SIRT1, high p-TRIM21, and high CD44 expression. In conclusion, our study provides a novel mechanism by which oxidized ATM governing BCSCs stemness and reveals an important link among oxidized ATM, histone acetylation, and BCSCs maintenance.

Retroperitoneal Soft Tissue Sarcoma: Emerging Therapeutic Strategies.

Retroperitoneal soft tissue sarcoma (RPS) is a rare and heterogenous disease for which surgery is the cornerstone of treatment. However, the local recurrence rate is much higher than in soft tissue sarcoma of the extremities since wide resection is usually unfeasible in RPS due to its large size, indistinct tumour borders, anatomical constraints and the thinness of the overlying peritoneum. Local recurrence is the leading cause of death for low-grade RPS, whereas high-grade tumours are prone to distant metastases. In recent decades, the role of emerging therapeutic strategies, such as more extended surgery and (neo)adjuvant treatments to improve oncological outcome in primary localised RPS, has been extensively investigated. In this review, the recent data on the evolving multidisciplinary management of primary localised RPS are comprehensively discussed. The heterogeneity of RPS, with their different histological subtypes and biological behaviour, renders a standard therapeutic 'one-size-fits-all' approach inappropriate, and treatment should be modified according to histological type and malignancy grade. There is sufficient evidence that frontline extended surgery with compartmental resection including all ipsilateral retroperitoneal fat and liberal en bloc resection of adjacent organs and structures, even if they are not macroscopically involved, increases local tumour control in low-grade sarcoma and liposarcoma, but not in leiomyosarcoma for which complete macroscopic resection seems sufficient. Additionally, preoperative radiotherapy is not indicated for all RPSs, but seems to be beneficial in well-differentiated liposarcoma and grade I/II dedifferentiated liposarcoma, and probably in solitary fibrous tumour. Whether neoadjuvant chemotherapy is of benefit in high-grade RPS remains unclear from retrospective data and is subject of the ongoing randomised STRASS 2 trial, from which the results are eagerly awaited. Personalised, histology-tailored multimodality treatment is promising and will likely further evolve as our understanding of the molecular and genetic characteristics within RPS improves.

CSIG-13. DIELECTRIC PROPERTIES OF INTRACRANIAL TUMORS – ROLE OF MYELIN CONTENT

Abstract INTRODUCTION Recently, tumor treating fields (TTFields) were established for the treatment of newly diagnosed glioblastoma (GBM). One of the most crucial parameters defining the treatment efficacy of TTFields is the electric field intensity, which depends on the dielectric properties of the tumor tissue. In this study we determined the dieclectric properties of brain tumors by analyzing resected tissue. In GBM patients, histological analysis for cellularity, vascularization and myelin content was performed. In addition, sensitivity analyses for specific parameters were conducted. METHODS A cohort of 130 patients with tumors of different histology and malignancy grade have been recruited. Tissue samples were placed into a cylindrical cell with a known diameter. The impedance was recorded at frequencies 20Hz-1MHz. The measured impedance was translated into dielectric properties (conductivity and relative permittivity) based on the parallel plate model. Myelin, which is the most powerful electric isolator in the brain, was assessed in GBM samples by luxol fast blue staining, and quantified in a three-tier scale. To assess the impact of tissue conditions on the measurements, probes were warmed to 35 degree Celsius, dehydrated or irrigated with 0.9% saline solution. RESULTS We found significant differences between the conductivity of different types of tumors with meningiomas showing the lowest and GBM tissue exhibiting the highest conductivity values. GBM samples with very high median conductivity values displayed a consistently lower myelin content. In addition, GBM patients with particularly high conductivity had a significantly shorter overall survival (log rank analysis, p = 0.024). While tissue temperature had no detectable effects on the dielectric properties in GBM, saline irrigation tissue hydration significantly affected the results. CONCLUSION The dielectric properties of intracranial tumors depend on histological class and malignancy grade. GBM patients with high conductivity values showed a significantly poorer prognosis, indicating this parameter as potential marker for TTF efficacy.

