Aggressive Pathological Features Research Articles

Rapid growth of an atypical meningioma in association with cyproterone acetate use: Case report

Meningiomas are extremely common intracranial tumours. When classified based on their histological appearance, the majority (approximately 80%) are World Health Organisation (WHO) Grade 1 benign tumours. A small percentage of meningiomas are atypical (WHO Grade 2) or anaplastic (WHO Grade 3), with higher-grade tumours demonstrating aggressive clinical and pathological characteristics. There is a well-recognised relationship between meningioma growth during periods of elevated circulating female sex hormones; this has been demonstrated in pregnancy or with the administration of exogenous synthetic hormones.

Selecting Patients with Favorable Risk, Grade Group 2 Prostate Cancer for Active Surveillance-Does Magnetic Resonance Imaging Have a Role?

The National Comprehensive Cancer Network® recommends that selected men with grade group 2 prostate cancer be considered for active surveillance. However, selecting which patients with grade group 2 disease can be safely managed by active surveillance remains controversial. The aim of this study was to evaluate the association of multiparametric magnetic resonance imaging with adverse pathology in the radical prostatectomy specimen of men with favorable risk grade group 2 prostate cancer, which could help select patients for active surveillance. We retrospectively analyzed a cohort of patients with favorable grade group 2 disease who underwent radical prostatectomy between 2010 and 2019. Preoperative multiparametric magnetic resonance imaging was scored as negative (no identifiable lesion), positive (identifiable lesion) or equivocal. We defined a multivariable logistic regression model with multiparametric magnetic resonance imaging score as the predictor and adverse pathology (up staging to T3a/b disease, upgrading to ≥grade group 3 or lymph node invasion) as the outcome, adjusting for preoperative prostate specific antigen, biopsy Gleason grade, clinical stage, and number of negative and positive prostate biopsy cores. Secondary outcomes of biochemical recurrence, grade group upgrading alone and the added value of incorporating multiparametric magnetic resonance imaging data into the nomogram were also investigated. We identified 1,117 patients with favorable risk grade group 2 disease who underwent radical prostatectomy. Positive multiparametric magnetic resonance imaging was associated with higher rates of adverse pathology (OR 2.55, 95% CI 1.75-3.40, p <0.0001) and upgrading (OR 3.89, 95% CI 2.00-7.56, p <0.0001). However, as our study included only grade group 2 patients who underwent radical prostatectomy, our cohort may represent a higher risk group than grade group 2 patients as a whole. Adding multiparametric magnetic resonance imaging results to a standard prediction model led to higher net benefit on decision curve analysis. An identifiable lesion on multiparametric magnetic resonance imaging was associated with an increased risk of aggressive pathological features in the radical prostatectomy specimen of patients with favorable risk grade group 2 prostate cancer who were potential active surveillance candidates. This information could be used to inform biopsy strategy, counsel patients on treatment options and guide strategies for those on active surveillance. Combining multiple magnetic resonance imaging modalities (multiparametric magnetic resonance imaging) provides a more accurate prediction of the risk presented by prostate cancer than current prediction methods. In this study, positive magnetic resonance imaging results approximately doubled the chances that a patient with favorable risk prostate cancer would be found to have adverse pathology when their prostate was removed. Thus, multiparametric magnetic resonance imaging could help select patients with favorable risk cancer who may be good candidates for active surveillance, and help guide biopsy and surveillance strategies for such patients.

Prognostic significance of PD-L1 in advanced non-small cell lung carcinoma.

This study aimed to investigate the prognostic value of PD-L1 in Chinese patients with non-small cell lung carcinoma (NSCLC).In this retrospective study, 97 patients with NSCLC were consecutively recruited. The expression profiling of PD-1, PD-L1, p53 and Ki-67 was detected by immunohistochemistry. Median survival time was estimated by Kaplan–Meier survival curve with log-rank test. Risk factors were evaluated by Cox Proportional Hazards regression models.The median tumor size was larger (3.5 cm) among patients with positive PD-L1 expression, compared to those with negative expression (2.0 cm; P < .01). Compared to those with negative PD-L1 expression, patients with positive PD-L1 expression had significantly higher rates of nerve invasion (26.3% vs 5.0%; P < .01), blood vessel invasion (47.4% vs 20.0%; P < .01) and lymph node metastasis (64.9% vs 27.5%; P < .01), more advanced tumor stage (P < .01) and Ki-67 index (P < .01). PD-L1 expression status was not significantly associated with disease-free (DFS) or overall survival (OS). However, for patients with advanced disease, PD-L1 positive expression was related to worse outcome (HR: 4.13; 95% CI: 1.06–16.12).Positive PD-L1 expression is associated with more aggressive pathological features and poorer prognosis in advanced stage NSCLC.

TGF-β1-regulated miR-3691-3p targets E2F3 and PRDM1 to inhibit prostate cancer progression.

