Marker Of Tumor Aggressiveness Research Articles

Serum lactate dehydrogenase as a prognostic marker for treatment response in IDH wild-type glioblastoma patients undergoing stupp protocol.

Elevated lactate dehydrogenase (LDH), a marker of tumor aggressiveness and metabolic alterations, may predict treatment response and overall survival across various tumors. This study investigates the correlation between serum LDH levels and clinical outcomes in glioblastoma patients treated with radiotherapy (RT) and temozolomide (TMZ). This retrospective study analysed patients with IDH wild-type glioblastoma (IDH-wt GB) treated at the Radiotherapy Department of Azienda Ospedaliero-Universitaria Senese from 2018 to 2023. Clinical data, including hematologic parameters (e.g., LDH), imaging (MRI), and MGMT promoter methylation status, were collected. All patients received RT and TMZ following the Stupp protocol. Serum LDH levels were measured one week before RT, and Radiological Response (RR) was assessed using RANO criteria. Overall survival (OS), progression-free survival (PFS), and RR were primary endpoints. Statistical analyses included Kaplan-Meier, Cox regression, and decision tree analysis for LDH cut-off determination. In a cohort of 147 IDH wild-type glioblastoma patients treated with the Stupp protocol, the median OS was 14 months and median PFS was 8 months. Elevated baseline LDH levels were associated with significantly poorer outcomes, showing a median OS of 9 months versus 20 months and a median PFS of 6 months versus 13 months for lower LDH levels (p < 0.001 and p = 0.0001, respectively). LDH levels also correlated with RR (p = 0,001), Multivariate analysis confirmed high LDH as an independent predictor of worse OS (HR = 2.31) and PFS (HR = 2.60), suggesting its utility as a prognostic biomarker. Elevated LDH levels before starting the Stupp protocol are clinically significant as they predict poorer overall survival and progression-free survival in glioblastoma patients and worse RR. Incorporating LDH measurements into treatment planning can help identify patients at higher risk of poor outcomes, allowing for more tailored and potentially aggressive treatment strategies to improve management and therapeutic responses in glioblastoma.

The value of multiple diffusion metrics based on whole-lesion histogram analysis in evaluating the subtypes and proliferation status of non-small cell lung cancer.

Limited studies have explored the utility of whole-lesion histogram analysis in discerning the subtypes and proliferation status of non-small cell lung cancer (NSCLC), despite its potential to provide comprehensive tissue assessment through the computation of additional quantitative metrics. This study sought to assess the significance of intravoxel incoherent motion (IVIM) and diffusion kurtosis imaging (DKI) histogram parameters in discriminating between squamous cell carcinoma (SCC) and adenocarcinoma (AC), and to examine the correlation of each parameter with the proliferative marker Ki-67. Patients with space-occupying lesions detected by chest CT examination and with further routine MRI, DKI and IVIM functional sequence scans were enrolled. Based on the pathological results, seventy patients with NSCLC were selected and divided into AC and SCC groups. Histogram parameters of IVIM (D, D*, f) and DKI (Dapp, Kapp) were calculated, and the Mann-Whitney U test or independent samples t test was used to analyze the differences in each histogram parameter of the SCC and AC groups. Receiver operating characteristic (ROC) curves were used to evaluate the diagnostic performance of the histogram parameters. The correlation coefficient between histogram parameters and Ki-67 was calculated using Spearman's or Pearson's methods. The D 10th percentile, D 90th percentile, D mean, D median, Dapp 10th percentile, Dapp 90th percentile, Dapp mean, Dapp median, Dapp skewness, Dapp SD of the AC groups were significantly higher than those of the SCC groups, while the Kapp entropy and Kapp SD of the SCC groups were significantly higher than those of the AC groups. All the above differences were statistically significant (all P < 0.05). ROC curve analysis revealed that Dapp mean showed the best performance for differentiating AC from SCC lesions, with an area under the ROC curve of 0.832 (95% confidence interval [CI]: 0.707-0.919). But there was no statistically significant difference in diagnostic efficacy compared to other histogram parameters (all P>0.05). Dapp 90thpercentile, Dapp mean, Kapp skewnes showed a slight negative correlation with Ki-67 expression (r value -0.340, -0.287, -0.344, respectively; P< 0.05), while the other histogram parameters showed no significant correlation with Ki-67 (all P > 0.05). Our study demonstrates the utility of IVIM and DKI histogram analyses in differentiating NSCLC subtypes, particularly AC and SCC. Correlations with the Ki-67 index suggest that Dapp mean, Dapp 90th percentile, and Kapp skewness may serve as markers of tumor aggressiveness, supporting their use in NSCLC diagnosis and treatment planning.

