Indicator Of Tumor Aggressiveness Research Articles

The specific shapes of capillaries are associated with worse prognosis in patients with invasive breast cancer.

Angiogenesis is considered essential for tumor progression; however, whether histological counting of blood vessel numbers, expressed as microvessel density (MVD), can be a prognostic factor in breast cancer remains controversial. It has been suggested that the specific morphology of blood vessels such as glomeruloid microvascular proliferation (GMP) is associated with clinical parameters. Here, we aimed to clarify the significance of MVD with revised immunohistochemistry and to identify new blood vessel shapes that predict prognosis in breast cancer. Four hundred and eleven primary breast cancer specimens were collected, and the sections were immunohistochemically stained with CD31 (single staining) and CD31 and Collagen IV (double staining). The prognosis of patients was examined based on the MVD value, and the presence of GMP and other blood vessels with other specific shapes. As a result, high MVD value and the presence of GMP were not associated with worse prognosis. By contrast, patients with deep-curved capillaries surrounding tumor cell nests (C-shaped) or excessively branched capillaries near tumor cell nests showed a significantly poor prognosis. The presence of these capillaries was also correlated with clinicopathological parameters such as Ki-67 index. Thus, the morphology of capillaries rather than MVD can be a better indicator of tumor aggressiveness.

Relationship between Eccentricity and Volume Determined by Spectral Algorithms Applied to Spatially Registered Bi-Parametric MRI and Prostate Tumor Aggressiveness: A Pilot Study.

(1) Background: Non-invasive prostate cancer assessments using multi-parametric MRI are essential to the reliable detection of lesions and proper management of patients. While current guidelines call for the administration of Gadolinium-containing intravenous contrast injections, eliminating such injections would simplify scanning and reduce patient risk and costs. However, augmented image analysis is necessary to extract important diagnostic information from MRIs. Purpose: This study aims to extend previous work on the signal to clutter ratio and test whether prostate tumor eccentricity and volume are indicators of tumor aggressiveness using bi-parametric (BP)-MRI. (2) Methods: This study retrospectively processed 42 consecutive prostate cancer patients from the PI-CAI data collection. BP-MRIs (apparent diffusion coefficient, high b-value, and T2 images) were resized, translated, cropped, and stitched to form spatially registered BP-MRIs. The International Society of Urological Pathology (ISUP) grade was used to judge cases of prostate cancer as either clinically significant prostate cancer (CsPCa) (ISUP ≥ 2) or clinically insignificant prostate cancer (CiPCa) (ISUP < 2). The Adaptive Cosine Estimator (ACE) algorithm was applied to the BP-MRIs, followed by thresholding, and then eccentricity and volume computations, from the labeled and blobbed detection maps. Then, univariate and multivariate linear regression fittings of eccentricity and volume were applied to the ISUP grade. The fits were quantitatively evaluated by computing correlation coefficients (R) and p-values. Area under the curve (AUC) and receiver operator characteristic (ROC) curve scores were used to assess the logistic fitting to CsPCa/CiPCa. (3) Results: Modest correlation coefficients (R) (>0.35) and AUC scores (0.70) for the linear and/or logistic fits from the processed prostate tumor eccentricity and volume computations for the spatially registered BP-MRIs exceeded fits using the parameters of prostate serum antigen, prostate volume, and patient age (R~0.17). (4) Conclusions: This is the first study that applied spectral approaches to BP-MRIs to generate tumor eccentricity and volume metrics to assess tumor aggressiveness. This study found significant values of R and AUC (albeit below those from multi-parametric MRI) to fit and relate the metrics to the ISUP grade and CsPCA/CiPCA, respectively.