Thirty-day surgical morbidity and risk factors in pediatric brain tumor surgery: a 10-year nationwide retrospective study.

Pediatric neuro-oncological surgery is often associated with significant risk; however, comprehensive data on surgical morbidity remain limited. The purpose of this study was therefore to provide national population-based data on both the incidence and characteristics of poor postoperative outcomes following pediatric intracranial neuro-oncological surgery. Additionally, the authors aimed to evaluate key risk factors for poor postoperative outcomes including overall morbidity, significant morbidity, and the most frequent types of morbidity. The authors conducted a registry-based, nationwide, retrospective study including all children receiving surgical treatment for a CNS tumor over a 10-year period. Patients were identified using the Danish Childhood Cancer Registry, and 30-day morbidity was assessed through manual review of electronic health records. Significant morbidity was defined as complications in need of treatment under general anesthesia, ICU admission, or persistent neurological deficits at 30 days following surgery or death. Risk factors including sex, age, tumor location, tumor malignancy grade, and preoperative hydrocephalus were investigated using multivariate logistic regression analysis. A total of 349 children undergoing 473 tumor procedures were included, with an overall morbidity rate of 66.0% and a significant morbidity rate of 34.2%. The most frequent complications included neurological deficits (41.4%) and CSF-related morbidity consisting of CSF leaks, pseudomeningoceles, and postoperative hydrocephalus. Highly significant associations between infratentorial tumor location and both significant morbidity (OR 1.26, 95% CI 1.11-1.43; p < 0.001) and neurological deficits (OR 1.38, 95% CI 1.21-1.57; p < 0.001) were identified. In addition, younger age was revealed as a major risk factor of both postoperative CSF leakage and CSF-related morbidity in general. In this large, population-based cohort, the authors show that postoperative morbidity is frequent, occurring in about two-thirds of all patients, largely driven by neurological deficits and CSF-related complications. In addition, infratentorial tumor location and younger age emerged as key risk factors for poor postoperative outcomes.

Advances in Glioblastoma Therapy: An Update on Current Approaches.

Glioblastoma multiforme (GBM) is a primary malignant brain tumor characterized by a high grade of malignancy and an extremely unfavorable prognosis. The current efficacy of established treatments for GBM is insufficient, necessitating the prompt development of novel therapeutic approaches. The progress made in the fundamental scientific understanding of GBM is swiftly translated into more advanced stages of therapeutic studies. Despite extensive efforts to identify new therapeutic approaches, GBM exhibits a high mortality rate. The current efficacy of treatments for GBM patients is insufficient due to factors such as tumor heterogeneity, the blood-brain barrier, glioma stem cells, drug efflux pumps, and DNA damage repair mechanisms. Considering this, pharmacological cocktail therapy has demonstrated a growing efficacy in addressing these challenges. Towards this, various forms of immunotherapy, including the immune checkpoint blockade, chimeric antigen receptor T (CAR T) cell therapy, oncolytic virotherapy, and vaccine therapy have emerged as potential strategies for enhancing the prognosis of GBM. Current investigations are focused on exploring combination therapies to mitigate undesirable side effects and enhance immune responses against tumors. Furthermore, clinical trials are underway to evaluate the efficacy of several strategies to circumvent the blood-brain barrier (BBB) to achieve targeted delivery in patients suffering from recurrent GBM. In this review, we have described the biological and molecular targets for GBM therapy, pharmacologic therapy status, prominent resistance mechanisms, and new treatment approaches. We also discuss these promising therapeutic approaches to assess prospective innovative therapeutic agents and evaluated the present state of preclinical and clinical studies in GBM treatment. Overall, this review attempts to provide comprehensive information on the current status of GBM therapy.

