High Nuclear Grade Research Articles

Succinate Dehydrogenase-Deficient Renal Cell Carcinoma: A Short Review.

Succinate dehydrogenase (SDH) is a mitochondrial enzyme complex composed of 4 protein subunits (SDHA, SDHB, SDHC, and SDHD). Germ line mutations of the genes encoding these SDH subunits result in hereditary syndromes harboring pheochromocytomas/paragangliomas, gastrointestinal stromal tumors, renal cell carcinomas, and pituitary adenomas. SDH-deficient renal cell carcinomas are rare, with a mean age of 38 to 40 years. Histologically, these tumors show a characteristic appearance that includes a solid, nested, or tubular architecture with variable cysts. Cells are typically cuboidal, have indistinct cell borders and eosinophilic cytoplasm, and show flocculent intracytoplasmic inclusions. Loss of immunohistochemical staining for SDHB is the hallmark of these tumors. Although most SDH-deficient renal cell carcinomas are clinically indolent, some tumors may behave aggressively, particularly those with a high nuclear grade, tumor necrosis, or sarcomatoid differentiation. Accurate classification of these tumors is important for clinical follow-up, screening, and genetic evaluation of the patients and other family members for this hereditary tumor syndrome.

Only estrogen receptor “positive” is not enough to predict the prognosis of breast cancer

Beginning in 2018, biomarkers including estrogen receptor (ER) status were incorporated in the 8th AJCC staging system. ER expression levels were not considered in these changes. We hypothesized that the levels of ER expression could affect the prognosis of breast cancer. A retrospective review was conducted to identify all female patients with invasive breast cancer between 2003 and 2012. ER negative (group I), weakly ER-positive (group II), and strongly ER-positive (group III) were defined as Allred total scores of 0-2, 3-5, and 6-8, respectively. We examined a multigene panel, designated the BCT score, which is a newly developed prognostic model for predicting the risk of a distant metastasis. Among the 4949 patients enrolled in this study, 1310 (26.5%), 361 (7.3%), and 3277 (66.2%) were categorized as group I, II, and III, respectively. Median F/U duration was 57.8 months. Compared to group III, patients in group II were younger, had larger tumors, and were also more likely to have PR-negative tumors, HER-2 amplification, high Ki-67, and high nuclear grade. Between group II and III, there was a significant difference in OS (P = 0.0764, 0.909, and 0.010, respectively). After adjusting for additional factors that may affect OS, the HR for OS showed higher in group II than in group III. The baseline median BCT score indicated that lower ER expression was associated with significantly higher BCT score (P < 0.0001) and significantly more likely to have high risk group (P < 0.0001) relative to higher levels of ER expression group. ER expression levels affect the prognosis of breast cancer. The risk for patients with weakly ER-positive breast cancer should not be underestimated.

Clear Cell Renal Cell Carcinoma: Machine Learning-Based Quantitative Computed Tomography Texture Analysis for Prediction of Fuhrman Nuclear Grade.

To evaluate the performance of quantitative computed tomography (CT) texture analysis using different machine learning (ML) classifiers for discriminating low and high nuclear grade clear cell renal cell carcinomas (cc-RCCs). This retrospective study included 53 patients with pathologically proven 54 cc-RCCs (31 low-grade [grade 1 or 2]; 23 high-grade [grade 3 or 4]). In one patient, two synchronous cc-RCCs were included in the analysis. Mean age was 57.5 years. Thirty-four (64.1%) patients were male and 19 were female (35.9%). Mean tumour size based on the maximum diameter was 57.4 mm (range, 16-145 mm). Forty patients underwent radical nephrectomy and 13 underwent partial nephrectomy. Following pre-processing steps, two-dimensional CT texture features were extracted using portal-phase contrast-enhanced CT. Reproducibility of texture features was assessed with the intra-class correlation coefficient (ICC). Nested cross-validation with a wrapper-based algorithm was used in feature selection and model optimisation. The ML classifiers were support vector machine (SVM), multilayer perceptron (MLP, a sort of neural network), naïve Bayes, k-nearest neighbours, and random forest. The performance of the classifiers was compared by certain metrics. Among 279 texture features, 241 features with an ICC equal to or higher than 0.80 (excellent reproducibility) were included in the further feature selection process. The best model was created using SVM. The selected subset of features for SVM included five co-occurrence matrix (ICC range, 0.885-0.998), three run-length matrix (ICC range, 0.889-0.992), one gradient (ICC = 0.998), and four Haar wavelet features (ICC range, 0.941-0.997). The overall accuracy, sensitivity (for detecting high-grade cc-RCCs), specificity (for detecting high-grade cc-RCCs), and overall area under the curve of the best model were 85.1%, 91.3%, 80.6%, and 0.860, respectively. The ML-based CT texture analysis can be a useful and promising non-invasive method for prediction of low and high Fuhrman nuclear grade cc-RCCs. • Based on the percutaneous biopsy literature, ML-based CT texture analysis has a comparable predictive performance with percutaneous biopsy. • Highest predictive performance was obtained with use of the SVM. • SVM correctly classified 85.1% of cc-RCCs in terms of nuclear grade, with an AUC of 0.860.