New Supramolecular Hypoxia-Sensitive Complexes Based on Azo-Thiacalixarene

Hypoxia accompanies many human diseases and is an indicator of tumor aggressiveness. Therefore, measuring hypoxia in vivo is clinically important. Recently, complexes of calix[4]arene were identified as potent hypoxia markers. The subject of this paper is new hypoxia-sensitive host-guest complexes of thiacalix[4]arene. We report a new high-yield synthesis method for thiacalix[4]arene with four anionic carboxyl azo fragments on the upper rim (thiacalixarene L) and an assessment of the complexes of thiacalixarene L with the most widespread cationic rhodamine dyes (6G, B, and 123) sensitivity to hypoxia. Moreover, 1D and 2D NMR spectroscopy data support the ability of the macrocycles to form complexes with dyes. Rhodamines B and 123 formed host-guest complexes of 1:1 stoichiometry. Complexes of mixed composition were formed with rhodamine 6G. The association constant between thiacalixarene L and rhodamine 6G is higher than for other dyes. Thiacalixarene L-dye complexes with rhodamine 6G and rhodamine B are stable in the presence of various substances present in a biological environment. The UV-VIS spectrometry and fluorescence showed hypoxia responsiveness of the complexes. Our results demonstrate that thiacalixarene L has a stronger binding with dyes compared with the previously reported azo-calix[4]arene carboxylic derivative. Thus, these results suggest higher selective visualization of hypoxia for the complexes with thiacalixarene L.

Predicting Oncologic Outcomes in Small Renal Tumors

BackgroundMost patients diagnosed with renal cancer today present with small renal masses (SRMs). Although these patients have a low risk of dying from their disease and many are followed with active surveillance protocols, a small subset of renal cell carcinomas (RCCs) behave aggressively. Knowledge regarding features of aggressive behavior would enable better adoption of active surveillance strategies among these patients. ObjectiveWe sought to improve prognostic models to predict metastasis-free survival after nephrectomy through focused analyses of clinicopathologic characteristics of SRMs associated with adverse outcomes. Design, setting, and participantsWe identified consecutive patients with surgically resected SRMs (≤4 cm) at the University of Texas Southwestern Kidney Cancer Program between 1998 and 2020. In addition, we evaluated the ability of SRMs to form tumors when implanted in mice, an indicator of tumor aggressiveness. Outcome measurements and statistical analysisWe examined the clinicopathologic factors associated with metastasis including prospectively performed BAP1 immunohistochemistry at our Clinical Laboratory Improvement Amendments laboratory. Multivariable Cox proportional hazard regression was used to predict metastasis-free survival. Results and limitationsA total of 3900 evaluable nephrectomies (from 3674 ethnically diverse patients) were identified, of which 1984 (51%) were SRMs including 1720 RCC. Of these patients with RCC (SRMRCC), 1576 did not have synchronous or metachronous larger RCCs and among these, 37 (2%) developed metastases. SRMRCC that metastasized were significantly enriched for aggressive morphologic phenotypes and engrafted in mice at comparable rates as larger metastatic tumors. BAP1 loss remained significantly associated with metastasis-free survival after accounting for TNM (tumor-node-metastasis) stage and SSIGN (stage, size, grade, and necrosis) score in multivariable analysis. ConclusionsWe identified clinicopathologic features that influence metastasis-free survival for patients with SRMRCC. If validated independently, these data should assist with patient prognosis and help with active surveillance strategies. Patient summaryWe report the identification of features of aggressiveness in small renal tumors that influence the likelihood of metastases after surgery.

Fibroblast activation protein (FAP) expression in CK5/6 expressed (Basal subtype) & CK20 expressed (Luminal subtype) urothelial bladder carcinoma: an immunohistochemical study