Construction and validation of a nomogram for predicting the prognosis of patients with lymph node-positive invasive micropapillary carcinoma of the breast: based on SEER database and external validation cohort

BackgroundInvasive micropapillary carcinoma (IMPC) of the breast is a rare subtype of breast cancer with high incidence of aggressive clinical behavior, lymph node metastasis (LNM) and poor prognosis. In the present study, using the Surveillance, Epidemiology, and End Results (SEER) database, we analyzed the clinicopathological characteristics and prognostic factors of IMPC with LNM, and constructed a prognostic nomogram.MethodsWe retrospectively analyzed data for 487 breast IMPC patients with LNM in the SEER database from January 2010 to December 2015, and randomly divided these patients into a training cohort (70%) and an internal validation cohort (30%) for the construction and internal validation of the nomogram, respectively. In addition, 248 patients diagnosed with IMPC and LNM at the Fourth Hospital of Hebei Medical University from January 2010 to December 2019 were collected as an external validation cohort. Lasso regression, along with Cox regression, was used to screen risk factors. Further more, the discrimination, calibration, and clinical utility of the nomogram were assessed based on the consistency index (C-index), time-dependent receiver operating characteristic (ROC), calibration curve, and decision curve analysis (DCA).ResultsIn summary, we identified six variables including molecular subtype of breast cancer, first malignant primary indicator, tumor grade, AJCC stage, radiotherapy and chemotherapy were independent prognostic factors in predicting the prognosis of IMPC patients with LNM (P &amp;lt; 0.05). Based on these factors, a nomogram was constructed for predicting 3- and 5-year overall survival (OS) of patients. The nomogram achieved a C-index of 0.789 (95%CI: 0.759-0.819) in the training cohort, 0.775 (95%CI: 0.731-0.819) in the internal validation cohort, and 0.788 (95%CI: 0.756-0.820) in the external validation cohort. According to the calculated patient risk score, the patients were divided into a high-risk group and a low-risk group, which showed a significant difference in the survival prognosis of the two groups (P&amp;lt;0.0001). The time-dependent ROC curves, calibration curves and DCA curves proved the superiority of the nomogram.ConclusionsWe have successfully constructed a nomogram that could predict 3- and 5-year OS of IMPC patients with LNM and may assist clinicians in decision-making and personalized treatment planning.

Intracranial hemangiopericytoma: long-term surgical outcomes

BACKGROUND: According to 2021 WHS Classification, intracranial hemangiopericytomas or solitary fibrous tumors are rare meningeal neoplasms involving blood vessels and soft tissues. Such neoplasms are commonly classified as malignant due to their aggressive growth, metastasizing beyond the cranial cavity, and frequent recurrencies. Since these tumors rarely occur in neurosurgical patients, publications in Russian do not cover big cohorts of patients whose conditions would be assessed during both early and late observation periods.&#x0D; AIM: The present study analyzed our experience in surgical treatment of hemangiopericytomas and its long-term results.&#x0D; METHODS: The study was arranged as a single-center, pro-and retrospective trial that included hemangiopericytomas patients (n=17), whose tumors of different grades of malignancy (13) were operated at the Federal Neurosurgical Center in Novosibirsk from 2013 to 2021. The follow-up estimates included survivability; physical status (Karnofskys Scale); radicality; metastatic foci; need for postoperative chemo-and radiation therapy; adjuvant therapy effect on patients survivability, and delaying time to relapse.&#x0D; RESULTS: In total, 17 patients were included. 11 of them underwent total hemangiopericytomas removal (65%), and 6 subtotal removal (35%). Their survivability within the first year after the operation was 100%. As for the 5-year follow up, only 8 patients out of 17 were available, their mean observation time comprising 64.7 months. The 5-year survivability was 75% (6 out of 8 patients). A relapse occured in 3 out of 17 (17.5%). The mean delaying time comprised 67 months. 6 out of 17 patients (35%) underwent radiation therapy. Among the patients with total and subtotal removals who underwent postoperative radiation treatment neither a relapse nor tumor growth nor metastases were found.&#x0D; CONCLUSION: Intracranial hemangiopericytoma is a rare malignant space-occupying neoplasm. Considering our experience and published data, its treatment requires aggressive tactics that includes a radical removal of the tumor followed by early irradiation of the tumors residual volume or bed either in a proton accelerator or a gamma-knife facility notwithstanding its malignancy grade. It is also recommended to extend the follow-up period for such patients to 1015 years that should include annual cancer screening to detect local relapses and metastases.