Transforming growth factor-β1 (TGF-β1) acts as a tumor promoter in advanced prostate cancer (PCa). We speculated that microRNAs (miRNAs) that are inhibited by TGF-β1 might exert anti-tumor effects. To assess this, we identified several miRNAs downregulated by TGF-β1 in PCa cell lines and selected miR-3691-3p for detailed analysis as a candidate anti-oncogene miRNA. miR-3691-3p was expressed at significantly lower levels in human PCa tissue compared with paired benign prostatic hyperplasia tissue, and its expression level correlated inversely with aggressive clinical pathological features. Overexpression of miR-3691-3p in PCa cell lines inhibited proliferation, migration, and invasion, and promoted apoptosis. The miR-3691-3p target genes E2F transcription factor 3 (E2F3) and PR domain containing 1, with ZNF domain (PRDM1) were upregulated in miR-3691-3p-overexpressing PCa cells, and silencing of E2F3 or PRDM1 suppressed PCa cell proliferation, migration, and invasion. Treatment of mice bearing PCa xenografts with a miR-3691-3p agomir inhibited tumor growth and promoted tumor cell apoptosis. Consistent with the negative regulation of E2F3 and PRDM1 by miR-3691-3p, both proteins were overexpressed in clinical PCa specimens compared with noncancerous prostate tissue. Our results indicate that TGF-β1-regulated miR-3691-3p acts as an anti-oncogene in PCa by downregulating E2F3 and PRDM1. These results provide novel insights into the mechanisms by which TGF-β1 contributes to the progression of PCa.

Clinicopathological Characteristics and Outcome of Adolescent and Young Adult-Onset Microsatellite Stable Colorectal Cancer Patients.

Purpose: Colorectal cancer (CRC) incidence is increasing in adults younger than 50 years. This study evaluated clinicopathological characteristics and outcome of adolescent and young adult (AYA)-onset sporadic CRC patients. Methods: Medical records of patients who were diagnosed adenocarcinoma of colon or rectum at Siriraj Hospital between 2007 and 2018 were retrospectively reviewed. The patients were classified into two groups: AYA-onset CRC (age 15-39 years) and adult-onset CRC (age >50 years). Associations between sporadic microsatellite stable (MSS) AYA-/adult-onset CRC and clinicopathological features and outcome were evaluated. Results: A total of 203 patients were diagnosed with AYA-onset CRC with no known history of familial CRC syndromes, 119 had data on mismatch repair status; 98 confirmed MSS CRC. AYA-onset CRC patients were commonly found with left-sided rather than right-sided tumors (77.1% vs. 22%) and late stage of disease (80.7% in stage III-IV vs. 19.3% in stage I-II). Compared with adult-onset CRC (218 patients), AYA-onset MSS CRC had more patients with female gender (p = 0.038), perineural invasion (p = 0.003), and signet ring cell/mucinous histology (p = 0.132). On univariate analysis, male gender and mucinous/signet ring cell histology had worse overall survival (OS) (p = 0.004 and p = 0.072, respectively) and remained significant in multivariate analysis for signet ring cell histology (p = 0.008). There was no difference in disease-free survival and OS between both age groups. Conclusion: Sporadic MSS AYA-onset CRC patients were associated with female gender and aggressive pathological characteristics. However, there was no difference in survival outcome between AYA-onset and adult-onset groups.

Can LI-RADS imaging features at gadoxetic acid-enhanced MRI predict aggressive features on pathology of single hepatocellular carcinoma?

PurposeTo investigate whether Liver Imaging Reporting and Data System (LI-RADS) imaging features at preoperative gadoxetic acid-enhanced MRI can predict microvascular invasion (MVI) and histologic grade of hepatocellular carcinoma (HCC) and to evaluate their associations with recurrence after curative resection of single HCC. Materials and methodsFrom July 2015 to September 2018, 111 consecutive patients with pathologically confirmed HCC who underwent gadoxetic acid–enhanced MRI within 1 month before surgery were included in this retrospective study. Significant MRI findings and clinical parameters for predicting MVI, high-grade HCCs and postoperative recurrence were identified by logistic regression model and Cox proportional hazards model. ResultsTwenty-six of 111 (23.4 %) patients had MVI and 36 of 111 (32.4 %) patients had high-grade HCCs, whereas 44 of 95 (46.3 %) patients experienced recurrence. Tumor size > 5 cm (OR = 9.852; p < 0.001) and absence of nodule-in-nodule architecture (OR = 8.302; p = 0.001) were independent predictors of MVI. Enhancing capsule (OR = 4.396; p = 0.004) and corona enhancement (OR = 3.765; p = 0.021) were independent predictors of high-grade HCCs. Blood products in mass (HR = 2.275; p = 0.009), corona enhancement (HR = 4.332; p < 0.001), and serum AFP level > 400 ng/mL (HR = 2.071; p = 0.023) were independent predictors of recurrence. ConclusionLI-RADS imaging features can be used as potential biomarkers for predicting aggressive pathologic features and recurrence of HCC. The identification of prognostic LI-RADS imaging features may facilitate the selection of surgical candidates and optimize the management of HCC patients.