Radiomic score is prognostic in clinical stage I lung adenocarcinoma ≤2 cm undergoing surgery.

As sub-lobar resection becomes acceptable for lung cancer ≤2 cm, a preoperative marker of tumor aggressiveness to choose an appropriate extent of resection becomes necessary. We sought to assess the utility of Computer-Aided Nodule Assessment and Risk Yield (CANARY), a validated radiomic tool, in clinical stage I adenocarcinoma ≤2 cm. We performed a retrospective review of resected lung cancer patients from 2016-2022. Our eligibility criteria included clinical stage I adenocarcinoma, availability of pre-operative computed tomography (CT) imaging, and a lesion size of ≤2 cm. Preoperative imaging was input into the CANARY program, and this was then used to categorize each lesion into good, intermediate, and poor. Kaplan-Meier curve was used to compare the recurrence-free survival (RFS). Descriptive statistics and log-rank tests were conducted to compare RFS between risk groups. Study population (n=134) had a median age of 68.6 and follow up of 2.9 years. By CANARY profile, 29 patients (21.6%) were good risk, 52 (38.8%) intermediate, and 53 (39.6%) poor. By procedure, 52 patients (38.8%) received wedge resections. Overall, the 3-year RFS was 96.3%, 92.0%, and 72.7% for patients with good, intermediate, and poor risks, respectively. There was a statistically significant difference in RFS between each risk group (χ2=12.6, P=0.002). Patients with poor risk were associated with a significantly increased risk of recurrence relative to those with good/intermediate risks [hazard ratio (HR) =5.7, 95% confidence interval (CI): 1.9-17.5]. Poor risk on CANARY analysis is significantly associated with increased risk of recurrence after resection in clinical stage I adenocarcinoma lesions ≤2 cm.

Abstract C020: Nuclear encoded mitochondrial protein MAGMAS as a potential predictor of taxane sensitivity in advanced prostate cancer patients and differential diagnostic marker of tumor aggressiveness in men of African ancestry

Abstract Prostate cancer (PCa) is the most commonly diagnosed malignancy and the second leading cause of cancer-related death among men in the United States (U.S.). Strikingly, men of African ancestry (AA) are 1.7 times more likely to be diagnosed with PCa and more than twice as likely to die of PCa than men of European origin (EU). These disparities are driven by socioeconomic, lifestyle, environmental, and biological/genetic factors. Prostate-specific antigen screening is limited in identifying men with aggressive PCa and exposes men to increased harm with minimal reduction in mortality from PCa. Specifically, several studies report that men of AA are considered to have low-risk prostate cancer by clinical parameters, and those who enrolled in active surveillance programs progress to a higher Gleason-grade cancer and high-volume status than men of EA. Also, men of AA in low to moderate-risk groups appear to be at a higher risk for biochemical recurrence after curative-intent treatment. Therefore, there is a need to understand molecular mechanisms underlying PCa aggressiveness in men of AA that are translatable to the clinic as reliable biomarkers and for the development of novel therapeutic targets. Evidence supports that the mitochondria have a fundamental influence on all steps of oncogenesis, including malignant transformation, tumor progression, and treatment resistance. Regarding cancer health disparities, genes encoding mitochondrial complexes involved in oxidative phosphorylation are upregulated to a greater extent in tumor specimens from AA patients than those from EA patients, supporting the rationale for investigating the role of mitochondria in cancer health disparities. This study investigates Magmas, a nuclear-encoded mitochondrial protein, as a potential mitochondrial marker for PCa tumor aggressiveness and a therapeutic target for advanced PCa. Several observations support the rationale for this study: 1) Magmas overexpression in multiple aggressive cancer subtypes, including high-grade prostate, ovarian cancer, and malignant gliomas. 2) AA PCa cell line overexpresses Magmas similar to chemo-resistant PCa cells, whereas the EA cell line is shown to exhibit lower expression. 3) In human cells, overexpression of Magmas suppresses oxidative stress by regulating the reactive oxygen species (ROS) levels. 4) In chemo-resistant PCa cell lines, pharmacological inhibition of Magmas re-sensitized PCa cells to taxane treatment; and 5) non-cytotoxic pharmacological inhibition of Magmas in chemo-resistant PCa cells dramatically reduced clonogenicity potential. We will evaluate the hypothesis that AA PCa tissue will overexpress Magmas and that overexpression will predict tumor aggressiveness, and 2) that pharmacological inhibition of Magmas will overcome treatment resistance in advanced PCa models. The proposed exploratory study is highly relevant as it will reveal the biological basis for race-related differential expression of Magmas, providing critical insights into mitochondrial determinants that contribute to PCa mortality disparities. Citation Format: Alfonso Duran, Kristen Whitley, Krystal Santiago, Bhaskar Das, Carlos Casiano, Frankis Almaguel. Nuclear encoded mitochondrial protein MAGMAS as a potential predictor of taxane sensitivity in advanced prostate cancer patients and differential diagnostic marker of tumor aggressiveness in men of African ancestry [abstract]. In: Proceedings of the 17th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2024 Sep 21-24; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2024;33(9 Suppl):Abstract nr C020.