Genome-wide association study of mammary gland tumors in Maltese dogs.

A genome-wide association study (GWAS) is a valuable tool for investigating genetic and phenotypic variation in many diseases. The objective of this study was to identify variations in the genomes of Maltese dogs that are associated with the mammary gland tumor (MGT) phenotype and to assess the association between each biological condition and MGT phenotype in Maltese dogs. DNA was extracted from 22 tumor samples and 11 whole blood samples from dogs with MGTs. Genome-wide single-nucleotide polymorphism (SNP) genotyping was performed, and the top 20 SNPs associated with various conditions and genetic variations were mapped to their corresponding gene locations. The genotyping process successfully identified 173,662 loci, with an overall genotype completion rate of 99.92%. Through the quality control analysis, 46,912 of these SNPs were excluded. Allelic tests were conducted to generate Manhattan plots, which showed several significant SNPs associated with MGT phenotype in intergenic region. The most prominent SNP, located within a region associated with transcription and linked to the malignancy grade of MGT, was identified on chromosome 5 (p = 0.00001) though there may be lack of statistical significance. Other SNPs were also found in several genes associated with oncogenesis, including TNFSF18, WDR3, ASIC5, STAR, and IL1RAP. To our knowledge, this is the first GWAS to analyze the genetic predisposition to MGT in Maltese dogs. Despite the limited number of cases, these analyzed data could provide the basis for further research on the genetic predisposition to MGTs in Maltese dogs.

CBX7 reprograms metabolic flux to protect against meningioma progression by modulating the USP44/c-MYC/LDHA axis.

Meningioma is one of the most common primary neoplasms in the central nervous system, but no specific molecularly targeted therapy has been approved for the clinical treatment of aggressive meningiomas. There is hence an urgent demand to decrypt the biological and molecular landscape of malignant meningioma. Here, through the in-silica prescreening and 10-year follow-up studies of 445 meningioma patients, we uncovered that CBX7 expression progressively decreases with malignancy grade and neoplasia stage in meningioma, and a high CBX7 expression level predicts a favorable prognosis in meningioma patients. CBX7 restoration significantly induces cell cycle arrest and inhibits meningioma cell proliferation. iTRAQ-based proteomics analysis indicated that CBX7 restoration triggers the metabolic shift from glycolysis to oxidative phosphorylation. The mechanistic study demonstrated that CBX7 promotes the proteasome-dependent degradation of c-MYC protein by transcriptionally inhibiting the expression of a c-MYC deubiquitinase, USP44, consequently attenuates c-MYC-mediated transactivation of LDHA transcripts, and further inhibits glycolysis and subsequent cell proliferation. More importantly, the functional role of CBX7 was further confirmed in subcutaneous and orthotopic meningioma xenograft mouse models and meningioma patients. Altogether, our results shed light on the critical role of CBX7 in meningioma malignancy progression and identify the CBX7/USP44/c-MYC/LDHA axis as a promising therapeutic target against meningioma progression.

Immunoexpression of HSP27 does not seem to influence the prognosis of oral tongue squamous cell carcinoma.

New methods of early detection and risk assessment have been studied aiming to predict the prognosis of patients and directing a specialized treatment of the oral tongue squamous cell carcinoma (OTSCC). In this context, several molecular biomarkers have been investigated for this purpose, and, among them, the heat shock protein 27 (HSP27) can be named. The study aimed to analyze whether heat shock protein 27 (HSP27) exerts any influence on OTSCC, correlating its immunoexpression with clinicopathological parameters, and patient survival. The sample comprised 55 OTSCC cases and 20 normal oral mucosa specimens. The malignancy grading systems proposed by the WHO in 2005, Brandwein-Gensler et al., and Almangush et al. were applied in a histomorphological study. HSP27 expressions were evaluated through the Immunoreactivity Score System (IRS). Significant values were considered at p <0.05 for all statistical tests. Higher IRS results were observed for normal oral mucosa specimens when compared to OTSCC cases (p <0.001). No significant associations between HSP27 immunostaining, the analyzed clinicopathological parameters and patient survival were observed. The results of the present study indicate lower HSP27 expression in OTSCC cases compared to normal oral mucosa specimens. Thus, HSP27 expression does not seem to influence patient prognosis.

