Prognostic Indicator Of Recurrence Research Articles

Prognostic indicators of recurrence after surgical resection in non-pancreatic gastrointestinal neuroendocrine tumors.

e16287 Background: The incidence of gastrointestinal neuroendocrine tumors (GI-NETs) has continued to increase over the last two decades. In patients with locoregional disease, surgical resection of the primary tumor without additional therapies is considered standard of care. The frequency and risk factors associated with recurrence and survival in patients with non-pancreatic GI-NETs are poorly defined. We aimed to evaluate clinical and pathological factors associated with recurrence and survival in patients with resected non-pancreatic GI-NETs. Methods: We conducted a retrospective review of patients who presented to the Johns Hopkins Hospital between 2000-2019 with locoregional small bowel, colon, appendiceal, and rectal neuroendocrine tumors who underwent surgical resection with curative intent. We collected clinical and pathological data including tumor primary site, tumor differentiation, grade using Ki-67 labeling index (grade 1, 2, or 3), margin involvement, perineural or vascular invasion, time of recurrence, patterns of recurrence, and death. Patients with metastatic disease at the time of diagnosis and insufficient follow up were excluded. Results: A total of 133 patients met inclusion criteria. Most patients had tumors originating from the small bowel (n = 87, 66%), followed by the appendix (n = 19, 15%), rectum (n = 18, 14%), and colon (n = 7, 5%). With a median follow-up of 35 months, 23 patients (17%) had tumor progression after curative-intent surgery, with the liver (n = 13, 57%) as the most common site. In the majority of patients, tumors were well-differentiated (n = 118, 97%) and grade 1 (n = 78, 75%). Intermediate/high grade tumors (grade 2/3) occurred in 26 (25%) of patients. Median progression-free survival was 226 months (18.8 years). Age (greater than 60) and intermediate/high grade tumors (grade 2 or 3) were associated with worse overall survival HR = 5.5 (95% CI: 1.5, 19.6), p = 0.009, and HR = 3.3 (95% CI: 1.1, 10.2), p = 0.034, respectively. Tumor grade (2 or 3) and positive nodes were associated with worse progression-free survival HR = 4.5 (95% CI: 2.0, 10.1), p = 4e-04, and HR = 3.1 (95% CI: 1.4, 6.8), p = 0.009, respectively. Conclusions: A significant number of patients (17%) with non-pancreatic GI-NETs had tumor progression after curative-intent surgery. Risk factors for recurrence include intermediate/high-grade tumors and positive lymph nodes. Further studies are needed to evaluate the role of adjuvant therapy in patients at higher risk of recurrence following surgical resection for non-pancreatic GI-NETs.

Post-treatment detection of circulating methylated BCAT1 and IKZF1 as prognostic indicators for recurrence in patients with colorectal cancer.