Organotypic Culture of Acinar Cells for the Study of Pancreatic Cancer Initiation.

Simple SummaryPancreatic Cancer is a deadly disease, with a dismal prognosis. A better understanding of the molecular alterations that cause the malignant transformation of pancreatic epithelial cells is pivotal to curtail disease incidence and detect the disease early when it can be surgically resected. The culture of pancreatic pre-malignant cells is technically challenging, but a great tool for the study of tumor evolution and early oncogenic alterations. Here, we will describe the isolation of pancreatic acinar cells and its value for the study of tumor initiation, from a technical and historical perspective.The carcinogenesis of pancreatic ductal adenocarcinoma (PDA) progresses according to multi-step evolution, whereby the disease acquires increasingly aggressive pathological features. On the other hand, disease inception is poorly investigated. Decoding the cascade of events that leads to oncogenic transformation is crucial to design strategies for early diagnosis as well as to tackle tumor onset. Lineage-tracing experiments demonstrated that pancreatic cancerous lesions originate from acinar cells, a highly specialized cell type in the pancreatic epithelium. Primary acinar cells can survive in vitro as organoid-like 3D spheroids, which can transdifferentiate into cells with a clear ductal morphology in response to different cell- and non-cell-autonomous stimuli. This event, termed acinar-to-ductal metaplasia, recapitulates the histological and molecular features of disease initiation. Here, we will discuss the isolation and culture of primary pancreatic acinar cells, providing a historical and technical perspective. The impact of pancreatic cancer research will also be debated. In particular, we will dissect the roles of transcriptional, epigenetic, and metabolic reprogramming for tumor initiation and we will show how that can be modeled using ex vivo acinar cell cultures. Finally, mechanisms of PDA initiation described using organotypical cultures will be reviewed.

Abstract 2959: Glycogen synthase kinase 3-β expression in prostate cancer (PCa) correlates with aggressive pathological features and its blockade with 9-ING-41 inhibits viability of PCa cell lines

Abstract Castration-resistant prostate cancer (CRPC) represents a lethal stage of disease with limited treatment options beyond androgen receptor (AR) inhibitors and chemotherapy. GSK-3β is a serine/threonine kinase established as a therapeutic target in several solid tumors. GSK-3β inhibitors reduce prostate cancer cell growth and inhibit AR-V7 transcriptional activity in vitro (Rinnab L et al 2008; Schütz SV et al 2011; Nakata et al 2017). This study aimed to characterize the GSK-3β expression in molecular subtypes of PCa and the antitumor activity of 9-ING-41, a selective small molecule GSK-3β inhibitor currently in phase 1/2 clinical studies (NCT03678883). We hypothesized that GSK3-β expression may correlate with sensitivity to GSK3-β inhibition as well as suppression of anti-apoptotic pathways. We evaluated the expression of GSK-3β in a tissue microarray of 134 specimens of PCa tumors from radical prostatectomies (median age 69, serum PSA 10.5 ± 7.6 ng/ml; grade groups (GG): 18 - GG 1 (13.4%), 67 - GG 2 (48.5%), 29 - GG 3 (21.4%), 7 - GG 4 (5.2%), 13 - GG 5 (9.7%); 72 patients (54.9%) had pT2 tumors, and 52 (39,1%) were pT3. Seven patients (5.7%) had positive lymph node (pN1 disease). ERG expression and PTEN loss were observed in 52% (71/134) and 42%, respectively. The GSK-3β histologic score (% of positive tumor cells multiplied by intensity 0-3) correlated with higher Gleason grade (p&amp;lt;0.05), extraprostatic extension (pT3a, p&amp;lt;0.05), but not with serum PSA, tumor volume, margin status or size of index nodule. Cases with predominant nuclear localization of GSK-3β (5%; N=7) had higher Gleason score, pathologic stage, and all but one had PTEN loss. The antiproliferative effect of 9-ING-41 in four PCa human cell lines (PC3, DU145, LNCAP and 22rV1) was investigated using Cell-Titer-Glo (CTG) viability assay. 9-ING-41 demonstrated a dose-dependent decrease in proliferation of AR positive (IC50s 0.3 μM LNCAP; 0.8 μM 22rV1) and AR negative cell lines (IC50 0.6 μM PC3, 0.2 μM DU145). 9-ING-41 induced robust apoptosis (cleaved PARP) in LNCAP and PC3 cells, but not in DU145. All four cell lines expressed GSK-3β, the target of 9-ING-41 and its level were not altered by treatment. 9-ING-41 decreased the expression of phosphorylated NF-kβ (Ser536), anti-apoptotic proteins MCL-1 and BCL-2 by western immunoblotting. Interestingly, the most sensitive cell line, DU145, had lower levels of NF-kβ and suppressed both MCL-1 and BCL-2 after exposure to 9-ING-41. Our current work is evaluating the extent of apoptosis versus growth arrest, especially in the DU145 cell line, where PARP cleavage was not observed. We are also evaluating the effects of the 9-ING-41 on cellular targets of GSK-3β as potential markers of drug efficacy. 9-ING-41 has potent anti-proliferative activity against PCa cell lines. These data support the inclusion of patients with CRPC in clinical studies of 9-ING-41 and its further investigation for the treatment of CRPC. Citation Format: Fabio Tavora, Tamara Lotan, Marclesson Alves, Lanlan Zhou, Ali Amin, Navaraj Arunasalam, Andre De Souza, Anthony Mega, Dragan Golijanin, Frank Giles, Wafik El-Deiry, Benedito Carneiro. Glycogen synthase kinase 3-β expression in prostate cancer (PCa) correlates with aggressive pathological features and its blockade with 9-ING-41 inhibits viability of PCa cell lines [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2959.