Diagnostic accuracy of anti-3-[18F]-FACBC PET/MRI in gliomas

PurposeThe primary aim was to evaluate whether anti-3-[18F]FACBC PET combined with conventional MRI correlated better with histomolecular diagnosis (reference standard) than MRI alone in glioma diagnostics. The ability of anti-3-[18F]FACBC to differentiate between molecular and histopathological entities in gliomas was also evaluated.MethodsIn this prospective study, patients with suspected primary or recurrent gliomas were recruited from two sites in Norway and examined with PET/MRI prior to surgery. Anti-3-[18F]FACBC uptake (TBRpeak) was compared to histomolecular features in 36 patients. PET results were then added to clinical MRI readings (performed by two neuroradiologists, blinded for histomolecular results and PET data) to assess the predicted tumor characteristics with and without PET.ResultsHistomolecular analyses revealed two CNS WHO grade 1, nine grade 2, eight grade 3, and 17 grade 4 gliomas. All tumors were visible on MRI FLAIR. The sensitivity of contrast-enhanced MRI and anti-3-[18F]FACBC PET was 61% (95%CI [45, 77]) and 72% (95%CI [58, 87]), respectively, in the detection of gliomas. Median TBRpeak was 7.1 (range: 1.4–19.2) for PET positive tumors. All CNS WHO grade 1 pilocytic astrocytomas/gangliogliomas, grade 3 oligodendrogliomas, and grade 4 glioblastomas/astrocytomas were PET positive, while 25% of grade 2–3 astrocytomas and 56% of grade 2–3 oligodendrogliomas were PET positive. Generally, TBRpeak increased with malignancy grade for diffuse gliomas. A significant difference in PET uptake between CNS WHO grade 2 and 4 gliomas (p < 0.001) and between grade 3 and 4 gliomas (p = 0.002) was observed. Diffuse IDH wildtype gliomas had significantly higher TBRpeak compared to IDH1/2 mutated gliomas (p < 0.001). Adding anti-3-[18F]FACBC PET to MRI improved the accuracy of predicted glioma grades, types, and IDH status, and yielded 13.9 and 16.7 percentage point improvement in the overall diagnoses for both readers, respectively.ConclusionAnti-3-[18F]FACBC PET demonstrated high uptake in the majority of gliomas, especially in IDH wildtype gliomas, and improved the accuracy of preoperatively predicted glioma diagnoses.Clinical trial registration ClinicalTrials.gov ID: NCT04111588, URL: https://clinicaltrials.gov/study/NCT04111588

Simultaneous quantification of Gadoxetic acid and Cisplatin in hepatocellular carcinomas using laser ablation-inductively coupled plasma-mass spectrometry.

The gadolinium-based contrast agent Gadoxetic acid and the platinum-based antitumor agent Cisplatin were quantitatively imaged in liver and liver cancer (hepatocellular carcinoma, HCC) tissue of rats by means of laser ablation-inductively coupled plasma-mass spectrometry. HCC bearing rats simultaneously received a tail vein injection of the hepatocyte-specific magnetic resonance imaging contrast agent Gadoxetic acid and a transarterial injection of Cisplatin 15min before sacrifice and liver removal. Resecting HCC with adjacent liver tissue allows the comparison of Gd, Pt, and endogenous elements like Fe, Cu, and Zn in the various tissue types. Region of interest analysis reveals lower concentrations of Gd in HCC and higher Gd content in the adjacent liver, fitting the selective uptake of Gadoxetic acid into hepatocytes. Furthermore, two malignancy grades and their possible impact on the Gadoxetic acid and Cisplatin uptake are compared. For this, four high grade (G3) and two moderate grade (G2) HCCs were analysed, including a control sample each. Gd concentrations were lower in HCC irrespective of the grade of dedifferentiation (G2, G3) compared to adjacent liver. Despite local arterial Cisplatin injection, concentrations of Pt were similar or also reduced in HCC compared to liver tissue. In addition, endogenous Fe, Cu, and Zn were quantified. While Zn was homogenously distributed, higher Fe concentrations were determined in liver tissue compared to HCC. Hotspots of Cu suggest a deregulated copper homeostasis in certain liver lesions. The Gd and Fe distributions are compared in detail with cellular alterations examined by hematoxylin and eosin staining.