Association Between BRCA Status and Triple-Negative Breast Cancer: A Meta-Analysis.

Triple-negative breast cancer (TNBC) is a subtype of aggressive breast cancer and characterized by a lack of the expression of estrogen receptor, progesterone receptor and human epidermal growth factor receptor 2. BRCA genes are tumor-suppressor genes that are involved in DNA damage repair and mutations of BRCA genes may increase the risk of developing breast cancer and/or ovarian cancer due to defective DNA repair mechanisms. However, the relationship between BRCA status and TNBC needs to be further investigated and validated. The aim of this meta-analysis was to evaluate the association between BRCA status and TNBC. We systematically searched the electronic databases of MEDLINE (PubMed), Embase, and Cochrane Library to identify relevant publications from April, 1959 to November, 2017. The data from the studies were examined by a meta-analysis using STATA software to calculate the odds ratio (OR) with 95% confidence interval (CI) by fixed-effect and random-effect models. We identified 16 qualified studies from 527 publications with 46,870 breast cancer patients including 868 BRCA1 mutations (BRCA1Mut) carriers, 739 BRCA2 mutations (BRCA2Mut) carriers, and 45,263 non-carriers. The results showed that breast cancer patients with BRCA1Mut carriers were more likely to have TNBC than those of BRCA2Mut carriers (OR: 3.292; 95% CI: 2.773–3.909) or non-carriers (OR: 8.889; 95% CI: 6.925–11.410). Furthermore, high expression of nuclear grade and large tumor burden (>2 cm) were significantly more common in breast cancer patients with BRCA1Mut carriers than those of BRCA2Mut carriers (OR: 2.663; 95% CI: 1.731–4.097; P = 0.211) or non-carriers (OR: 1.577; 95% CI: 1.067–2.331; P = 0.157). The data suggest that breast cancer patients with BRCA1Mut are more likely to have TNBC, high nuclear grade, and larger tumor burden.

Prognostic Impact of Nutritional Status Assessed by the Controlling Nutritional Status (CONUT) Score in Patients with Surgically Treated Renal Cell Carcinoma

Purpose: The prognostic role of the controlling nutritional status (CONUT) score in renal cell carcinoma (RCC) has not been evaluated. The aim of the current study was to clarify the prognostic significance of the CONUT score in Korean patients with surgically treated RCC.Materials and methods: A database of 1,881 patients with surgically treated RCC from a multiinstitutional Korean collaboration between 1999 and 2015 was analyzed. The preoperative CONUT score was calculated from serum albumin, total cholesterol concentrations, and total lymphocyte count. Clinicopathological variables and survival rates were compared between the CONUT score groups.Results: A high CONUT score was associated with older age, lower body mass index, lower preoperative prognostic nutritional index, and presence of diabetes or hypertension (each P < 0.001). Regarding pathologic features, a high CONUT score was associated with aggressive tumor characteristics including large tumor size, advanced stage, high nuclear grade, lymphovascular invasion, and sarcomatous differentiation (each P < 0.001). Multivariate Cox regression analysis indicated that a high CONUT score (≥ 2) was an independent predictor of cancer-specific mortality (hazard ratio, 1.892; 95% CI: 1.118–3.201; P = 0.018).Conclusion: The CONUT score, an easily measurable immune-nutritional biomarker, may provide useful prognostic information in patients with surgically treated RCC.