Tumour budding as a prognostic biomarker in biopsies and resections of neoadjuvant-treated rectal adenocarcinoma.

Tumour budding (TB) is a marker of tumour aggressiveness which, when measured in rectal cancer resection specimens, predicts worse outcomes and response to neoadjuvant therapy. We investigated the utility of TB assessment in the setting of neoadjuvant treatment. A single-centre, retrospective cohort study was conducted. TB was assessed using the hot-spot International Tumour Budding Consortium (ITBCC) method and classified by the revised ITBCC criteria. Haematoxylin and eosin (H&E) and AE1/AE3 cytokeratin (CK) stains for ITB (intratumoural budding) in biopsies with PTB (peritumoural budding) and ITB (intratumoural budding) in resection specimens were compared. Logistic regression assessed budding as predictors of lymph node metastasis (LNM). Cox regression and Kaplan-Meier analyses investigated their utility as a predictor of disease-free (DFS) and overall (OS) survival. A total of 146 patients were included; 91 were male (62.3%). Thirty-seven cases (25.3%) had ITB on H&E and 79 (54.1%) had ITB on CK assessment of biopsy tissue. In univariable analysis, H&E ITB [odds (OR) = 2.709, 95% confidence interval (CI) = 1.261-5.822, P = 0.011] and CK ITB (OR = 2.165, 95% CI = 1.076-4.357, P = 0.030) predicted LNM. Biopsy-assessed H&E ITB (OR = 2.749, 95% CI = 1.258-6.528, P = 0.022) was an independent predictor of LNM. In Kaplan-Meier analysis, ITB identified on biopsy was associated with worse OS (H&E, P = 0.003, CK: P = 0.009) and DFS (H&E, P = 0.012; CK, P = 0.045). In resection specimens, CK PTB was associated with worse OS (P = 0.047), and both CK PTB and ITB with worse DFS (PTB, P = 0.014; ITB: P = 0.019). In multivariable analysis H&E ITB predicted OS (HR = 2.930, 95% CI = 1.261-6.809) and DFS (HR = 2.072, 95% CI = 1.031-4.164). CK PTB grading on resection also independently predicted OS (HR = 3.417, 95% CI = 1.45-8.053, P = 0.005). Assessment of TB using H&E and CK may be feasible in rectal cancer biopsy and post-neoadjuvant therapy-treated resection specimens and is associated with LNM and worse survival outcomes. Future management strategies for rectal cancer might be tailored to incorporate these findings.

Microvascular Invasion in Hepatocellular Carcinoma: Some Puzzling Facets.

Hepatocellular carcinoma is the main type of primary liver cancer. Macroscopic vascular invasion is usually identified during imaging, whereas microvascular invasion is usually determined by histopathological evaluation. We aim to identify the association between microvascular invasion and other markers of tumor aggressiveness and to identify the role of microvascular invasion in the prognosis of patients who were treated by liver transplantation for hepatocellular carcinoma. This is a single-center retrospective analysis of prospectively collected data. Patients who received liver transplantation for hepatocellular carcinoma were included in the study. Data were collected regarding sociodemographic variables, criteria of selection for liver transplantation, pretransplant alpha-fetoprotein, presence or absence of microvascular invasion, presence or absence of recurrence, overall survival, and disease-free survival. Data were analyzed using Statistical Package for the Social Sciences. Sociodemographic laboratory values and radiologic tumor characteristics were found to be similar in patients with or without microvascular invasion. Our study revealed that microvascular invasion is associated with increased recurrence, decreased diseasedfree survival, and decreased overall survival, only for patients with hepatocellular carcinoma beyond Milan criteria at the time of liver transplantation. For patients beyond Milan criteria, but not within Milan criteria, microvascular invasion plays a significant role in predicting recurrence and shorter survival after liver transplantation.