ABSTRACT Urinary bladder cancer incidence varies all over the world. Egypt displays high incidence rates. Molecular subtyping helps risk stratification and personalized treatment. Cancer-associated fibroblasts (CAFs) in the tumor microenvironment may provoke tumor-promotion or tumor suppression. Fibroblast activation protein (FAP) is a marker of CAFs, suggested to accelerate tumor progression in various cancers. In urothelial carcinoma, investigations regarding impact of FAP expression on prognosis are needed. This work aims to study impact of FAP expression in urothelial carcinoma and find its relation to CK 5/6 (basal) expressed and CK 20 (luminal) expressed immunohistochemical markers. This retrospective study included 70 urothelial carcinoma specimens. Immunohistochemistry was performed and results were analyzed. FAP was expressed in 67.1% of cases and showed significant association with advanced tumor stage, muscle invasion, mitoses in tumor cells and stratified groups; as 73.9% of FAP positive cases were of Ck5/6+/Ck20- (basal subtype). All studied parameters did not show significant association with patient’s overall survival. In conclusion, FAP could have a role in modulating tumor microenvironment and promoting tumor invasion. FAP is correlated with basal subtype of urothelial carcinoma, which may be an indicator of tumor aggressiveness. FAP antagonists may be helpful in preventing tumor progression.

Delphian lymph node metastasis is a novel indicator of tumor aggressiveness and poor prognosis in papillary thyroid cancer

Although the significance of Delphian lymph nodes (DLNs) in patients with papillary thyroid carcinoma (PTC) has been reported, all studies have been based on a small sample size and lack a direct statement concerning prognosis. A total of 904 consecutive patients were enrolled in the current study, and all patients were divided into two groups (DLN-positive and DLN-negative) according to the presence of DLN metastasis. DLN was detected in 687 patients (76.0%), and 123 (17.9%) had DLN metastasis. Compared to those in the DLN-negative group, the proportion of other central lymph node (CLN) metastases, mean number of metastatic CLNs, and mean metastatic CLN ratio were higher in the DLN-positive group (86.2 vs. 50.2%, 6.70 ± 5.19 vs. 1.60 ± 2.37, and 0.54 ± 0.25 vs. 0.18 ± 0.26, respectively; p < .001). The same phenomena were observed in the metastatic lateral lymph nodes (LLNs) between the DLN-positive and DLN-negative groups (52.0 vs. 15.4%, 7.28 ± 6.08 vs. 3.38 ± 3.73, and 0.23 ± 0.15 vs. 0.13 ± 0.12, respectively; p < .001). Patients in the DLN-positive group had shorter LLN metastasis-free survival and distant metastasis-free survival than patients in the DLN-negative group (93.5% vs. 98.6% and 95.9% vs. 98.8%, respectively, p < .05). DLN metastasis in PTC is associated with tumor aggressiveness and a poor prognosis.

Otoferlin is a prognostic biomarker in patients with clear cell renal cell carcinoma: A systematic expression analysis.

To comprehensively investigate the role of otoferlin as a prognostic and diagnostic biomarker in clear cell renal cell carcinoma. Three independent cohorts were used to study otoferlin in clear cell renal cell carcinoma: The Cancer Genome Atlas cohort (messenger ribonucleic acid expression; clear cell renal cell carcinoma n=514, normal renal tissue n=81); study validation cohort (messenger ribonucleic acid expression; clear cell renal cell carcinoma n=79, normal renal tissue n=44); and immunohistochemistry cohort (protein expression; clear cell renal cell carcinoma n=142, normal renal tissue n=30). Otoferlin gene expressions were extracted from The Cancer Genome Atlas database or determined using quantitative real-time polymerase chain reaction, respectively. Protein expression was assessed using immunohistochemistry staining against otoferlin on tissue microarrays. Correlations between otoferlin messenger ribonucleic acid/protein expression and clinicopathological data/patient survival were statistically tested. Otoferlin messenger ribonucleic acid expression was significantly upregulated in clear cell renal cell carcinoma compared with normal renal tissue. High expression levels correlated with advanced stage, higher grade and metastatic tumors, accompanied by independent prognostic significance for overall and cancer-specific survival. In contrast, otoferlin protein expression was downregulated in tumor tissue. Although, high otoferlin expression in clear cell renal cell carcinoma was positively correlated with histological grading and independently predictive of a shortened progression-free survival. Our data suggest otoferlin as an indicator of tumor aggressiveness and as a prognostic biomarker for patients with clear cell renal cell carcinoma, leading to the conclusion that otoferlin could promote the malignancy of clear cell renal cell carcinoma.