Prognostic value of PD-1 and PD-L1 expression in patients with metastatic clear cell renal cell carcinoma

ObjectiveIn renal cell carcinoma (RCC), several prognostic biomarkers have been identified and are under investigation. Several reports have shown that the expression of programmed death 1 (PD-1) and its ligand PD-L1 is associated with poor outcome for patients with RCC. The present study is aimed at evaluating the expression of PD-1 and PD-L1 and to investigate their clinical and prognostic significance in patients with clear cell RCC (CCRCC) having received molecular targeted therapies. In addition, we also evaluated the relationship between the expression of PD-1 and PD-L1 and intratumoral tumor infiltrating lymphocytes (TILs). MethodsA total of 33 patients with metastatic CCRCC who underwent surgery and received molecular targeted therapies from March 2008 to April 2016 were retrospectively reviewed and analyzed. Tissue specimens from the patients were analyzed for PD-1 and PD-L1 expression by immunohistochemistry. ResultsThe median patient age was 64 years old (range=53-78). The majority of patients were male (81.8%). All Memorial Sloan Kettering Cancer Center risk groups were represented among the patients with 39.4% with favorable-, 51.5% with intermediate- and 9.1% with poor-risk. The expression of PD-1 and PD-L1 was observed in 16 (48.5%) and 9 (27.3%) patients, respectively. The expression of PD-1 and PD-L1 was associated with a larger primary renal tumor size, higher nuclear grade and sarcomatoid feature. Kaplan-Meier analysis revealed that no significant difference in progression free survival of first line molecular targeted therapy was found for PD-1 (P=0.2396) and PD-L1 (P=0.5919) expression. However, PD-1 expression has a significant worse impact on overall survival (OS) (P=0.0385), while for PD-L1 expression only a trend is seen for OS (P=0.1542). The patients with PD-1 and PD-L1 expression showed higher infiltration of CD4 (P<0.0001 and P<0.0001, respectively), CD8 (P=0.0328 and P=0.0044, respectively) and FOXP3 (P<0.0001 and P=0.0033, respectively) positive TILs. ConclusionPD-1 and PD-L1 expression is significantly associated with adverse clinicopathological features in CCRCC. Furthermore, PD-1 expression could be one of the biomarkers suggesting poor outcome in patients with metastatic CCRCC receiving molecular targeted therapies.

Histogram analysis of quantitative pharmacokinetic parameters on DCE-MRI: correlations with prognostic factors and molecular subtypes in breast cancer.

Breast cancer heterogeneity influences poor prognoses thorough therapy resistance. This study quantitatively evaluated intratumoral heterogeneity through a histogram analysis of dynamic contrast-enhanced MRI (DCE-MRI) pharmacokinetic parameters, and determined correlations with prognostic factors and molecular subtypes. We retrospectively investigated 101 invasive ductal breast cancers from 99 women who underwent preoperative DCE-MRI between July 2012 and November 2014. Pharmacokinetic parameters (Ktrans, kep, and ve) were obtained by the Tofts model. For each parameter, the mean, standard deviation, coefficient of variation, skewness, and kurtosis values of tumor were calculated, and prognostic factors and subtypes associations were assessed. The mean of ve was lower in cancers with high Ki-67 than in cancers with low Ki-67 (P = 0.002). The coefficient of variation of ve was higher in cancers with estrogen receptor negativity than in cancers with estrogen receptor positivity (P < 0.001). The coefficient of variation of ve was also higher in cancers with high Ki-67 than in cancers with low Ki-67 (P < 0.001). The skewness of ve was higher in cancers with high nuclear grade than in cancers with low nuclear grade (P = 0.006). Triple-negative cancers showed higher ve coefficient of variation than did those with luminal A (P < 0.001) and B (P = 0.006). Various ve parameters correlated with breast cancer prognostic factors and molecular subtypes.

