31-Phosphorus Magnetic Resonance Spectroscopy in Evaluation of Glioma and Metastases in 3T MRI

Background: 31-Phosphorus magnetic resonance spectroscopy (31-P MRS) has excellent potential for clinical neurological practice because of its noninvasive in-vivo assessment of cellular energy metabolism and the indirect evaluation of the phospholipid composition of the cell membrane, intracellular pH, and intracellular Mg2+ concentration. Purpose: The aim of this study was to evaluate the metabolic characteristics of glioma and metastases using 31-P MRS and assess utility to differentiate both. Study Type: Prospective study. Population: Fifteen consecutive patients with brain tumor. Field Strength/Sequence: Three-tesla magnetic resonance imaging/three-dimensional MRS imaging sequence. Statistical Tests: Unpaired sample t-test, and one-way analysis of variance with Tukey's post-hoc test. Results: Significantly decreased values of phosphomonoesters/inorganic phosphate (PME/Pi) in the tumor group (1.22 ± 0.72) compared with controls (2.28 ± 1.44) with a p-value of 0.041 were observed. There is a significant decrease in phosphocreatine (PCr)/Pi values (energy demand) in the tumor group (2.76 ± 0.73) compared with controls (4.13 ± 1.75) with a p-value of 0.050. Significant increase in Pi/adenosine triphosphate (ATP) was noted in tumor group (0.28 ± 0.09) compared with controls (0.22 ± 0.08) with p-value 0.049. Among tumor group, PME/PCr values were significantly decreased in gliomas (0.35 ± 0.17) than metastasis (0.58 ± 0.23) compared with controls with a p-value of 0.047. A significant decrease in PME/ATP was noted in gliomas (0.25 ± 0.12) than metastasis (0.41 ± 0.14) compared with controls with a p-value of 0.034. The tumor group exhibits alkaline pH (7.12 ± 0.10) compared with the normal parenchyma (7.04 ± 0.06) with a significant p-value of 0.025. Glioma and metastasis could not be differentiated with pH. However, the perilesional edema of glioma shows alkaline pH (7.09 ± 0.06) and metastasis shows acidic pH (7.02 ± 0.05) with a significant p-value of 0.030. Conclusion: Our study provides new insight into the cellular constituents and pH of gliomas and metastases and results were significant in differentiation between these two. However, due to the additional high expense, it is available as a research tool in very few institutions in India.

Placental Leucine Aminopeptidase as a Potential Specific Urine Biomarker for Invasive Ovarian Cancer

Background: A non-invasive and sensitive biomarker for the detection of ovarian cancer (OvCa) is lacking. We aim to investigate if urinary placental leucine aminopeptidase (P-LAP) can serve as a reliable biomarker for OvCa. Methods: P-LAP activity was measured using a LAP assay kit (Serotech Co., Ltd., Sapporo, Japan) in the urine of 22 patients with benign or borderline malignant ovarian tumors and 18 patients with OvCa. In this assay, L-methionine was added at 20 mM because P-LAP is functional, but other aminopeptidases are inhibited at this dose of L-methionine. Results: The mean urinary P-LAP activity was significantly higher in the OvCa group than in the benign or borderline malignant tumor group. When the cut-off value of P-LAP was determined as 11.00 U/L, its sensitivity and specificity for differentiating invasive cancer were 77.8% and 95.5%, respectively. Conclusion: Although the usefulness of this test should be confirmed in a larger cohort of cases and controls, our study is the first to highlight the importance of urinary P-LAP as a biomarker for OvCa.

Primary Small Cell Malignancies of the Breast: Are They Rare Malignancies?

In contrast with the other organs such as the lung, small cell tumors have been less studied in the breast due to their relatively less frequency. Although rare, neuroendocrine neoplasms, some lymphomas, and some small cell sarcomas such as undifferentiated small round cell sarcoma and rhabdomyosarcoma can be seen in small cell morphology in the breast. Many cytological specimens such as fine-needle aspiration biopsies and touch imprint cytology are used for diagnosis and further prognostic/predictive marker determination in primary breast masses, sentinel and axillary lymph nodes, and metastatic masses. Lobular carcinoma deserves to be considered in the small cell tumor group because of its small, monomorphic, discohesive, scant cytoplasmic cytological features. Since so many different types of tumors in the breast can have small cell characteristics, they should be divided into small cell neuroendocrine tumors and small cell nonneuroendocrine tumors. When evaluating small cell breast tumors cytologically, wide tumor diversity should be kept in mind, and clinical, hematological, and radiological features should be taken into consideration.