Prognostic implications of dual tracer PET/CT: PSMA ligand and [18F]FDG PET/CT in patients undergoing [177Lu]PSMA radioligand therapy

BackgroundProstate-specific membrane antigen (PSMA)-targeted radioligand therapy (RLT) with 177Lu-labeled PSMA ligands has achieved remarkable results in advanced disease stages of metastatic castration-resistant prostate cancer (mCRPC). However, not all patients benefit from this therapy. Different treatment responses could be explained by tumor heterogeneity triggered by progression and the number of prior treatments. PSMA-negative lesions can be missed on PSMA ligand PET/CT, which subsequently results in an underestimation of tumor burden. Conversely, high FDG uptake may also be an indicator of tumor aggressiveness and thus a poor prognostic marker for response to RLT and overall survival (OS). The aim of this analysis was to investigate the prognostic value of combined PSMA ligand PET/CT and [18F]fluorodeoxyglucose (FDG) PET/CT for outcome prediction in patients undergoing RLT.Materials and methodsThis bicentric analysis included 54 patients with mCRPC who underwent both FDG and PSMA ligand PET/CT imaging before RLT. In all patients, the pattern of PSMA ligand and FDG uptake was visually assessed. Patients with at least one FDG-positive, but PSMA-negative (FDG+/PSMA−) lesions were compared to patients without any FDG+/PSMA− lesions. A log-rank analysis was used to assess the difference in OS between subgroups.ResultsMedian OS was 11 ± 1.8 months (95% CI 7.4–14.6). A significantly lower OS (p < 0.001) was found in patients with at least one FDG+/PSMA− lesion at baseline PET/CTs (n = 18) with a median OS of 6.0 ± 0.5 months (95% CI: 5.0–7.0 months). In comparison, patients without any FDG+/PSMA− lesions (n = 36) had a median OS of 16.0 ± 2.5 months (95% CI: 11.2–20.8 months).ConclusionFDG+/PSMA− lesions are a negative predictor of overall survival in patients with mCRPC undergoing RLT. However, it remains to be determined if patients with FDG+/PSMA− lesions should be excluded from PSMA RLT.

Water exchange between intra and extracellular compartments studied by nuclear magnetic resonance relaxometry and optical microscopy

Nuclear magnetic resonance (NMR) techniques, in particular 1H relaxometry, enable the acquisition of information on the water exchange between different compartments in real-time and in a non-invasive and non-destructive way. Therefore, these are currently the methods of choice for studying the diffusion of water in living tissues and cells. The multi-compartmental nature of these systems may generate multi-exponential decays of the nuclear magnetization vector components to be analyzed in terms of discrete or continuous distributions of the so-called relaxation times. We have evaluated the sensitivity of the continuous distributions of the transverse component relaxation time (T2) to detect and monitor, over time, the water diffusion caused by osmotic pressure variations in tumor cells suspended in isotonic and hypotonic/hypertonic culture media. Our results indicated that the T2 distribution shapes were capable of describing the water compartmentalization and exchange, with evolutions that strongly depended on the degree of tonicity alterations. In order to validate the NMR results we also monitored the samples by phase contrast optical microscopy finding consistency between the two methods. Moreover, a study of T2–T2 correlation function allowed us to observe the exchange between cytoplasmic water and intracellular 1H spin groups. Using a two-site exchange model we also discussed, as a function of the uncertainties on the intra-to-extra water fraction and on the T2 values, the computed intracellular average water lifetime at equilibrium, an important parameter recently proposed as indicator of tumor aggressiveness. The results support the idea that the information conveyed by the T2 parameter might be useful for an MRI diagnostic approach to diseases in which the fluid tonicity or the cellular membranes permeability are altered.

Extracapsular Lymph Node Involvement in Ovarian Carcinoma.