Abstract LB-148: CTCs positively correlate clinical manifestations in Indian oral cancer patients

Abstract Head and neck squamous cell carcinoma is leading cancer in the Indian subcontinent with Oral squamous cell carcinoma (OSCC) as the most frequent subtype. Conventionally OSCC is classified as a locoregional disease and its increased frequency is attributed to lack of good biomarkers compared to other epithelial cancers. At the time of diagnosis, above 50% of cases present the manifestation of advanced-stage disease, and are predisposed to disease failure in spite of appropriate treatment. Thus, early diagnosis of OSCC can significantly reduce the disease burden. Here we describe a novel, regulatory approved method to establish Circulating tumor cells (CTCs) presence in peripheral blood of OSCC Indian patients and its positive correlation with various clinicopathological parameters, suggesting the potential use of CTCs as a significant parameter to stratify oral cancer with respect to the disease advancement. Methods: In a cross-sectional observational study, 230 OSCC patients at the different pathological stage of the disease and treatment mode were enrolled. CTCs were isolated using approved OncoDiscover liquid biopsy technology (Drug controller general of India approved)', platform technology based on immunomagnetic CTC enumeration. CTCs were detected for cytokeratin 18 (CK18 marker) presence and well-defined, DAPI-stained nuclei. Enumerated CTC subsequently analyzed for various clinic-pathological parameters such as pstage, extra-capsular spread (ECS), lymphovascular emboli (LVE), perineural invasion (PNI) and depth of invasion (DOI). CTC cut off values were obtained to differentiate early vs advanced stages with respect to different clinical stages and parameters.Results: CTCs obtained from peripheral blood of OSCC patients correlated positively with the cancer stages (clinical as well as pathological) as well as aggressive pathological features such as presence or absence of ECS, LVE, PNI and DOI. Interestingly, with the presence of aggressive pathological features that often suggest the poor outcome of the disease, we observed a 25-50 % increase in CTC number. On the other hand early stage, treatment naïve patients had a lower number of CTCs. Mean CTC number in advanced-stage patients was 50 % higher than early-stage OSCC patients. Conclusions: Efficient and rapid isolation of CTCs from peripheral blood of OSCC patients using proprietary technology suggested a positive correlation between CTC number and pathological stages of the disease. Considering a positive correlation of CTC number with various pathophysiological features, CTC can be contemplated as a reliable parameter to predict the disease outcome in oral cancer. The consistent presence of CTC across all disease stages also suggests a probable nature of OSCC as a biological systematic disease. Citation Format: Jayant Khandare, Burhanuddin Nuruddin Qayyumi, Atul Bharde, Gourishankar Aland, Sreeja Jayant, Swati Tripathi, Nitin Singh, Reecha Badwe, Alain D'Souza, Balram Singh, Smriti Arora, Narendra Kale, Aravindan Vasudevan, Kumar Prabhash, Pankaj Chaturvedi. CTCs positively correlate clinical manifestations in Indian oral cancer patients [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr LB-148.

The Predictive and Prognostic Factors in Patients with Gastric Cancer Accompanied by Gastric Outlet Obstruction.

Purpose This study is aimed at evaluating the clinicopathological features and prognostic significance of gastric outlet obstruction (GOO) in patients with distal gastric cancer. Methods A retrospective review of 1564 individuals with distal gastric cancer from 2002 to 2010 was performed. In total, 157 patients had GOO. The clinicopathological features of the patients with GOO were compared with those of the patients without GOO. A Kaplan-Meier survival analysis and Cox proportional hazard model were used to assess the overall survival. Results The patients with distal gastric cancer with GOO generally presented more aggressive pathologic features, a poorer nutritional status, more duodenal infiltration, and peritoneal dissemination than those with cancer without GOO. In the univariate analysis, curability, GOO, age, prealbumin, albumin, hemoglobin (Hb), the tumor size, the macroscopic type, lymph node metastasis, and the depth of invasion had a statistically significant influence on prognosis. The multivariate analysis showed that curability, GOO, the tumor size, lymph node metastasis, and the depth of invasion were independent prognostic factors. Conclusions Gastric cancer with GOO exhibits aggressive biological features and has poor outcomes. The multivariate analysis showed that curability, GOO, the tumor size, lymph node metastasis, and the depth of invasion were independent prognostic factors. The gastric outlet status should be considered in the selection of surgical treatment methods for patients with gastric cancer.