Comparison of rarely seen tumors of the colorectal region clinicopathologically

Background: Majority of colorectal neoplasms are adenocarcinomas but there is a small percentage of tumors from other histological cell lines Method: One thousand one hundred patients who were applied surgical treatment due to colorectal cancer at general surgical clinic between years of 2010-2020 were examined. Patients have been grouped as Diffuse large b cell lymphoma (DLBCL) (group1), Malignant melanoma (group2), Medullary carcinoma (group3), Neuroendocrine tumor (group4) and they were included in the study in this way. In the groups,clinicopathological data of patients and their survival periods have been compared. Results: Twenty patients are included in our study: Group 1 was composed of 5, Group 2 was composed of 4, Group 3 was composed of 3, and Group 4 was composed of 8 patients. Emergency application rate (60%) was higher in Group 1 (p: 0.004). A verage age was above 50 in 4 groups and there was no difference between groups (p:0,966).Tumor diameter was on average (cm)(8 vs 6,55 vs 5,4 vs 3,75 p:0,073) in the groups, The number of lymph nodes dissected were (13 vs 14.5 vs 19 vs 19 p:0.373) The number of metastatic lymph nodes were ( 0 vs 1.5 vs 0 vs 0.5 p:0.188). Survival was significantly shorter in the malignant melanoma group, the longest survival was in the neuroendocrine tumor group (15.625vs8.5vs20 vs 40.857 p:0.001) Conclusions: Although clinicopathological features and postoperative follow-up results were similar, there were differences in survival among patients. Maligant melanoma histopathological type had a worse prognosis than other tumors

PATH-27. MGMT PROMOTER STATUS IN IDH1/2 MUTANT ANAPLASTIC ASTROCYTOMA PATIENTS ASSESSED BY DNA METHYLATION PROFILING AND QMS-PCR: A REPORT FROM THE EORTC BRAIN TUMOR GROUP

BACKGROUND Temozolomide efficacy in high-grade glioma is related to MGMTp methylation. We compared the prognostic and predictive effect of MGMTp between DNA methylation profiling (MGMT-STP27 model) and qMS-PCR in IDH1/2mt anaplastic astrocytoma patients. METHODS The 2x2 factorial design phase III CATNON trial randomized 751 adult patients with newly diagnosed 1p/19q non-codeleted anaplastic glioma to 59.4Gy radiotherapy, radiotherapy with concurrent temozolomide, radiotherapy with 12 cycles of adjuvant temozolomide, or radiotherapy with concurrent and adjuvant temozolomide. MGMTp methylation status was assessed with the MGMT-STP27 model using 850k EPIC data, and qMS-PCR. IDH1/2 mutation status was determined with next-generation sequencing. OS was measured from randomization date. RESULTS We identified 444 IDH1/2mt anaplastic astrocytoma patients. MGMTp was methylated in 365/440 patients (83.0%) with MGMT-STP27 data, and 168/361 patients (46.5%) with qMS-PCR data. The agreement between both modalities is 59.9% (Cohen’s Kappa score 0.229). At database lock, 289 patients with MGMT-STP27 data were alive and 236 patients with qMS-PCR data. The median OS of MGMTp methylated glioma patients was 9.1 yrs [95%CI 7.5-not reached] for the MGMT-STP27 model, and not reached [95%CI 9.1-not reached] for qMS-PCR. For MGMTp unmethylated glioma patients, the median OS was 6.9 yrs [95%CI 6.2-not reached] for the MGMT-STP27 model, and 6.8 yrs [95%CI 6.2-9.7] for qMS-PCR. The HR for OS based on MGMTp methylation was 0.88 [95%CI 0.58-1.31] for the MGMT-STP27 model, and 0.72 [95%CI 0.50-1.03]) for qMS-PCR. The HR for OS after radiotherapy with any temozolomide vs radiotherapy alone for the MGMT-STP27 model was 0.53 [95%CI 0.37-0.78] for MGMTp methylated, and 0.54 [95%CI 0.25-1.18] for MGMTp unmethylated glioma patients; and for MS-PCR was 0.34 [95%CI 0.19-0.61] for MGMTp methylated, and 0.53 [95%CI 0.33-0.85] for MGMTp unmethylated glioma patients. CONCLUSION MGMTp methylation, regardless of assay, was neither prognostic nor predictive for outcome to temozolomide in IDH1/2mt anaplastic astrocytoma patients.