Skeletal muscle and visceral adipose radiodensities are pre-surgical, non-invasive markers of aggressive kidney cancer.

Most studies on body composition in kidney cancer have been conducted among patients with metastatic disease. Given that aggressive tumours can adversely impact body composition and even non-metastatic tumours can be aggressive, we evaluated associations between pre-surgical body composition features and tumour pathological features in patients with non-metastatic clear cell renal cell cancer (ccRCC). The Resolve Cohort consists of 1239 patients with non-metastatic ccRCC who underwent nephrectomy at Memorial Sloan Kettering Cancer Center between 2000 and 2020. The cross-sectional areas and radiodensities of skeletal muscle, visceral adipose, and subcutaneous adipose tissues were determined from pre-surgical computed tomography (CT) scans at the third lumbar vertebrae using Automatica software. Pearson's correlation coefficients describe inter-relationships among BMI and body composition variables, while odds ratios (OR) and 95% confidence intervals (CI) estimate associations between continuous body composition features (per 1-standard deviation) and advanced stage (Stage III vs. Stages I-II) and high Fuhrman grade (Grades 3-4 vs. 1-2) from multivariable logistic regression models that considered the potential impact of biological sex, contrast enhanced CTs, and early age at onset of ccRCC. The cohort was predominantly male (69%), white (89%), and had a median age of 58. The proportion of patients presenting with advanced stage and high-grade disease were 31% and 51%, respectively. In models that adjusted for demographics and all body composition variables simultaneously, decreasing skeletal muscle radiodensity (i.e., more fat infiltration) but increasing visceral adipose tissue radiodensity (i.e., more lipid depletion) were associated with advanced tumour features. Per 8.4 HU decrease in skeletal muscle radiodensity, the odds of presenting with advanced stage was 1.61 (95% CI: 1.34-1.93). Per 7.22 HU increase in visceral adipose tissue radiodensity, the odds of presenting with advanced stage was 1.45 (95% CI: 1.22-1.74). Skeletal muscle index (i.e., sarcopenia) was not associated with either tumour feature. Similar associations were observed for Fuhrman grade, a more direct marker of tumour aggressiveness. Associations did not differ by sex, contrast use, or age at onset of ccRCC. Lipid infiltrated skeletal muscle, but lipid depleted visceral adipose tissue were independently associated with advanced tumour features in non-metastatic ccRCC. Findings highlight the importance of evaluating the full range of body composition features simultaneously in multivariable models. Interpreting pre-surgical CTs for body composition for patients may be a novel and non-invasive way to identify patients with aggressive renal tumours, which is clinically relevant as renal biopsies are not routinely performed.

Subcentimetric Papillary Thyroid Carcinoma: Does the Diagnosis Kind Impact Prognosis?

Subcentimetric papillary thyroid carcinoma (SPTC) (papillary thyroid carcinoma with less than 10 mm in size) usually presents an excellent prognosis, with few aggressive reported cases. Given the globally increased incidenceof SPTC, physicians are struggling with the need to identify prognostic factors to stratify SPTC. The aim was to compare clinicopathological variables and prognosis between clinically and incidentally diagnosed SPTC. Materials and methodsː This is a retrospective observational study on patients with SPTC who underwent thyroidectomy between 2002 and 2015. Two groups were considered: G1 (n=60 (61.9%)), clinical diagnosis (Bethesda III-VI cytology in the thyroid tumor/in cervical lymphadenopathies) and G2 (n=37 (38.1%)), incidental diagnosis (thyroidectomy for benign thyroid pathology). The histological material was reviewed, and molecular analysis of the BRAF, RAS, and TERTpromoter (TERTp) genes was performed. Resultsː Ninety-seven individuals were included, 60 (61.9%) of which were from G1, with a predominance of female sex (n=83 (85.6%)). Individuals of G1 were younger (53.0±14.2 versus 59.3±13.9 years; p=0.035), were more frequently treated with 131-iodine (39.2% versus 13.4%; p=0.007), had the largest diameter (8(p25-p75: 7-9) versus 5(p25-p75: 4-6.5) mm; p<0.001), and higher frequency of minimal extracapsular invasion (45% versus 24.3%; p=0.041). Increased tumor size was the only independent predictor of a clinical diagnosis (p<0.001). Conclusionsː Clinically and incidentally diagnosed SPTC showed excellent medium- to long-term prognosis. A larger SPTC was more likely a driver of clinical detection than a marker of tumor aggressiveness, but caution should be taken as contradictory data persists.