Comprehensive evaluation of 68Ga-PSMA-11 PET/CT parameters for discriminating pathological characteristics in primary clear-cell renal cell carcinoma.

To evaluate parameters derived from 68Ga-PSMA-11 PET/CT images for discriminating pathological characteristics in primary clear-cell renal cell carcinoma (ccRCC). The study retrospectively examined data for 36 ccRCC patients with preoperative 68Ga-PSMA-11 PET/CT scan and surgical specimens. Radiological parameters including maximal tumor diameter, mean CT value, and maximal standard uptake value (SUVmax) were derived from PET/CT images. Pathological characteristics included WHO/ISUP grade and adverse pathology (tumor necrosis or sarcomatoid or rhabdoid feature). Values of radiological parameters were compared within subgroups of pathological characteristics. Receiver operating characteristic (ROC) curve analysis was used for the effectiveness of radiological parameters in differentiating pathological characteristics, estimating area under the ROC curve (AUC) and 95% confidence intervals (CIs). The WHO/ISUP grade distribution for 36 tumors was grade 1, 9 (25.0%); grade 2, 12 (33.3%); grade 3, 9 (25.0%); and grade 4, 6 (16.7%). Adverse pathology was positive for 15 (41.7%). Radiological tumor diameter and SUVmax significantly differed by WHO/ISUP grade, pT stage, and adverse pathology (all P < 0.05), with no difference by CT value. Tumor diameter demonstrated sensitivity 86% and specificity 88% for pT stage, with cutoff 6.70 and AUC 0.91 (95% CI, 0.79-1.00, P< 0.001). SUVmax could effectively differentiate WHO/ISUP grade (3-4 vs. 1-2) and adverse pathology (positive vs. negative), with AUC 0.89 (95% CI, 0.81-0.98, P< 0.001), cutoff 16.4, sensitivity 100%, and specificity 71% and AUC 0.92 (95% CI, 0.85-0.99, P< 0.001), cutoff 18.5, sensitivity 94%, and specificity 87%, respectively. 68Ga-PSMA-11 PET/CT could effectively identify aggressive pathological features of ccRCC.

Characteristics of Microinvasive Ductal Carcinoma In Situ Versus Noninvasive and Invasive Breast Cancer

BackgroundThe present literature is conflicting regarding the management of microinvasive ductal carcinoma in situ (miDCIS) as to following recommendations for DCIS (margin status, surgical axillary staging, and possible observation) versus invasive breast cancer. We hypothesize that miDCIS represents more aggressive disease than pure DCIS. MethodsWe performed a retrospective review of female miDCIS patients compared with age-matched cohorts of DCIS and T1b/c patients with invasive breast cancer. We collected demographic, clinicopathologic, treatment, and outcome information. Analysis of variance or Kruskal–Wallis tests were used to analyze continuous variables and chi-square or Fisher's exact tests for categorical variables. Survival outcomes were analyzed using Kaplan–Meier curves. ResultsWe included 375 patients (125 in each group) with median age 59 y (range 33-91 y). miDCIS tumors were more likely to be hormone receptor negative and human epidermal growth factor receptor 2 positive compared with DCIS or invasive ductal carcinoma (IDC; all P < 0.001). Subgroup analysis by miDCIS focality demonstrated no significant differences. The number of involved lymph nodes was not significantly different from DCIS patients but was significantly fewer than invasive cancer patients. Of 115 miDCIS patients (88%) staged with sentinel lymph node biopsy, eight (7%) had nodal metastases. Six miDCIS patients (5%) were treated with adjuvant chemotherapy. Over a median follow-up of 23.3 mo, there were no significant differences in local or distant recurrence. ConclusionsBased on our results, miDCIS has more aggressive pathologic features compared with DCIS and warrants surgical treatment and nodal staging similar to the management of IDC. In addition, similar to IDC, nodal and receptor status may influence medical management.

Galectins and Ovarian Cancer.

Ovarian cancer is known for its aggressive pathological features, including the capacity to undergo epithelial to mesenchymal transition, promoting angiogenesis, metastatic potential, chemoresistance, inhibiting apoptosis, immunosuppression and promoting stem-like features. Galectins, a family of glycan-binding proteins defined by a conserved carbohydrate recognition domain, can modulate many of these processes, enabling them to contribute to the pathology of ovarian cancer. Our goal herein was to review specific galectin members identified in the context of ovarian cancer, with emphasis on their association with clinical and pathological features, implied functions, diagnostic or prognostic potential and strategies being developed to disrupt their negative actions.