3575 Background: Patient risk for recurrence after completion of initial treatment of colorectal cancer (CRC) is difficult to predict. Post-treatment circulating tumor DNA (ctDNA) analysis is a promising approach for stratifying such patients but the value of using tumor-uninformed biomarkers, such as methylated BCAT1 and IKZF1, is unknown. This study aimed to determine whether detection of circulating methylated BCAT1 and IKZF1 DNA following completed initial treatment with curative intent, identified patients at elevated risk of CRC recurrence. Methods: CRC stage I-III cases were eligible for study inclusion if a BCAT1/IKZF1 methylation test result was available at least 2 weeks after, but within 12mo, of completing initial treatment, and had had at least 2y follow-up unless recurrence was evident sooner (n = 142). Surveillance included regular clinical assessments and radiographic imaging. Level of methylation was reported as the total methylated BCAT1/ IKZF1 expressed as percent of cell-free DNA; levels ≥0.07% were considered positive. Primary outcome measure was recurrence-free survival. Mantel-Cox (logrank) method was used to assess the association between BCAT1/IKZF1 results and recurrence-free survival. Multivariable survival analysis by Cox proportional hazards modelling assessed the impact of covariates, including: BCAT1/IKZF1 result, age, gender, T-stage (T1-2 vs T3-4), N-stage (N0 vs N1-2), extra- and/or intra-mural vascular invasion (EMVI/IMVI) and nature of treatment. Time to recurrence was measured from the date of treatment completion to first evidence of recurrence and data were censored to last date of follow-up. Results: 33/142 (23.2%) cases had recurrence detected at a median 1.6y (IQR: 0.8-2.4). Follow-up time for those who remained recurrence free was 5.3y (IQR: 3.7-6.9). The time between completing treatment and BCAT1/IKZF1 testing was not different between these groups (median 2.4 vs 3.1mo, p = 0.530). 13 (9.2%) cases were positive for methylated BCAT1/IKZF1 after completing treatment and a positive result was associated with a significant risk of recurrence (hazard ratio [HR], 10.0 (95%CI 2.6-39.3), p < 0.001). In the multivariable survival analysis, only a positive BCAT1/IKZF1 methylation result following treatment (HR 2.6, 95%CI: 1.0-6.0, p = 0.041) and evidence of EMVI or IMVI (HR 2.3, 95%CI: 1.0-5.1, p = 0.044) were significant predictors of survival. Conclusions: This study shows that post-treatment BCAT1/IKZF1 methylation testing, which does not need personalization using tumor genotyping, is a promising independent prognostic indicator for CRC recurrence. Such cases are at high risk of recurrence compared to those who had no detectable ctDNA post treatment. These patients warrant enhanced and/or extended surveillance for recurrence. Clinical trial information: 12611000318987.

A nomogram for predicting the risk of postoperative recurrence of hepatitis B virus-related hepatocellular carcinoma in patients with high preoperative serum glutamyl transpeptidase.

Recurrence is a major risk factor affecting the postoperative survival of patients with hepatocellular carcinoma (HCC), especially those with high preoperative serum γ-glutamyl transpeptidase (GGT) levels. This study had the aim of developing a personalized predictive tool to accurately determine the risk of postoperative recurrence of hepatitis B-virus (HBV)-related HCC in patients with high preoperative serum GGT levels. Patients who underwent curative liver resection of HBV-related HCC and had high preoperative GGT levels were consecutively enrolled between 2008 and 2011. Prognostic indicators for recurrence were determined using Cox regression analysis. A nomogram was then developed and assessed by integrating the independent risk factors into the model. A total of 603 eligible patients were included. The final nomogram for predicting HCC recurrence in patients with high preoperative GGT levels consisted of five independent prognostic factors: α-fetoprotein (AFP), HBV-DNA, satellite nodules, microvascular invasion, and tumor grade. The C-index of the nomogram for predicting recurrence was 0.759, and validation showed high accuracy and discriminatory. The predictive nomogram developed and validated in this study performs well in predicting postoperative recurrence of HBV-related HCC in patients with high preoperative GGT levels. It can provide personalized assessments to inform the development of surveillance strategies and allows patients with a high risk of recurrence to be selected for further adjuvant treatment.

Recurrence of Papillary Thyroid Cancer: A Systematic Appraisal of Risk Factors.

ContextThyroid cancer recurrence is associated with increased mortality and adverse outcomes. Recurrence risk is currently predicted using clinical tools, often restaging patients after treatment. Detailed understanding of recurrence risk at disease onset could lead to personalized and improved patient care.ObjectiveWe aimed to perform a comprehensive bioinformatic and experimental analysis of 3 levels of genetic change (mRNA, microRNA, and somatic mutation) apparent in recurrent tumors and construct a new combinatorial prognostic risk model.MethodsWe analyzed The Cancer Genome Atlas data (TCGA) to identify differentially expressed genes (mRNA/microRNA) in 46 recurrent vs 455 nonrecurrent thyroid tumors. Two exonic mutational pipelines were used to identify somatic mutations. Functional gene analysis was performed in cell-based assays in multiple thyroid cell lines. The prognostic value of genes was evaluated with TCGA datasets.ResultsWe identified 128 new potential biomarkers associated with recurrence, including 40 mRNAs, 39 miRNAs, and 59 genetic variants. Among differentially expressed genes, modulation of FN1, ITGα3, and MET had a significant impact on thyroid cancer cell migration. Similarly, ablation of miR-486 and miR-1179 significantly increased migration of TPC-1 and SW1736 cells. We further utilized genes with a validated functional role and identified a 5-gene risk score classifier as an independent predictor of thyroid cancer recurrence.ConclusionOur newly proposed risk model based on combinatorial mRNA and microRNA expression has potential clinical utility as a prognostic indicator of recurrence. These findings should facilitate earlier prediction of recurrence with implications for improving patient outcome by tailoring treatment to disease risk and increasing posttreatment surveillance.