Chelators as Antineuroblastomas Agents.

Neuroblastoma represents 8-10 % of all malignant tumors in childhood and is responsible for 15 % of cancer deaths in the pediatric population. Aggressive neuroblastomas are often resistant to chemotherapy. Canonically, neuroblastomas can be classified according to the MYCN (N-myc proto-oncogene protein) gene amplification, a common marker of tumor aggressiveness and poor prognosis. It has been found that certain compounds with chelating properties may show anticancer activity, but there is little evidence for the effect of chelators on neuroblastoma. The effect of new chelators characterized by the same functional group, designated as HLZ (1-hydrazino phthalazine), on proliferation (WST-1 and methylene blue assay), cell cycle (flow cytometry), apoptosis (proliferation assay after use of specific pharmacological inhibitors and western blot analysis) and ROS production (fluorometric assay based on dichlorofluorescein diacetate metabolism) was studied in three neuroblastoma cell lines with different levels of MYCN amplification. The molecules were effective only on MYCN-non-amplified cells in which they arrested the cell cycle in the G0/G1 phase. We investigated the mechanism of action and identified the activation of cell signaling that involves protein kinase C.

Preoperative prediction of Ki-67 status in invasive breast carcinoma using dynamic contrast-enhanced MRI, diffusion-weighted imaging and diffusion tensor imaging

BackgroundThe Ki-67 is a beneficial marker of tumor aggressiveness. It is proliferation index that has been used to distinguish luminal B from luminal A breast cancers. By fast progress in quantitative radiology modalities, tumor biology and genetics can be assessed in a more accurate, predictive, and cost-effective method. The aim of this study was to assess the role of dynamic contrast-enhanced magnetic resonance imaging, diffusion-weighted imaging and diffusion tensor imaging in prediction of Ki-67 status in patients with invasive breast carcinoma estimate cut off values between breast cancer with high Ki-67 status and those with low Ki-67 status.ResultsCut off ADC (apparent diffusion co-efficient) value of 0.657 mm2/s had 96.4% sensitivity, 75% specificity and 93.8% accuracy in differentiating cases with high Ki67 from those with low Ki67. Cut off maximum enhancement value of 1715 had 96.4% sensitivity, 75% specificity and 93.8% accuracy in differentiating cases with high Ki67 from those with low Ki67. Cut off washout rate of 0.73 I/S had 60.7% sensitivity, 75% specificity and 62.5% accuracy in differentiating cases with high Ki67 from those with low Ki67. Cut off time to peak value of 304 had 71.4% sensitivity, 75% specificity and 71.9% accuracy in differentiating cases with high Ki67 from those with low Ki67.ConclusionsADC, time to peak and maximum enhancement values had high sensitivity, specificity and accuracy in differentiating breast cancer with high Ki-67 status from those with low Ki-67 status.

Abstract 551: MDM2 inhibition in combination with imipridone ONC201 treatment as a synergistic combination in solid tumors

Abstract Mouse double minute 2 homolog (MDM2) has emerged as a target of increasing interest in recent years following its initial identification as an oncogene and subsequent identification as an often-amplified marker of tumor aggressiveness across several cancer types, including breast cancer and several soft tissue and osteo-sarcomas. MDM2 is best characterized as a p53-targeting E3-ubiquitin ligase, and significant efforts have been made to develop inhibitors that function to block MDM2-p53 binding and subsequent ubiquitination, thereby stabilizing p53. One such inhibitor, milademetan (RAIN-32), for instance has progressed to the clinic and has completed phase I and II trials both alone and as a combination agent in several hematological malignancies and solid tumors, and a phase III trial (MANTRA, NCT04979442) is currently underway. Given the role of p53 in contributing to transcriptional activation of MDM2, however, such inhibitors of MDM2-p53WT interaction serve to increase cellular levels of MDM2, a result which we have confirmed across several MDM2-p53 inhibitors and cell lines. Non-p53 mediated roles of MDM2 have become of increasing interest in recent years, and we have previously reported on MDM2 mediated immune effects. Further, studies of immune checkpoint blockade driven hyperprogressive disease in clinical cases have preliminarily identified MDM2 amplification as a potential predictor. Indeed, use of small-molecule degrader SP-141 which drives MDM2 autoubiquitination and subsequent proteolysis in both p53WT and p53-/- HCT116 cell lines demonstrates a remarkably similar IC50 (523 and 505 nM, respectively, at 72h) that suggests the importance of non-p53-dependent MDM2 pathways. ONC201 is a small molecule imipridone that is currently in clinical trials for brain cancers and a variety of other tumor types. Initially identified for its role in driving the TRAIL-pathway and integrated stress response (ISR), we recently identified an additional effect of ONC201 in demonstrably reducing detectable MDM2 levels in cell lines upon treatment. Preliminary investigation into this effect suggests synergism in combination with milademetan treatment, with the MDM2-p53 inhibition driven increase in MDM2 levels being abolished upon cotreatment of ONC201 and milademetan. Further exploration of this combination is underway, and may serve as a novel translatable therapeutic approach, particularly in combination with checkpoint blockade. Citation Format: Andrew George, Ilyas Sahin, Shengliang Zhang, Maximilian Schwermann, Francesca Di Cristofano, Charlotte DeGeorge, Wafik S. El-Deiry. MDM2 inhibition in combination with imipridone ONC201 treatment as a synergistic combination in solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 551.