Prognostic significance of tumor-infiltrating lymphocytes in ductal carcinoma in situ of the breast

Tumor-infiltrating lymphocytes (TILs) provide prognostic value in invasive breast cancer and guidelines for their assessment have been published. This study aims to evaluate: (a) methods of TILs assessment, and (b) their prognostic significance in breast ductal carcinoma in situ (DCIS). Hematoxylin and eosin sections from two clinically annotated DCIS cohorts; a training set (n = 150 pure DCIS) and a validation set (n = 666 comprising 534 pure DCIS and 132 cases wherein DCIS and invasive breast carcinoma were co-existent) were assessed. Seven different scoring methods were applied to the training set to identify the most optimal reproducible method associated with strongest prognostic value. Among different methods, TILs touching ducts' basement membrane or away from it by one lymphocyte cell thickness provided the strongest significant association with outcome and highest concordance rate [inter-cluster correlation coefficient = 0.95]. Assessment of periductal TILs at increasing distances from DCIS (0.2 , 0.5 , and 1 mm) as well as percent of stromal TILs were practically challenging and showed lower concordance rates than touching TILs. TILs hotspots and lymphoid follicles did not show prognostic significance. Within the pure DCIS validation set, dense TILs were associated with younger age, symptomatic presentation, larger size, higher nuclear grade, comedo necrosis and estrogen receptor negativity as well as shorter recurrence-free interval (p = 0.002). In multivariate survival analysis, dense TILs were independent predictor of shorter recurrence-free interval (p = 0.002) in patients treated with breast conservation. DCIS associated with invasive carcinoma showed denser TILs than pure DCIS (p = 9.0 × 10−13). Dense TILs is an independent prognostic variable in DCIS. Touching TILs provides a reproducible method for their assessment that can potentially be used to guide management

Loss of PDPK1 abrogates resistance to gemcitabine in label-retaining pancreatic cancer cells

BackgroundLabel-retaining cancer cells (LRCC) have been proposed as a model of slowly cycling cancer stem cells (CSC) which mediate resistance to chemotherapy, tumor recurrence, and metastasis. The molecular mechanisms of chemoresistance in LRCC remain to-date incompletely understood. This study aims to identify molecular targets in LRCC that can be exploited to overcome resistance to gemcitabine, a standard chemotherapy agent for the treatment of pancreas cancer.MethodsLRCC were isolated following Cy5-dUTP staining by flow cytometry from pancreatic cancer cell lines. Gene expression profiles obtained from LRCC, non-LRCC (NLRCC), and bulk tumor cells were used to generate differentially regulated pathway networks. Loss of upregulated targets in LRCC on gemcitabine sensitivity was assessed via RNAi experiments and pharmacological inhibition. Expression patterns of PDPK1, one of the upregulated targets in LRCC, was studied in patients’ tumor samples and correlated with pathological variables and clinical outcome.ResultsLRCC are significantly more resistant to gemcitabine than the bulk tumor cell population. Non-canonical EGF (epidermal growth factor)-mediated signal transduction emerged as the top upregulated network in LRCC compared to non-LRCC, and knock down of EGF signaling effectors PDPK1 (3-phosphoinositide dependent protein kinase-1), BMX (BMX non-receptor tyrosine kinase), and NTRK2 (neurotrophic receptor tyrosine kinase 2) or treatment with PDPK1 inhibitors increased growth inhibition and induction of apoptosis in response to gemcitabine. Knockdown of PDPK1 preferentially increased growth inhibition and reduced resistance to induction of apoptosis upon gemcitabine treatment in the LRCC vs non-LRCC population. These findings are accompanied by lower expression levels of PDPK1 in tumors compared to matched uninvolved pancreas in surgical resection specimens and a negative association of membranous localization on IHC with high nuclear grade (p < 0.01).ConclusionPancreatic cancer cell-derived LRCC are relatively resistant to gemcitabine and harbor a unique transcriptomic profile compared to bulk tumor cells. PDPK1, one of the members of an upregulated EGF-signaling network in LRCC, mediates resistance to gemcitabine, is found to be dysregulated in pancreas cancer specimens, and might be an attractive molecular target for combination therapy studies.

Relationship Between FDG Uptake and Neutrophil/Lymphocyte Ratio in Patients with Invasive Ductal Breast Cancer.