Ovarian cancer (OC) spread to retro-peritoneal lymph nodes is detected in about one out of two patients at primary diagnosis. Whether the histologic pattern of lymph node involvement i.e., intra-(ICG) or extracapsular (ECG) cancer growth may affect patients’ prognosis remains unknown. The aim of the current study was to analyze the prevalence of ECG and ICG in lymph node positive ovarian cancer. We further investigated whether ECG may be related to patients’ prognosis and whether biomarkers expressed in the primary tumor may predict the pattern of lymph node involvement. Lymph node samples stemming from 143 OC patients were examined for presence of ECG. Capsular extravasation was tested for statistical association with clinico-pathological variables. We further tested 27 biomarkers that had been determined in primary tumor tissue for their potential to predict ECG in metastatic lymph nodes. ECG was detected in 35 (24.5%) of 143 lymph node positive patients. High grade (p = 0.043), histologic subtype (p = 0.006) and high lymph node ratio (LNR) (p < 0.001) were positively correlated with presence of ECG. Both ECG (p = 0.024) and high LNR (p = 0.008) were predictive for shortened overall survival. A four-protein signature determined from the primary tumor tissue was associated with presence of concomitant extracapsular spread in lymph nodes of the respective patient. This work found extracapsular spread of lymph node metastasis to be a common feature of lymph node positive ovarian cancer. Since ECG was positively associated with grade, LNR and shortened overall survival, we hypothesize that the presence of ECG may be interpreted as an indicator of tumor aggressiveness.

Gastric mixed neuroendocrine-non-neuroendocrine neoplasm (MiNEN) with pancreatic acinar differentiation: a case report

BackgroundGastric mixed neuroendocrine-non-neuroendocrine neoplasms (MiNENs) are infrequently encountered in routine practice. Some gastric neuroendocrine carcinomas (NECs) have a variety of differentiation patterns; however, pancreatic acinar differentiation in gastric NECs is rare. The molecular abnormalities of NECs with pancreatic acinar differentiation are not well understood.Case presentationA 67-year-old male with a gastric MiNEN with pancreatic acinar differentiation without any symptoms. The tumor consisted of two components, including both glandular and solid histological features. Although the former component was a common type of adenocarcinoma, the latter showed endocrine differentiation and expressed pancreatic acinar enzymes immunohistochemically. A positive signal with the anti-BCL10 antibody, which detects one of the pancreatic acinar enzymes, was also present specifically in the latter component. We also examined TP53 genomic mutations, DNA methylation status, and allelic imbalance (AI), which is an indicator of tumor aggressiveness. Although both components of this tumor showed no genomic mutation and a low methylation epigenotype, the frequency of AI was higher in the acinar-endocrine component than in the adenocarcinomatous component. The finding of AI indicated the progression of the conventional adenocarcinoma to an acinar-endocrine component and identified the aggressive potential of the acinar-endocrine component.ConclusionsWe report a rare case of gastric MiNEN with pancreatic acinar differentiation. AI analysis revealed tumor progression and aggressiveness. In addition, the usefulness of the anti-BCL10 antibody for detecting the acinar-endocrine component was suggested.

Abstract P2-01-12: Detection of circulating cancer stem cells: A novel approach as a predictive marker for breast cancer metastases. This may be especially useful in patients with undetectable circulating epithelial tumor cells