Correlation of CTCs with disease progression in Indian oral cancer patients.

e15541 Background: Head and neck squamous cell carcinoma is leading cancer in the India with Oral squamous cell carcinoma (OSCC) as the most frequent subtype. OSCC is classified as a locoregional disease and its increased frequency is attributed to lack of good biomarkers compared to other epithelial cancers. At the time of diagnosis, above 50% of cases present the manifestation of advanced-stage disease, and are predisposed to disease failure in spite of appropriate treatment. Thus, early diagnosis of OSCC can significantly reduce the disease burden. Here we describe regulatory approved method to establish Circulating tumor cells (CTCs) presence in OSCC Indian patients and its positive correlation with various clinicopathological parameters, suggesting the potential use of CTCs as a significant parameter to stratify oral cancer with respect to the disease advancement. Methods: In a cross-sectional observational study, 230 OSCC patients at the different pathological stage of the disease and treatment mode were enrolled. CTCs were isolated using approved OncoDiscover liquid biopsy technology (Drug controller general of India approved), platform technology based on immunomagnetic CTC enumeration. CTCs were detected for CK18 presence and well-defined, DAPI-stained nuclei. Enumerated CTC subsequently analyzed for various clinic-pathological parameters such as pstage, extra-capsular spread (ECS), lymphovascular emboli (LVE), perineural invasion (PNI) and depth of invasion (DOI). CTC cut off values were obtained to differentiate early vs advanced stages with respect to different clinical stages and parameters. Results: CTCs of OSCC patients correlated positively with the cancer stages (clinical as well as pathological) as well as aggressive pathological features. The presence of aggressive pathological features that often suggest the poor outcome of the disease, we observed a 25-50 % increase in CTC number. Early stage, treatment naïve patients had lower number of CTCs. Mean CTC number in advanced-stage patients was 50 % higher than early-stage OSCC patients. Conclusions: Considering a positive correlation of CTC number with various pathophysiological features, CTC can be contemplated as a reliable parameter to predict the disease outcome in oral cancer. The consistent presence of CTC across all disease stages also suggests a probable nature of OSCC as a biological systematic disease. Clinical trial information: CTRI/2018/03/012905.

Hepatobiliary MR contrast agent uptake as a predictive biomarker of aggressive features on pathology and reduced recurrence-free survival in resectable hepatocellular carcinoma: comparison with dual-tracer 18F-FDG and 18F-FCH PET/CT

To compare the performance of the quantitative analysis of the hepatobiliary phase (HBP) tumor enhancement in gadobenate dimeglumine (Gd-BOPTA)-enhanced MRI and of dual-tracer 18F-FDG and 18F-fluorocholine (FCH) PET/CT for the prediction of tumor aggressiveness and recurrence-free survival (RFS) in resectable hepatocellular carcinoma (HCC). This retrospective, IRB approved study included 32 patients with 35 surgically proven HCCs. All patients underwent Gd-BOPTA-enhanced MRI including delayed HBP images, 18F-FDG PET/CT, and (for 29/32 patients) 18F-FCH PET/CT during the 2months prior to surgery. For each lesion, the lesion-to-liver contrast enhancement ratio (LLCER) on MRI HBP images and the SUVmax tumor-to-liver ratio (SUVT/L) for both tracers were calculated. Their predictive value for aggressive pathological features-including the histological grade and microvascular invasion (MVI)-and RFS were analyzed and compared using area under receiver operating characteristic (AUROC) curves and Cox regression models, respectively. The AUROCs for the identification of aggressive HCCs on pathology with LLCER, 18F-FDG SUVT/L, and 18F-FCH SUVT/L were 0.92 (95% CI 0.78, 0.98), 0.89 (95% CI 0.74, 0.97; p = 0.70), and 0.64 (95% CI 0.45, 0.80; p = 0.035). At multivariate Cox regression analysis, LLCER was identified as an independent predictor of RFS (HR (95% CI) = 0.91 (0.84, 0.99), p = 0.022). LLCER - 4.72% or less also accurately predicted moderate-poor differentiation grade (Se = 100%, Sp = 92.9%) and MVI (Se = 93.3%, Sp = 60%) and identified patients with poor RFS after surgical resection (p = 0.030). HBP tumor enhancement after Gd-BOPTA injection may help identify aggressive HCC pathological features, and patients with reduced recurrence-free survival after surgical resection. • In patients with resectable HCC, the quantitative analysis of the HBP tumor enhancement in Gd-BOPTA-enhanced MRI (LLCER) accurately identifies moderately-poorly differentiated and/or MVI-positive HCCs. • After surgical resection for HCC, patients with LLCER - 4.72% or less had significantly poorer recurrence-free survival than patients with LLCER superior to - 4.72%. • Gd-BOPTA-enhanced MRI with delayed HBP images may be suggested as part of pre-surgery workup in patients with resectable HCC.

Molecular and Clinical Relevance of ZBTB38 Expression Levels in Prostate Cancer.