18F-Fluorodeoxyglucose-positron-emission tomography (FDG-PET) is used to evaluate the glucose metabolic rates of tumors. Several studies have reported that high FDG uptake is predictive of poor prognosis and aggressive features in patients with breast cancer. FDG uptake is influenced by many factors, including inflammation. In this study, the relationship between FDG uptake and neutrophil/lymphocyte ratio (NLR), which is an indicator of systemic inflammation, was investigated. A retrospective investigation of the cases of 143 consecutive patients with invasive ductal carcinoma who had undergone surgery and FDG-PET preoperatively. PET was evaluated using standardized uptake value max (SUVmax). The median SUVmax was 2.5 (range=0-10.5). The cases were divided into two groups based on the value of SUVmax: low (<2.5) and high (≥2.5). The relationships between SUVmax and clinicopathological features, including NLR, were investigated. Among the 143 patients, 73 (51.0%) had high SUVmax in the primary tumor. The analysis revealed that large tumor size (p<0.001), high nuclear grade (p<0.001), the presence of lymphovascular invasion (p<0.001), high C-reactive protein (p=0.046) and high NLR (p<0.001) were significantly associated with high SUVmax in the primary tumor. SUVmax and NLR were significantly positively correlated (r=0.323, p<0.001). Among the 70 cases with low SUVmax, there was no recurrent disease, while out of the 73 cases with high SUVmax had disease recurrence. It is interesting to note that the group with high SUVmax and low NLR had no recurrent disease. The present study demonstrated that the finding of high preoperative FDG uptake in breast cancer may be reflective of poor prognosis and that a high NLR may be predictive of aggressive features among patients with breast cancer. On the other hand, among patients with breast cancer with high SUVmax in the primary tumor, it will be useful to identify those with a low NLR in order to improve prognostic accuracy.

Can tumor-associated macrophages in ductal carcinoma in situ on biopsy predict invasive carcinoma on excision?

Recent trials have explored surveillance of ductal carcinoma in situ (DCIS) without complete excision, but it is difficult to fully exclude an associated, unsampled invasive focus. Tumor microenvironment, including tumor-associated macrophages, may play a role in the transition from in situ to invasive carcinoma, and the presence of CD163-positive cells with DCIS has been associated with increased risk of progression to invasive carcinoma. We aimed to evaluate the role of DCIS-associated CD163-positive cells on biopsy in predicting associated invasion on excision. Immunohistochemistry for CD163 was performed on 57 total biopsy cases of DCIS of low (n = 13), intermediate (n = 21), and high (n = 23) nuclear grade, 27 (47%) of which showed invasion on the subsequent excision specimen. Positive intratumoral and stromal cells were quantified independently by 2 observers based on the percentage of cells staining. Intratumoral CD163 scores ranged from 0 to 2 (mean, 0.7). Stromal CD163 scores ranged from 0 to 3 (mean, 1.3). Intratumoral and stromal CD163 levels were not significantly associated with the presence of subsequent invasion when evaluated as a whole group (P = .36 and P = .47) or when subdivided into low (P = .36 and P = .17), intermediate (P = .82 and P = .82), or high (P = .09 and P = .68) nuclear grades. There was no correlation between intratumoral CD163 content and DCIS grade (P = .257). A trend for higher stromal CD163 expression was seen with higher-grade DCIS, although not statistically significant (P = .178). In conclusion, CD163 on breast core biopsy does not help select patients who may safely forgo excision of DCIS.

Intracellular hypoxia measured by 18F-fluoromisonidazole positron emission tomography has prognostic impact in patients with estrogen receptor-positive breast cancer

BackgroundHypoxia is a key driver of cancer progression. We evaluated the prognostic impact of 18F-fluoromisonidazole (FMISO) prior to treatment in patients with breast cancer.MethodsForty-four patients with stage II/III primary breast cancer underwent positron emission tomography/computed with 18F-fluorodeoxyglucose (FDG-PET/CT) and FMISO. After measurement by FDG-PET/CT, the tissue-to-blood ratio (TBR) was obtained using FMISO-PET/CT. FMISO-TBR was compared for correlation with clinicopathological factors, disease-free survival (DFS), and overall survival (OS). Multiplex cytokines were analyzed for the correlation of FMISO-TBR.ResultsTumors with higher nuclear grade and negativities of estrogen receptor (ER) and progesterone receptor had significantly higher FMISO-TBR than other tumors. Kaplan-Meier survival curves showed that patients with a higher FMISO-TBR (cutoff, 1.48) had a poorer prognosis of DFS (p = 0.0007) and OS (p = 0.04) than those with a lower FMISO-TBR. Multivariate analysis indicated that higher FMISO-TBR and ER negativity were independent predictors of shorter DFS (p = 0.01 and 0.03). Higher FMISO-TBR was associated with higher plasma levels of angiogenic hypoxic markers such as vascular endothelial growth factor, transforming growth factor-α, and interleukin 8.ConclusionsFMISO-PET/CT is useful for assessing the prognosis of patients with breast cancer, but it should be stratified by ER status.Trial registrationUMIN Clinical Trials Registry, UMIN000006802. Registered on 1 December 2011.