Abstract Background: Breast cancer is one of the most common types of cancer in women worldwide. It has been demonstrated that even localized tumors without clinically apparent metastases give rise to circulating epithelial tumor cells (CETCs). Recent studies have provided strong support for the circulating cancer stem cell (cCSC) hypothesis, which suggests that a more aggressive subpopulation of circulating tumor cells are the source of metastatic spread from the primary tumor. Measuring CETCs in blood of patients has emerged as a non-invasive diagnostic procedure for screening patients who may be at high risk for developing metastatic cancers. However, accurate detection of CETCs may provide erroneous results, since CETCs undergoing EMT during metastasis are down-regulated for the expression of epithelial cell markers. Methods: 26 breast cancer patients were included into the study. The determination of CETCs and cCSC was performed using maintrac® method and tumorsphere forming assay, respectively. Cell viability, surface marker expression and ALDH 1 activity of the cells in the spheres were evaluated by fluorescence scanning microscope. Results: Sphere formation was observed in 80 % of patients. We found that the number of tumorspheres depended on stage of disease. The number of tumorspheres increased significantly with tumor progression, especially with the presence of metastases. Tumorsphere formation was observed in all metastatic patients (median of 30 tumorspheres/100μl of blood), although only 27% of them had detectable CETCs. Analysis of surface marker expression profile showed that the cells in the spheres had typical phenotype of cancer stem cells. Sphere formation was not observed in healthy subjects (n=20). Conclusion: There is a high correlation between the numbers of tumorspheres cultured from peripheral blood with clinical stage of disease. This may be an indicator of tumor aggressiveness, especially presence of metastases and may provide clinically useful prognostic information. Citation Format: Pizon M, Schott D, Pachmann U, Pachmann K. Detection of circulating cancer stem cells: A novel approach as a predictive marker for breast cancer metastases. This may be especially useful in patients with undetectable circulating epithelial tumor cells [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P2-01-12.

Preclinical 19F MRI cell tracking at 3 Tesla.

To develop methods for fluorine-19 (19F) MRI cell tracking in mice on a 3Tesla clinical scanner. Compared to iron-based cell tracking, 19F MRI has lower sensitivity and, consequently, preclinical 19F cell tracking has only been performed at relatively high magnetic field strengths (> 3T). Here, we focus on using 19F MRI to detect macrophages in tumors; macrophage density is an indication of tumor aggressiveness and, therefore, 19F MRI could be used as an imaging biomarker. Perfluorocarbon (PFC)-labeled macrophages were imaged at 3T and NMR spectroscopy was performed to validate 19F spin quantification. In vivo 19F MRI was performed on tumor-bearing mice, post-PFC at both 9.4T and 3T. 3T MRI utilized varying NEX and 19F images were analyzed two different ways for 19F quantification. As few as 25,000 cells could be detected as cell pellets at 3T. 19F quantification in cell pellets by 3T MRI agreed with NMR spectroscopy. 19F signal was observed in the liver, spleen and tumor in all mice at 9.4T and 3T and there was no significant difference in 19F spin quantification. This study demonstrates the ability to detect and quantify 19F signal in murine tumors using 19F MRI at 3T.

Can looking at density differences between liver parenchyma and oligometastatic lesions predict outcomes and toxicities in patients receiving stereotactic body radiation therapy for metastatectomy?

479 Background: Stereotactic body radiation therapy (SBRT) has found utility in oligometastatic liver lesions by providing excellent local control in most patients. These tumors are not routinely biopsied to evaluate for histologic grade due to high risk of seeding. Non-invasive pre-treatment radiographic findings may be able to identify a subset of patients at higher risk of local recurrence. Methods: Retrospective review of an IRB-approved database of liver metastases treated with SBRT yielded 55 patients for final analysis. Liver parenchyma and metastatic liver lesions were contoured using MIM version 6.6.5. Receiver Operating Characteristic curves and mean values were used to generate binary cutoffs for toxicities and Kaplan-Meier analysis, respectively. Computer Tomography features, like density, skew, kurtosis, variance, and volume, based on our pre-SBRT planning liver protocol images and their relationship with outcomes and toxicities were examined. Results: Largepre-SBRT density differences between oligometastatic lesions and liver parenchyma, as measured by Hounsfield Units, was associated with a 3.248 increased risk of local failures (p = 0.027) and grade 3 or higher late non-hepatobiliary toxicities (p = 0.032). There were no associations with overall survival. Lesions with large variance in density was associated with grade 3 or higher acute hepatobiliary toxicities (p = 0.043). Conclusions: Density metrics in metastatic liver lesions are readily available in most treatment planning systems and may be a prognostic indicator of tumor aggressiveness. Higher radiation doses may be needed to reduce rates of local recurrence in these patients. Further studies should examine if post-treatment density metrics are dose-dependent and correlate with outcomes.