NIMG-01. INTEROBSERVER VARIABILITY OF THE REVISED IMAGING SCORECARD FOR LEPTOMENINGEAL METASTASIS: A JOINT EORTC BRAIN TUMOR GROUP AND RANO EFFORT

BACKGROUND Validation of the 2016 LANO MRI scorecard for leptomeningeal metastasis failed for multiple reasons. The objective of this joint EORTC Brain Tumor Group and RANO effort was to validate the feasibility of the revised MRI scorecard for assessing response in leptomeningeal metastasis. METHODS Coded paired cerebrospinal MRI of 20 patients with leptomeningeal metastases from solid cancers at baseline and follow-up after treatment and instructions for assessment were provided via the EORTC imaging platform. The kappa coefficient (K) was used to evaluate inter-observer pairwise agreement. Statistical analyses were performed using SAS V9.4 software (Cary, NC). The sponsor of the study was the University Hospital Zurich (2018-00192). RESULTS Thirty-five raters participated, including 9 neuroradiologists, 17 neurologists, 4 radiation oncologists, 3 neurosurgeons and 2 medical oncologists. Among leptomeningeal metastases-related items at baseline, the best median concordance was noted for hydrocephalus (K=0.63), and the worst median for spinal linear enhancing disease (K=0.46). The median concordance for overall response was moderate (K=0.44). Notably, the interobserver agreement for the presence of parenchymal brain metastases at baseline was minimal (K=0.29). Significant differences were observed when considering the specialty of the raters. Only 394 of 700 ratings (56%) were fully completed. Among 394 fully completed ratings, perfect concordance was noted in 293 ratings (74%) when comparing the overall response according to the guidelines provided in the scorecard and the overall response provided by the raters. The main discordances were noted for partial response according to the rater versus stable disease according to the guidelines (n=44), followed by progression according to the raters versus stable disease according to the guidelines (n=23). CONCLUSION Electronic case report forms with "blocking solutions" are probably required to enforce completeness and quality of scoring. These results confirm the necessity of central review and the need for training of MRI assessment in clinical trials.

A Novel Defined Ferroptosis-Related Gene Signature for Predicting the Prognosis of Kidney Renal Clear Cell Carcinoma

Objective: Currently, the mechanism of ferroptosis in the progression of kidney renal clear cell carcinoma (KIRC) is still unclear. This paper aims to explore the potential mechanism of ferroptosis-related genes in KIRC.Methods: Using KIRC chip data in Gene Expression Synthesis (GEO) database, the differentially expressed genes (DEGs) between normal and tumor group were screened in GSE168845, GSE105261 and GSE11151 by limma package. Ferroptosis-related DEGs were gained by the intersection of DEGs and ferroptosis-related genes, which from the FerrDb database. Gene ontology (GO) enrichment analysis of ferroptosis-related DEGs was carried out by gene set enrichment analysis (GSEA). Univariate and multivariate Cox risk regression model was used to screen and establish gene prognosis risk prediction model. For ferroptosis-related DEGs, targeted small molecules are predicted for the treatment of KIRC.Results: In GSE168845, GSE105261 and GSE11151, 2532 DEGs were screened from normal group and tumor group. And 149 ferroptosis-related genes were obtained from the FerrDb database. Through the intersection of DEGs and ferroptosis-related genes, 17 ferroptosis-related DEGs were obtained. GO enrichment analysis indicated that primary biological processes of 17 ferroptosis-related DEGs enrichment had iron ion binding, microvillus membrane and regulation of transcription from RNA polymerase II promoter in response to stress. Based on univariate and multivariate Cox regression analysis, the multivariate prognostic risk prediction model composed of three ferroptosis DEGs including MT1G, LAMP2 and MIOX was constructed. The results of patient risk score indicated that the prognosis with high score was worse than those with low score. Meanwhile, we found that the exprssion of MT1G, LAMP2 and MIOX were related with methylation and immune infiltration in KIRC. Terroptosis-gene interaction and terroptosis-miRNA coregulatory network of MT1G, LAMP2 and MIOX were collected by Network Analyst. Then, the ferroptosis-related prognosis nomogram, including age, gender, grade, TNM and risk score, was found to predict the overall survival (OS) of KIRC patients. Finally, according to ferroptosis related DEGs, the potential therapeutic effects of emetine, cephaeline,scoulerline, sanguinarine, cicloheximide, tolfenamic acid, phenoxybenzamine and calmidazolium were predicted in KIRC.Conclusion: The risk prediction models of MT1G, LAMP2 and MIOX can effectively predict the prognosis of patients with KIRC. And MT1G, LAMP2 and MIOX are related to methylation and immune infiltration in KIRC, which is expected to play a guiding role in the clinical treatment of KIRC. Targeted these three genes, potential therapeutic drugs of emetine, cephaeline,scoulerline, sanguinarine, cicloheximide, tolfenamic acid, phenoxybenzamine and calmidazolium were also predicted in KIRC.