YM155 inhibits neuroblastoma growth through degradation of MYCN: A new role as a USP7 inhibitor

Amplification of the MYCN gene (MNA) is observed in approximately 25 to 35% of neuroblastoma patients, and is a well-recognized marker of tumor aggressiveness and poor outcome. Targeting MYCN is a novel therapy strategy to induce tumor regression. Here, we discovered that a BIRC5/Survivin inhibitor, YM155, specifically inhibits MNA neuroblastoma cell growth in vitro. We found that YM155 promotes MYCN degradation in MNA cells. Further, we found that YM155 inhibits USP7 deubiquitinase activity in vitro, using Ub-aminomethylcoumarin (Ub-AMC) as substrate. Results from in vivo studies further demonstrated that YM155 significantly inhibited the tumor growth in MNA neuroblastoma xenograft model. Our data support a novel mechanism of action of YM155 in inhibition of growth of cancer cells through inducing MYCN degradation by inibition of activity of deubiquitinase like USP7.

Metabolic Tumor Imaging in Head and Neck Oncology

Metabolic Tumor Imaging in Head and Neck Oncology Abstract. Fluorodeoxyglucose with position emission tomography combined with CT or MRI (FDG-PET) has become an important diagnostic and staging method in head and neck squamous cell carcinoma. Some regard FDG-PET merely as a tool able of displaying cancer cells as bright spots on imaging. However, quantification of FDG uptake can be used as a surrogate marker for tumor aggressiveness and predict tumor response before (chemo)-radiation. The FDG uptake of the primary tumor can also predict surgical outcome measures such as depth of invasion, occult nodal metastasis, or bone invasion for oral cancer and/or organ preservation in hypopharyngeal cancer.

Flare on [18F]PSMA-1007 PET/CT after short-term androgen deprivation therapy and its correlation to FDG uptake: possible marker of tumor aggressiveness in treatment-naïve metastatic prostate cancer patients

PurposeShort-term androgen deprivation therapy (ADT) is known to increase heterogeneously prostate-specific membrane antigen (PSMA) expression. This phenomenon might indicate the potential of cancer lesions to respond to ADT. In this prospective study, we evaluated the flare on [18F]PSMA-1007 PET/CT after ADT in metastatic prostate cancer (PCa). Given that aggressive PCa tends to display FDG uptake, we particularly investigated whether the changes in PSMA uptake might correlate with glucose metabolism.MethodsTwenty-five men with newly diagnosed treatment-naïve metastatic PCa were enrolled in this prospective registered clinical trial. All the patients underwent [18F]PSMA-1007 PET/CT immediately before and 3–4 weeks after ADT initiation (degarelix). Before ADT, [18F]FDG PET/CT was also performed. Standardized uptake values (SUV)max of primary and metastatic lesions were calculated in all PET scans. Serum PSA and testosterone blood samples were collected before the two PSMA PET scans. The changes in PSMA uptake after ADT were represented as ΔSUVmax.ResultsAll the patients reached castration levels of testosterone at the time of the second [18F]PSMA-1007 PET/CT. Overall, 57 prostate, 314 lymph nodes (LN), and 406 bone lesions were analyzed. After ADT, 104 (26%) bone, 33 (11%) LN, and 6 (11%) prostate lesions showed an increase (≥ 20%) in PSMA uptake, with a median ΔSUVmax of + 50%, + 60%, and + 45%, respectively. Among the lesions detected at the baseline [18F]PSMA-1007 PET/CT, 63% bone and 46% LN were FDG-positive. In these metastases, a negative correlation was observed between the PSMA ΔSUVmax and FDG SUVmax (p < 0.0001). Moreover, a negative correlation between the ΔSUVmax and the decrease in serum PSA after ADT was noted (p < 0.0001).ConclusionsA heterogeneous increase in PSMA uptake after ADT was detected, most evidently in bone metastases. We observed a negative correlation between the PSMA flare and the intensity of glucose uptake as well as the decrease of serum PSA, suggesting that lesions presenting with such flare might potentially be less aggressive.Trial registrationNCT03876912, registered 15 March 2019.