5. Imaging techniques in diagnostic approaches

Despite the considerable technological advances in imaging modalities which have occurred over the last years, EUS remains one of the most reliable and accurate technique for the study of gastroenteropancreatic neuroendocrine tumors. More specifically, EUS can detect very small lesions, assess the local extent and lymph node involvement and biopsy the lesion for cytophatological confirmation (EUS-FNA). In addition, nuclear medicine imaging has a relevant role in the evaluation of NET. However, its performance depends on series of patient-specific features (lesion size and uptake, depth and other anatomic features; metabolic activity, receptor expression, affinity and vacancy, tissue specificity) and technical features (choice of tracer, administered dose, and physical half-life; instrument sensitivity, acquisition technique, reader experience). In particular, current data show that PET/CT has greater intrinsic resolution and sensitivity than SPECT or SPECT/CT images resulting in improved tumor detection. However, the PET tracer of choice has not yet been identified. 18F-FDG has proved to be useful as indicator of tumor aggressiveness rather than detection of extent of disease, and 68Ga-DOTA-TOC has demonstrated good results in clinical trials. 11C-5HTP has performed well in limited trials, but the 20-min half life of 11C precludes widespread availability. Better information concerning biodistribution and further comparative data of these agent in larger clinical trials are warranted.

The Allosteric Hemoglobin Effector ITPP Inhibits Metastatic Colon Cancer in Mice.

To test the effects of enhanced intracellular oxygen contents on the metastatic potential of colon cancer. Colorectal cancer is the commonest gastrointestinal carcinoma. Distant metastases occur in half of patients and are responsible for most cancer-related deaths. Tumor hypoxia is central to the pathogenesis of metastases. Myo-Inositoltrispyrophosphate (ITPP), a nontoxic, antihypoxic compound, has recently shown significant benefits in experimental cancer, particularly when combined with standard chemotherapy. Whether ITPP protects from distant metastases in primary colon cancer is unknown. ITPP alone or combined with FOLFOX was tested in a mouse model with cecal implantation of green fluorescent protein-labeled syngeneic colorectal cancer cells. Tumor development was monitored through longitudinal magnetic resonance imaging-based morphometric analysis and survival. Established serum markers of tumor spread were measured serially and circulating tumor cells were detected via fluorescence measurements. ITPP significantly reduced the occurrence of metastases as well as other indicators of tumor aggressiveness. Less circulating tumor cells along with reduction in malignant serum markers (osteopontin, Cxcl12) were noted. The ITPP benefits also affected the primary cancer site. Importantly, animals treated with ITPP had a significant survival benefit compared with respective controls, while a combination of FOLFOX with ITPP conferred the maximum benefits, including dramatic improvements in survival (mean 86 vs 188 d). Restoring oxygen in metastatic colon cancer through ITPP inhibits tumor spread and markedly improves animal survival; an effect that is enhanced through the application of subsequent chemotherapy. These promising novel findings call for a clinical trial on ITPP in patients with colorectal cancer, which is under way.

ERα and ERβ co-expression: An indicator of aggressive tumors and hormonal sensitivity.

The estrogen receptors (ERs) ERα and ERβ are important factors in breast cancer progression. Nevertheless, the molecular interplay between ERα and ERβ and its clinical significance in breast cancer is controversial. The establishment of a clear association is required; therefore, the current study analyzed the expression patterns of ERα and ERβ in 32 breast tumor tissues using reverse transcription-quantitative polymerase chain reaction. Furthermore, human epidermal growth factor receptor 2 (HER2) and the Ki-67 status were detected by immunohistochemistry. The results revealed that the ERα and ERβ expression rates recorded were 68 and 65%, respectively. The ERα:ERβ ratio exhibited a decline along with disease progression. ERα and ERβ were found to be negatively correlated with HER2 status but positively correlated with Ki-67. Co-expression of ERα and ERβ was associated with breast cancer aggressiveness, including higher histological grade and positive nodal status, which commonly occur following the menopause. In addition, in cases where ERβ was coexpressed with ERα, HER2 expression was frequently found to be negative, whereas the Ki-67 index was upregulated. These data suggest that ERα and ERβ co-expression may be an indicator of tumor aggressiveness and the sensitivity of hormonal therapy via the downregulation of HER2.