Canine Natural Killer Cell-Derived Exosomes Exhibit Antitumor Activity in a Mouse Model of Canine Mammary Tumor

Natural killer (NK) cells are key immune cells engaged in fighting infection and malignant transformation. In this study, we found that canine NK cell-derived exosomes (NK-exosomes) separated from activated cytotoxic NK cell supernatants express specific markers including CD63, CD81, Alix, HSP70, TSG101, Perforin 1, and Granzyme B. We examined the antitumor effects of NK-exosomes in an experimental murine mammary tumor model using REM134 canine mammary carcinoma cell line. We observed changes in tumor size, tumor initiation, progression, and recurrence-related markers in the control, tumor group, and NK-exosome-treated tumor group. We found that the tumor size in the NK-exosome-treated tumor group decreased compared with that of the tumor group in the REM134-driven tumorigenic mouse model. We observed significant changes including the expression of tumorigenesis-related markers, such as B cell-specific Moloney murine leukemia virus insertion site 1 (Bmi-1), vascular endothelial growth factor (VEGF), matrix metallopeptidase-3 (MMP-3), interleukin-1β (IL-1β), IL-6, tumor necrosis factor-α (TNF-α), multidrug resistance protein (MDR), tumor suppressor protein p53 (p53), proliferating cell nuclear antigen (PCNA), and the apoptotic markers, B cell lymphoma-2 associated X (Bax) and B cell lymphoma-extra large (Bcl-xL) belonging to the Bcl-2 family, in the tumor group compared with those in the control group. The expression of CD133, a potent cancer stem cell marker, was significantly higher than that of the control. By contrast, the NK-exosome-treated tumor group exhibited a significant reduction in Bmi-1, MMP-3, IL-1β, IL-6, TNF-α, Bax, Bcl-xL, and PCNA expression compared with that in the tumor group. Furthermore, the expression of CD133, which mediates tumorigenesis, was significantly decreased in the NK-exosome-treated tumor group compared with that in the tumor group. These findings indicate that canine NK-exosomes represent a promising therapeutic tool against canine solid tumors, including mammary carcinoma.

The Role of miRNA in the Pathophysiology of Neuroendocrine Tumors

Neuroendocrine tumors (NETs) represent a tumor group that is both rare and heterogeneous. Prognosis is largely determined by the tumor grading and the site of the primary tumor and metastases. Despite intensive research efforts, only modest advances in diagnostic and therapeutic approaches have been achieved in recent years. For patients with non-respectable tumor stages, prognosis is poor. In this context, the development of novel diagnostic tools for early detection of NETs and prediction of tumor response to therapy as well as estimation of the overall prognosis would greatly improve the clinical management of NETs. However, identification of novel diagnostic molecules is hampered by an inadequate understanding of the pathophysiology of neuroendocrine malignancies. It has recently been demonstrated that microRNA (miRNA), a family of small RNA molecules with an established role in the pathophysiology of quite different cancer entities, may also play a role as a biomarker. Here, we summarize the available knowledge on the role of miRNAs in the development of NET and highlight their potential use as serum-based biomarkers in the context of this disease. We discuss important challenges currently preventing their use in clinical routine and give an outlook on future directions of miRNA research in NET.

Adoption of Diffusion Tensor Imaging under Optimized Fuzzy C-Means Cluster Algorithm in Intracerebral Benign and Malignant Tumor Resection

The study aimed to analyze the application of diffusion tensor imaging (DTI) in the surgery of benign and malignant intracranial tumors through improved fuzzy C-means (FCM). First, a method of combining the maximum and minimum distances was proposed to improve the FCM algorithm. Then, the optimized FCM was applied to the diffusion tensor imaging (DTI) diagnosis. The patients were rolled into the benign tumor group and the malignant tumor group, and relevant parameters were compared. Finally, the postoperative total resection rate and disability rate of the DTI experimental group and the traditional control (Ctrl) group were evaluated. It was found that the segmentation accuracy of the optimized FCM algorithm was higher than traditional one and the obtained corpus callosum edge contour was clearer. In 63 patients with intracranial space, there were obvious differences in pairwise comparison of meningioma and glioma, metastatic tumor’s apparent diffusion coefficient (ADC) value, relative apparent diffusion coefficient (r ADC) value, and relative anisotropy fraction (r FA) P < 0.05 . In terms of the ADC, r ADC, and r FA values of tumor parenchymal area, those of benign tumors were larger than malignant tumors P < 0.05 . The ADC value (8.21 ± 1.87) and r FA value (1.36 ± 0.41) of the contralateral normal white matter area of malignant tumor were greater than the ADC value (7.23 ± 2.31) and r FA value (0.61 ± 0.24) of the peritumor white matter area, with statistically significant differences P < 0.05 . The total cut rates of the experimental group and the Ctrl were 87.5% and 54.84%, and the disability rates were 6.25% and 34.38%. In conclusion, the optimized FCM has high accuracy. The ADC, r ADC, and r FA values of DTI are important in the diagnosis of intracranial tumors. Besides, DTI can improve the survival rate in guiding intracranial tumor resection.