APOBEC3B gene expression as a novel predictive factor for pathological complete response to neoadjuvant chemotherapy in breast cancer.

BackgroundApolipoprotein B mRNA editing enzyme catalytic polypeptide-like 3B (APOBEC3B) is a gene editing enzyme with cytidine deaminase activity and high expression of its mRNA in breast tumors have been shown to be associated with progressive cases and poor prognosis. In this study, we aimed to examine the relationship between the expression of APOBEC3B and the effect of neoadjuvant chemotherapy (NAC) using pretreatment biopsy tissue, and examined whether the expression of APOBEC3B influenced chemotherapy efficacy.MethodsWe retrospectively selected a total of 274 patients with primary breast cancer who received NAC in more than 4 courses and underwent surgery at our institute. We assessed the expression of APOBEC3B mRNA using pretreatment biopsy specimens of NAC by quantitative real-time PCR (qRT-PCR) and examined the relationship between APOBEC3B mRNA expression and sensitivity to chemotherapy using pathological complete response (pCR) as an indicator. Further, we assessed the prognostic value of APOBEC3B in the patients receiving NAC.ResultsAPOBEC3B mRNA expression levels were successfully assessed in 173 (63.1%) of the 274 specimens. The total pCR rate was 36.4% (n = 63). An association between APOBEC3B expression levels and pCR was observed (Wilcoxon test, P ≤ 0.0001). The patients were divided into two groups, low (n = 66) and high (n = 107), according to the APOBEC3B expression levels, using the cut-off value calculated by the receiver operating characteristics (ROC) curve for pCR. The rate of pCR was significantly higher among the patients in the high group than among those in the low group (47.7% vs 18.2%, P ≤ 0.0001). High APOBEC3B expression was significantly associated with high nuclear grade (P = 0.0078), high Ki-67 labeling index (P = 0.0087), estrogen receptor (ER) negativity (P ≤ 0.0001) and human epidermal growth factor receptor 2 (HER2) negativity (P = 0.032). Tumor size (P = 0.011), ER (P ≤ 0.0001), HER2 (P = 0.0013) and APOBEC3B expression (P = 0.037) were independent predictive factors for pCR in multivariate analysis. However, there was no association between APOBEC3B expression and prognosis.ConclusionsOur study showed that APOBEC3B mRNA expression correlated with sensitivity to NAC in breast cancer patients. In contrast to previous studies, APOBEC3B mRNA expression was not associated with breast cancer prognosis in patients receiving NAC.

CD44v9 as a poor prognostic factor of triple-negative breast cancer treated with neoadjuvant chemotherapy

BackgroundNeoadjuvant chemotherapy (NAC) is the standard therapeutic strategy for triple-negative breast cancer (TNBC). TNBC patients with residual disease after NAC have a significantly worse survival than those with pathological complete response (pCR); however, there is no apparent prognostic factor for non-pCR patients. Cancer stemness or epithelial–mesenchymal transition (EMT) might influence the sensitivity to chemotherapy.Patients and methodsForty-eight patients with TNBC who were treated with NAC were available were included in this study. The expressions of stemness marker CD44v9, EMT marker vimentin and BRCA1, and basal phenotype were evaluated with immunohistochemistry. The relationships between the expression of these proteins and the pCR rate and the prognosis, especially in the patients with residual tumors, were investigated.ResultsAmong the 48 patients, pCR was achieved in 14 cases. High nuclear grade and basal phenotype in the pre-NAC samples were significantly correlated with pCR (p = 0.0458 and 0.0343). There were no significant relationships between the pCR rate and the expression of CD44v9, vimentin, or BRCA1. Achieving pCR was significantly correlated with longer distant metastasis-free survival (DMFS) (p = 0.0206). High CD44v9 expression was significantly associated with shorter DMFS (p = 0.0291). Among the patients in whom pCR was not achieved, high grade in the residual tumor cells, poor pathological response and high CD44v9 expression in the pre-treatment CNB samples were significantly correlated with a poor DMFS (p = 0.0433, 0.0406 and p = 0.0333). In addition, high grade in the residual tumor cells was significantly associated with high CD44v9 expression in the pre-treatment CNB (p = 0.0389).ConclusionsHigh CD44v9 expression in pre-NAC samples was associated with poor prognosis in TNBC patients treated with NAC, especially for those in whom pCR was not achieved.