PD-L1 expression in Xp11.2 translocation renal cell carcinoma: Indicator of tumor aggressiveness

Programmed death ligand-1 (PD-L1), a promising antitumor target, has proven clinical value against many malignancies. However, the PD-L1 content of Xp11.2 translocation renal cell carcinoma (Xp11.2 RCC) and its correlation with clinical outcomes remain unclear. This study aimed to investigate PD-L1 expression in Xp11.2 RCC and to assess its prognostic value. Formalin-fixed paraffin-embedded specimens from 36 adult patients that were histologically confirmed (by fluorescence in situ hybridization) were subjected to immunohistochemical analysis. Of the 36 Xp11.2 RCC patients, 9 (25.0%) had tumors with positive PD-L1 expression and 27 (75.0%) had tumors with negative PD-L1 expression. Positive PD-L1 expression correlated with advanced tumor stage (P = 0.001), regional lymph node metastasis (P < 0.001), and distant metastasis (P < 0.001). A multivariate analysis identified positive PD-L1 expression was an independent adverse prognostic factor for both progression free survival (hazard ratio: 3.7, P = 0.018) and overall survival (hazard ratio: 4.5, P = 0.034). The median PFS and OS for the whole cohort were 13.0 months (95% confidence interval [CI], 9.4–16.6 months) and 36.0 months (95% CI, 23.9–48.1 months), respectively. Our findings suggest that positive PD-L1 expression is indicative of worse clinical outcome in Xp11.2 RCC. Further studies are needed to explore the potential efficacy of targeting PD-L1 in Xp11.2 RCC.

976 - PD-L1 expression in Xp11.2 translocation renal cell carcinoma: Indicator of tumor aggressiveness

976 - PD-L1 expression in Xp11.2 translocation renal cell carcinoma: Indicator of tumor aggressiveness

Kinesin Family Member 11 mRNA Expression Predicts Prostate Cancer Aggressiveness.

KIF11 (kinesin family member 11), a molecular motor protein, is essential to mitosis and cell cycle progression. Inhibitors of KIF11 have been developed as chemotherapeutic agents for the treatment of various cancers. Regarding prostate cancer (PCa), clinical trials using KIF11 inhibitors for the treatment of castration-resistant PCa have been initiated. We hypothesized that a relationship might exist between KIF11 expression and PCa. To investigate the functional activities and clinical usefulness of KIF11 in PCa, we used quantitative real-time reverse transcriptase polymerase chain reaction to monitor the KIF11 expression patterns. Tissue samples from 134 patients with PCa were analyzed using gene expression profiling and compared with tissues from 61 patients with benign prostatic hyperplasia. KIF11 expression was evaluated by real-time reverse transcriptase polymerase chain reaction and compared with indicators of tumor aggressiveness, such as prostate-specific antigen (PSA) levels, Gleason score (GS), and tumor stage (TNM stage). KIF11 mRNA expression in tissue was significantly greater in PCa patients with elevated serum PSA levels (≥ 10 ng/mL), GS≥ 8 [58(43.3%)], T stage≥ T3, or metastatic disease than in those with PSA levels< 10 ng/mL, GS of 7, or T2 stage. Additionally, the expression was remarkably greater in patients with a GS of≥ 9 than in patients with a GS of 3+4. KIF11 expression might be indicative of PCa aggressiveness and could be useful as a prognostic marker for patients with PCa.