Prostate cancer is one of the most commonly diagnosed cancers in men. A number of genomic and clinical studies have led to a better understanding of prostate cancer biology. Still, the care of patients as well as the prediction of disease aggressiveness, recurrence and outcome remain challenging. Here, we showed that expression of the gene ZBTB38 is associated with poor prognosis in localised prostate cancer and could help discriminate aggressive localised prostate tumours from those who can benefit only from observation. Analysis of different prostate cancer cohorts indicates that low expression levels of ZBTB38 associate with increased levels of chromosomal abnormalities and more aggressive pathological features, including higher rate of biochemical recurrence of the disease. Importantly, gene expression profiling of these tumours, complemented with cellular assays on prostate cancer cell lines, unveiled that tumours with low levels of ZBTB38 expression might be targeted by doxorubicin, a compound generating reactive oxygen species. Our study shows that ZBTB38 is involved in prostate cancer pathogenesis and may represent a useful marker to identify high risk and highly rearranged localised prostate cancer susceptible to doxorubicin.

Breast Cancer in Young Women Presents With More Aggressive Pathologic Characteristics: Retrospective Analysis From an Argentine National Database.

PURPOSEMultiple studies have reported that breast cancer in young patients is associated with aggressive characteristics, and it is suggested that prognosis is worse independently of pathologic variables.PATIENTS AND METHODSWe performed a retrospective analysis of the Breast Cancer Registry of the Argentinian Society of Mastology, including public and private centers. Patients ≤ 40 years of age at diagnosis were classified as “young,” and patients ≤ 35 years of age at diagnosis were classified as “very young.” Univariate and multivariate analyses were performed to detect differences between groups.RESULTSPatients ≤ 40 years of age comprised 10.40% (739/7,105) of the participants, with an average age of 35.61 ± 4.04 years. Multivariate analysis showed that human epidermal growth factor receptor 2 (HER2)-positive tumor phenotype (odds ratio [OR], 1.82), nodal involvement (OR, 1.69), histologic grade (grade 3 OR, 1.41), and tumor size (T2 OR, 1.37; T3-T4, 1.47) were independently associated with younger age at diagnosis. Patients ≤ 35 years of age (n = 286), compared with patients 36 to 40 years of age, had a higher proportion of HER2 tumors (24.58% v 16.94%; P = .021), absence of progesterone receptor expression (29.85% v 22.95%; P = .043), and stage 3 cancer (29.34% v 18.52%; P < .001). Fewer breast-conserving surgeries (75.37% v 62.89%; P < .001) and more adjuvant chemotherapy (59.04% v 36.66%; P < 0.001) were reported in patients ≤ 40 years of age.CONCLUSIONIn the population studied, breast cancer in young women was associated with aggressive pathologic features and locally advanced disease at the time of diagnosis. Moreover, tumor characteristics in very young patients with breast cancer nested in the population ≤ 40 years of age showed differences in important prognostic factors. More high-quality evidence is needed to improve treatment strategies in these patients.

Expression Pattern and Prognostic Utility of PME-1 in Patients with Hepatocellular Carcinoma.

PurposeHepatocellular carcinoma (HCC) remains one of the most common malignancies. While there is lack of markers capable of predicting which patients are at risk of aggressive course of the disease. Although a few protein phosphatase methyl-esterase-1 (PME-1) tumor-promoting mechanisms have been reported, the role of PME-1 in cancer including HCC occurrence and progression remains to be elucidated. The aim of this study was to explore the expression pattern and relationship between PME-1 with the pathological parameters in patients with HCC.MethodsPME-1 expression was assessed from HCC tissue chips via immunohistochemistry. Chi-square test was used to identify the association between PME-1 staining and clinicopathological variables of HCC patients. Kaplan–Meier analysis and Cox regression analysis were performed to draw survival curves and verify the independent prognostic factors of HCC patients, respectively.ResultsWe found that PME-1 expression was significantly higher in HCC tumor tissues compared with non-tumor tissues (P < 0.001). Furthermore, high expression level of PME-1 was significantly associated with differentiation (P = 0.047), tumor number (P = 0.001), intrahepatic or extrahepatic metastasis (P = 0.018), and recurrence (P = 0.001). Kaplan–Meier analysis revealed that high expression level of PME-1 was associated with shorter survival (P < 0.001). Univariate analysis with Log-rank test revealed that PME-1 expression status was significantly correlated with overall survival (P < 0.001). Furthermore, multivariate models with Cox proportional hazards analysis showed that high expression of PME-1 was a statistically independent predictive factor of poor prognosis in HCC patients (hazard ratio, 3.429; 95% confidence interval, 1.369–8.589; P = 0.009).ConclusionIn conclusion, these findings indicated that PME-1 expression was associated with aggressive pathological features and worse oncological outcomes, suggesting its potential therapeutic value for patients with HCC.

Influence of body mass index on the clinicopathological features of 13,995 papillary thyroid tumors.