PO-341 The role of cancer/testis antigens from MAGE-A family and NY-ESO-1 in ductal carcinoma in situ (DCIS)

IntroductionCancer/testis antigens (CTA) are a large family of tumor-associated antigens expressed in human tumours of different histological origin, but not in normal tissues except for testis and placenta. Several immunohistochemical studies confirmed the association of CT antigen expression and ER negativity in breast tumours and demonstrated their frequent expression in tumours with higher nuclear grade. The expression of cancer/testis antigens in ductal carcinoma in situ is not studied so extensively as in invasive breast cancer.Material and methodsThis retrospective study included archived paraffin-embedded specimens from 83 patients diagnosed with DCIS in the period between 2007. and 2014, a mean follow up time for local recurrence was 6.5 years. Antigens multi-MAGE-A, MAGE-A1, MAGE-A10 and NY-ESO-1 and were demonstrated by immunostaining. TILs were determined on all sections together with the histopathological variables of DCIS.Results and discussionsAll tested antigens showed association (positive or negative) with histopathological parameters. Expression of MAGE-A1 was significantly associated with cytoplasmic staining (p=0,007). Simultaneously cytoplasmic and nuclear staining was in statistically significant positive correlation with local recurrence (p=0,005) and central necrosis (p=0,016) and in negative correlation with expression of ER receptors (p=0,003) and PR receptors (p=0,009). Antigen MAGE-A10 was significantly associated with tumor-infiltrating lymphocytes (p=0.05). The additional analysis of TILs showed statistically significant positive correlation with grade (p=0.023), and central necrosis (p<0.001), and negative with tumour size (p=0.623), ER receptors (p=0.003) and PR receptors (p=0.027).ConclusionCancer/testis antigens from MAGE family (MAGE-A1, multi-MAGE-A and MAGE-A10) and NY-ESO-1 correlate with histopathological predictive variables of DCIS. The expression of antigen MAGE-A10 could have an important role in treatment of patients with negative histopathological predictive variables, but further analysis is required. Simultaneous cytoplasmic and nuclear protein expression of MAGE-A family and NY-ESO-1 cancer-testis antigens represent an independent marker for local recurrence. Cancer/testis antigens are not perfect indicators of invasiveness for DCIS, but in combination with others histopathological predictive variables they can be used as a guidance for better treatment of this patients. But, this is the small study and further larger studies are necessary to confirm our findings.

Intratumoral heterogeneity on dedicated breast positron emission tomography predicts malignancy grade of breast cancer.

Dedicated breast positron emission tomography (DbPET) provides detailed high-resolution images and can detect intratumoral heterogeneity using 18F-fluorodeoxyglucose (FDG). We aimed to evaluate the correlation between FDG uptake on DbPET and the clinicopathological features of breast cancer, particularly those with an intratumoral heterogeneous distribution of FDG on DbPET. We evaluated 195 consecutive patients with invasive breast cancer who underwent preoperative whole-body PET (WBPET) and DbPET concurrently between January 2016 and March 2017. The relationships between clinicopathological factors and the maximum standard uptake values (SUVmax) of DbPET and WBPET, including clinical stage, nuclear grade, Ki67 proliferation index, estrogen receptor (ER) and human epidermal growth factor receptor type 2 (HER2) statuses, and the intratumoral heterogeneous distribution of FDG on DbPET, were evaluated. The SUVmax of DbPET was significantly correlated with clinical T stage, N stage, nuclear grade, and Ki67 proliferation index (all p < 0.001) as well as the ER (p = 0.006) and HER2 (p = 0.040) statuses. Intratumoral heterogeneous distribution of FDG on DbPET was significantly related with high nuclear grade (p = 0.016) and high Ki67 proliferation index (p = 0.015) but not with clinical T stage, N stage, and ER and HER2 statuses. The SUVmax of DbPET correlates with clinicopathological factors and also WBPET does. In addition, intratumoral heterogeneity on DbPET provides predictive value for malignancy grade and could inform therapeutic decisions.