PTPRD and CNTNAP2 as markers of tumor aggressiveness in oligodendrogliomas

Oligodendrogliomas are typically associated with the most favorable prognosis among diffuse gliomas. However, many of the tumors progress, eventually leading to patient death. To characterize the changes associated with oligodendroglioma recurrence and progression, we analyzed two recurrent oligodendroglioma tumors upon diagnosis and after tumor relapse based on whole-genome and RNA sequencing. Relapsed tumors were diagnosed as glioblastomas with an oligodendroglioma component before the World Health Organization classification update in 2016. Both patients died within 12 months after relapse. One patient carried an inactivating POLE mutation leading to a clearly hypermutated progressed tumor. Strikingly, both relapsed tumors carried focal chromosomal rearrangements in PTPRD and CNTNAP2 genes with associated decreased gene expression. TP53 mutation was also detected in both patients after tumor relapse. In The Cancer Genome Atlas (TCGA) diffuse glioma cohort, PTPRD and CNTNAP2 expression decreased by tumor grade in oligodendrogliomas and PTPRD expression also in IDH-mutant astrocytomas. Low expression of the genes was associated with poor overall survival. Our analysis provides information about aggressive oligodendrogliomas with worse prognosis and suggests that PTPRD and CNTNAP2 expression could represent an informative marker for their stratification.

Liquid biopsies for early diagnosis of brain tumours: in silico mathematical biomarker modelling.

Brain tumours are the biggest cancer killer in those under 40 and reduce life expectancy more than any other cancer. Blood-based liquid biopsies may aid early diagnosis, prediction and prognosis for brain tumours. It remains unclear whether known blood-based biomarkers, such as glial fibrillary acidic protein (GFAP), have the required sensitivity and selectivity. We have developed a novel in silico model which can be used to assess and compare blood-based liquid biopsies. We focused on GFAP, a putative biomarker for astrocytic tumours and glioblastoma multi-formes (GBMs). In silico modelling was paired with experimental measurement of cell GFAP concentrations and used to predict the tumour volumes and identify key parameters which limit detection. The average GBM volumes of 449 patients at Leeds Teaching Hospitals NHS Trust were also measured and used as a benchmark. Our model predicts that the currently proposed GFAP threshold of 0.12 ng ml−1 may not be suitable for early detection of GBMs, but that lower thresholds may be used. We found that the levels of GFAP in the blood are related to tumour characteristics, such as vasculature damage and rate of necrosis, which are biological markers of tumour aggressiveness. We also demonstrate how these models could be used to provide clinical insight.

Cytoplasmic Colocalization of RXRα and PPARγ as an Independent Negative Prognosticator for Breast Cancer Patients

Retinoid X receptor α (RXRα) is a nuclear receptor (NR) which functions as the primary heterodimeric partner of other NRs including the peroxisome proliferator-activated receptor γ (PPARγ). We previously reported that, in breast cancers (BC), the subcellular localization of these two receptors was strongly associated with patient prognosis. In the present work, we investigated the prognosis value of the combined cytoplasmic expression of RXRα and PPARγ using a retrospective cohort of 250 BC samples. Patients with tumors expressing both NRs in tumor cell cytoplasm exhibited a significant shorter overall (OS) and disease-free survival (DFS). This was also observed for patients with stage 1 tumors. Cox univariate analysis indicated that patients with tumors coexpressing RXRα and PPARγ in the cytoplasm of tumor cells have a decreased 5 y OS rate. Cytoplasmic co-expression of the two NRs significantly correlated with HER2 positivity and with NCAD and CD133, two markers of tumor aggressiveness. Finally, in Cox multivariate analysis, the co-expression of RXRα and PPARγ in the cytoplasm appeared as an independent OS prognosticator. Altogether, this study demonstrates that the cytoplasmic co-expression of RXRα and PPARγ could be of relevance for clinicians by identifying high-risk BC patients, especially amongst those with early and node-negative disease.