Domain and Histopathology Adaptations–Based Classification for Malignancy Grading System

Accurate proliferation rate quantification can be used to devise an appropriate treatment for breast cancer. Pathologists use breast tissue biopsy glass slides stained with hematoxylin and eosin to obtain grading information. However, this manual evaluation may lead to high costs and be ineffective because diagnosis depends on the facility and the pathologists' insights and experiences. Convolutional neural network acts as a computer-based observer to improve clinicians' capacity in grading breast cancer. Therefore, this study proposes a novel scheme for automatic breast cancer malignancy grading from invasive ductal carcinoma. The proposed classifiers implement multistage transfer learning incorporating domain and histopathologic transformations. Domain adaptation using pretrained models, such as InceptionResNetV2, InceptionV3, NASNet-Large, ResNet50, ResNet101, VGG19, and Xception, was applied to classify the ×40 magnification BreaKHis data set into eight classes. Subsequently, InceptionV3 and Xception, which contain the domain and histopathology pretrained weights, were determined to be the best for this study and used to categorize the Databiox database into grades 1, 2, or 3. To provide a comprehensive report, this study offered a patchless automated grading system for magnification-dependent and magnification-independent classifications. With an overall accuracy (means ±SD) of 90.17%±3.08% to 97.67%±1.09% and an F1 score of 0.9013 to 0.9760 for magnification-dependent classification, the classifiers in this work achieved outstanding performance. The proposed approach could be used for breast cancer grading systems in clinical settings.

P02.06.B DIELECTRIC PROPERTIES OF INTRACRANIAL TUMORS

Abstract BACKGROUND Recently, tumor treating fields (TTFields) were established for the treatment of newly diagnosed glioblastoma (GBM). One of the most crucial parameters defining the treatment efficacy of TTFields is the electric field intensity, which depends on the dielectric properties of the tumor tissue. In this study we determined the dieclectric properties of brain tumors by analyzing resected tissue following a fast acquisition protocol. In GBM patients, histological analysis for cellularity, vascularization and myelin content was performed. In addition, sensitivity analyses for specific parameters (tissue hydration, temperature, and saline irrigation) were conducted. MATERIAL AND METHODS A cohort of 130 patients with tumors of different histology and malignancy grade have been recruited (meningioma: n=36; brain metastases n=29; low grade glioma n=7; anaplastic glioma = 12; other= 7; glioblastoma n=39, all treated with TTFields). Tissue samples were placed into a cylindrical cell with a known diameter. The impedance was recorded at frequencies 20Hz-1MHz using a software specifically developed for this study. The measured impedance was translated into dielectric properties of the sample (conductivity and relative permittivity) based on the parallel plate model. Myelin, which is the most powerful electric isolator in the brain, was assessed in GBM samples by luxol fast blue staining, and quantified in a three-tier scale. To assess the impact of tissue conditions on the measurements, probes were warmed to 35 degree Celsius, dehydrated or irrigated with 0.9% saline solution. RESULTS We found significant differences between the conductivity of different types of tumors with meningiomas showing the lowest and GBM tissue exhibiting the highest conductivity values. GBM samples with very high median conductivity values displayed a consistently lower myelin content. In addition, GBM patients with particularly high conductivity had a significantly shorter overall survival (log rank analysis, p = 0.024). While tissue temperature had no detectable effects on the dielectric properties in GBM, saline irrigation tissue hydration significantly affected the results. CONCLUSION The dielectric properties of intracranial tumors depend on histological class and malignancy grade. GBM patients with high conductivity values showed a significantly poorer prognosis, indicating this parameter as potential marker for TTF efficacy.