Evaluation of association between degree of background parenchymal enhancement on MRI and breast cancer subtype

PurposeEvaluate possible association between BPE and breast cancer tumor type/prognostic markers. MethodsIRB approved retrospective study from 1/2010–1/2014 identified 328 patients who had breast MRI and available clinical/pathology data. BPE was categorized according to BI-RADS. The association between BPE and breast cancer molecular subtype/prognostic factors was evaluated. ResultsNo significant association was present between high BPE and the following: HER2+ tumors, basal tumors, tumors with axillary nodal disease, high nuclear grade tumors, high Ki-67 index tumors or larger tumors. ConclusionPatients with high BPE may be at increased risk for breast cancer but not necessarily for those cancer subtypes with a poor prognosis.

Fluorination of nuclear graphite IG-110 in molten 2LiF-BeF2 (FLiBe) salt at 700 ºC

It is important for the development of advanced nuclear reactors to understand if the exposure to molten fluoride salts changes physical properties of graphite and its ability to absorb tritium. This paper demonstrated that the interaction between high purity nuclear grade graphite IG-110 and molten salt mixture 2LiF-BeF2 (FLiBe) at 700 °C for twelve hours in argon envirnoment resulted in graphite fluorination and changes in graphite microstructure. XPS C1s spectra analysis shows an increase in F functionalization (from 3.5% to 9.0–19.3%), an increase in the sp3/sp2 ratio (from 0.1496 to 0.1798), and F1s spectrum analysis confirms appearance of CF bonds. Raman spectra show an increase in ID/IG ratio from 0.35 to 0.69 and an appearance of peak shoulders characteristic of CF bond formation. GDMS depth analysis from the surface to 5 μm depth shows a higher depth penetration of F compared to that of Li and Be, indicative of surface salt reduction and bulk graphite fluorination. FLiBe reduction by graphite fluorination is not thermodynamically favorable, but certain carbon sites in the graphite are more reactive than the majority of carbon atoms in graphite. We argue that graphite fluorination occurred at these reactive sites, leading to the reduction of salt at the graphite surface. XRD and Raman confirmed microstructural changes. This indicates that the fluorination process may introduce new active sites as existing active sites are consumed, which could be advantageous for tritium chemisorption from FLiBe.

MP36-10 CHEST FOLLOW-UP SCHEDULE OF SURGICALLY RESECTED RENAL CELL CARCINOMA SHOULD BE DIFFERENTIATED ACCORDING TO HISTOLOGICAL SUBTYPE

MP36-10 CHEST FOLLOW-UP SCHEDULE OF SURGICALLY RESECTED RENAL CELL CARCINOMA SHOULD BE DIFFERENTIATED ACCORDING TO HISTOLOGICAL SUBTYPE

The Adverse Survival Implications of Bland Thrombus in Renal Cell Carcinoma With Venous Tumor Thrombus

To characterize the presence of bland (nontumor) thrombus in advanced renal cell carcinoma and assess the impact of this finding on cancer-specific survival. A multi-institutional database of patients treated with nephrectomy with caval thrombectomy for locally-advanced renal tumors was assembled from 5 tertiary care medical centers. Using clinicopathologic variables including patient age, body mass index, Eastern Cooperative Oncology Group performance status, tumor stage, grade, nodal status and histology, and nearest-neighbor and multiple-matching propensity score matched cohorts of bland thrombus vs nonbland thrombus patients were assessed. Multivariable analysis for predictors of cancer-specific survival was performed. From an initial cohort of 579 patients, 446 met inclusion criteria (174 with bland thrombus, 272 without). At baseline, patients with bland thrombus had significantly worse performance status, higher tumor stage, higher prevalence of regional nodal metastases and higher nuclear grade (P < .01 for all). In both nearest-neighbor and multiple-matching propensity score matched cohorts, the presence of bland thrombus presence was associated with inferior median cancer-specific survival (28.1 months vs 156.8 months, and 28.1 months vs 76.7 months, P < .001 for both). The presence of bland thrombus remained independently associated with an increased risk of cancer-specific mortality on multivariable analysis (hazard ratio 4.33, 95% confidence interval 2.79-6.73, P < .001). Presence of bland thrombus is associated with adverse survival outcomes in patients treated surgically for renal tumors with venous tumor thrombus. These findings may have important implications in patient counseling, selection for surgery and inclusion in clinical trials.