A prognostic hypoxia gene signature with low heterogeneity within the dominant tumour lesion in prostate cancer patients

BackgroundGene signatures measured in a biopsy have been proposed as hypoxia biomarkers in prostate cancer. We assessed a previously developed signature, and aimed to determine its relationship to hypoxia and its heterogeneity within the dominant (index) lesion of prostate cancer.MethodsThe 32-gene signature was assessed from gene expression data of 141 biopsies from the index lesion of 94 patients treated with prostatectomy. A gene score calculated from the expression levels was applied in the analyses. Hypoxic fraction from pimonidazole immunostained whole-mount and biopsy sections was used as reference standard for hypoxia.ResultsThe gene score was correlated with pimonidazole-defined hypoxic fraction in whole-mount sections, and the two parameters showed almost equal association with clinical markers of tumour aggressiveness. Based on the gene score, incorrect classification according to hypoxic fraction in whole-mount sections was seen in one third of the patients. The incorrect classifications were apparently not due to intra-tumour heterogeneity, since the score had low heterogeneity compared to pimonidazole-defined hypoxic fraction in biopsies. The score showed prognostic significance in uni-and multivariate analysis in independent cohorts.ConclusionsOur signature from the index lesion reflects tumour hypoxia and predicts prognosis in prostate cancer, independent of intra-tumour heterogeneity in pimonidazole-defined hypoxia.

Histological Grade and Tumor Stage Are Correlated with Expression of Receptor Activator of Nuclear Factor Kappa b (Rank) in Epithelial Ovarian Cancers.

The receptor activator of nuclear factor kappa B (RANK) is becoming recognized as a master regulator of tumorigenesis, yet its role in gynecological cancers remains mostly unexplored. We investigated whether there is a gradation of RANK protein and mRNA expression in epithelial ovarian cancer (EOC) according to malignancy and tumor staging. Immunohistochemical expression of RANK was examined in a cohort of 135 (benign n = 29, borderline n= 23 and malignant n = 83) EOCs. Wild type and truncated RANK mRNA isoform quantification was performed in a cohort of 168 (benign n = 26, borderline n = 13 and malignant n = 129) EOCs. RANK protein and mRNA values were increased in malignant vs. benign or borderline conditions across serous, mucinous and endometrioid cancer subtypes. Additionally, a trend of increased RANK values with staging was observed for the mucinous and serous histotype. Thus, increased expression of RANK appears associated with the evolution of disease to the onset of malignancy in EOC. Moreover, in some EOC histotypes, RANK expression is additionally associated with clinicopathological markers of tumor aggressiveness, suggesting a role in further progression of tumor activity.

Immunohistochemical Study of Ki-67 in Hyperplastic and Endometrium Carcinoma: A Comparative Study.

Endometrial hyperplasia is defined as a common clinical disorder caused by the increased levels of estrogens with low levels of progesterone; therefore, this hormonal imbalance leads to an increase in the proliferation rate of the endometrial cells. Endometrial carcinoma is one of the most important malignancies affecting women all over the world "accounting for 37.7% of all other disorders affecting the female reproductive system". The expression of the Ki-67 protein is related to the proliferative behavior of malignant tumor cell populations of their own, allowing it to be used as a marker of tumor aggressiveness. The present study was conducted to examine the expression of the proliferation marker, Ki-67 in various endometrial lesions. Ki-67 expression was evaluated in 60 endometrial samples that resulted as either endometrial curetting or hysterectomy specimens, diagnosed with simple hyperplasia (n=10), complex hyperplasia (n=20), atypical hyperplasia (n=6), and endometrial carcinoma (n=24). In patients with endometrial carcinoma, there was an increased expression of Ki-67, compared to proliferative endometrium and simple hyperplasia (P-value=0.0001). There was no such discrepancy between atypical hyperplasia and endometrial carcinoma cases. The expression of Ki-67 showed a positive association with the degree of endometrial cancer (P-value=0.0013), however, not with the age of the patients (P-value&gt;0.05). There is a wide range of variations in the proliferation rate within the development of different endometrial lesions, including benign and malignant lesions. Our findings may be of value in differential diagnosis and prognosis of endometrial hyperplasia and endometrial carcinoma.