This retrospective study aimed to assess the association between obesity, gender, and specific clinicopathological features in patients with papillary thyroid cancer (PTC) and whether diagnostic ultrasonography (US) is adversely affected by obesity in these patients. This study retrospectively analyzed 13,995 adult patients with PTC from a single medical center in China. Data stratification was performed to assess the association of obesity with US features and aggressive clinicopathological features in different models according to the World Health Organization Body Mass Index (WHO-BMI) and Chinese BMI classification (CN-BMI). The odds ratio (OR) of malignant US features and aggressive clinicopathological features was calculated from binary logistic regression models. The BMI, obesity ratio, malignant US features, and aggressive pathological characteristics of males were significantly higher than those of females. After adjusting for confounding factors, the association of obesity with malignant US features and aggressive pathological characteristics was found to be sex-dependent. Next, obesity (WHO-BMI) was found to have an "interfering effect" on the US assessment of PTC (OR = 0.754, 95% CI 0.609-0.932, P = 0.009) in women. Among both sexes, obesity (WHO-BMI) increased the risk of tumor size (ORmale = 1.539 and ORfemale = 1.521) and multifocality (ORmale = 1.659 and ORfemale = 1.449). However, obesity did not increase the risk of capsular invasion or tumor staging in males. The above results are consistent with the CN-BMI. In addition, age was found to have an "interfering effect" on the US evaluation of malignant nodules in both sexes. The results of our study confirm that higher BMI is significantly associated with aggressive clinicopathological features of PTC. Gender differences were present with obesity ratios and aggressive clinicopathological features being significantly higher in men.

Abstract P3-08-21: High CYP27A1 expression at protein and transcript level predicts favorable outcome in node negative, premenopausal breast cancer

Abstract Background: Experimental evidence suggests that pathogenicity caused by cholesterol in breast cancer is partly elicited by 27-hydroxycholesterol (27HC), a primary cholesterol metabolite produced by the sterol 27-hydroxylase cytochrome p450 27A1 (CYP27A1). Targeting CYP27A1 abrogated the adverse effects of cholesterol and 27HC in preclinical studies. The prognostic relevance of CYP27A1 expression in patients with breast cancer is however not clearly defined. Previous studies suggest that the intratumoral expression of CYP27A1 might have diverse effects on prognosis depending on menopausal status. The aim of this study was to comprehensively evaluate the impact of both CYP27A1 protein and mRNA expression on tumor pathobiology and prognosis in pre-menopausal, node-negative breast cancer. Materials and Methods: CYP27A1 expression at the protein and transcript level was evaluated in a prospective cohort of 237 premenopausal women with node-negative, primary invasive breast cancer. Protein and mRNA expression were assessed by immunohistochemistry (IHC) and in situ hybridization technique-RNAscope, respectively. Associations of CYP27A1 expression with tumor pathological features and prognosis were assessed with chi-square test and Cox regression models, respectively. Multivariable models were adjusted for age, hormone receptor status, Ki67, and histological grade. Results: CYP27A1 protein was overexpressed in 28% and CYP27A1 mRNA in 23% of the tumors. The concordance between CYP27A1 protein and mRNA expression was 77.8% (rs=0.430). Among the discordant cases, 13.9% were only positive by IHC. Elevated expression of both protein and mRNA was significantly associated with aggressive tumor pathological features like high histological grade and high Ki67 expression (P&amp;lt;0.001). In multivariable Cox regression analyses, overexpression of CYP27A1 protein was independently prognostic for more than a factor-two reduced risk of disease recurrence (Recurrence-Free Survival (RFS): HR=0.40, 95% CI=0.23-0.86; Distant Recurrence-Free Survival (DRFS): HR=0.40, 95% CI=0.16-0.95). High CYP27A1 expression conferred even stronger protective effect for patients with estrogen receptor (ER) positive tumors when the analyses were stratified by ER status (RFS: HR=0.18, 95% CI=0.06-0.55; DRFS: HR=0.20, 95% CI=0.06-0.81). Likewise, high CYP27A1 mRNA expression was also independently prognostic for a longer RFS (HR=0.40, 95% CI=0.2-0.8), DRFS (HR=0.28; 95%CI=0.1-0.7) and in addition better overall survival (OS) (HR=0.20, 95% CI=0.08-0.60) in the overall population and in the subgroup of patients with ER positive tumors (OS: HR=0.14; 95% CI=0.03-0.65; RFS: HR= 0.22; 95% CI= 0.07-0.68; DRFS: HR=0.16; 95% CI=0.03-0.73). Conclusion: These results indicate that high intratumoral expression of CYP27A1 is a strong indicator for an extensive recurrence-free interval and overall survival in premenopausal women with ER positive, lymph node-negative breast cancer. CYP27A1 transcript expression may serve as an even more sensitive prognostic biomarker. Citation Format: Maria Inasu, Pär Ola Bendahl, Mårten Fernö, Per Malmström, Signe Borgquist, Siker Kimbung. High CYP27A1 expression at protein and transcript level predicts favorable outcome in node negative, premenopausal breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-08-21.