Risk factors for recurrence in colorectal cancer: a retrospective analysis in a regional Australian hospital.

Colorectal cancer is the third most commonly diagnosed malignancy in Australia. Up to a third of patients who have undergone surgery with curative intent for colorectal cancer will have a recurrence of disease leading to significant morbidity and mortality. Regional Australians have disproportionately worse outcomes. To identify factors associated with recurrence in colorectal cancer patients treated at a regional Australian hospital. This study is a retrospective cohort analysis. Consecutive patients who have undergone curative resection at a regional public and private hospital by three surgeons from a single surgical practice for either rectal cancer or colon cancer were included. Prognostic indicators of recurrence were examined via both univariate and multivariate time-to-event analyses. Three hundred nine patients were included with 43 recurrences. Thirty presented with distant metastases, seven presented with locoregional recurrence and six presented with locoregional as well as distant recurrence. In univariable analysis, higher rates of recurrence were associated with tumour type, higher AJCC summary stage, higher preoperative levels of CA19-9, perineural invasion, lymphovascular invasion, <12 nodes examined, positive lymph nodes and emergency surgery status. On multivariable analysis recurrence remained associated with tumours with a mucinous and/or signet cell component, positive nodes and <12 lymph nodes examined. A combination of patient and treatment factors are relevant in determining the risk of recurrence for stage I-III colorectal cancer. This study emphasises the importance of histology in determining risk, particularly the number of nodes examined. CEA 19-9 may also be a useful pre-operative predictor of recurrence.

Tumor-related mutations in cell-free DNA in pre-operative plasma as a prognostic indicator of recurrence in endometrial cancer

ObjectivesCirculating tumor DNA (ctDNA) has potential as a basis for understanding the molecular features of a tumor non-invasively and for use as a diagnostic, prognostic, and disease-monitoring marker. The aim...

Abstract B70: Differential expression of regulatory T cells and Th17 cells are indicative of tumor recurrence in pN0 stage I lung cancer patients

Abstract Background: Up to 30% of lung cancer (Stage I) with the most favorable outcome recur within 5 years after surgery. Predicting relapse in patients treated curatively with surgical resection for stage I non-small cell lung cancer (NSCLC) remains difficult. The sentinel lymph nodes (SLNs) are the first lymph nodes reached by metastatic cancer cells from a primary tumor. In a recent immunologic study, immunologic changes were detected in these lymph nodes prior to pathologic invasion. This study evaluated the pattern of failure after surgical resection in pN0 lung cancers and determines whether regulatory T (Treg) cells and Th17 cells were prognostic indicator for recurrence. Methods: Patients over 18 years of age who were clinically diagnosed with stage I lung cancer were enrolled. Patients receiving prior lung cancer treatment or thoracic radiation were excluded from enrollment. During surgery, the sentinel lymph nodes were isolated using a handheld gamma probe, followed by the dissection of the visible mediastinal, hilar, and peribronchial lymph nodes. Samples from normal lung tissue, the tumor mass, and all dissected lymph nodes were sectioned and conventionally examined using H&amp;E staining and immunohistochemistry. In addition, the forkhead transcription factor3 (Foxp3) and transcription factor retinoic acid-related orphan receptor (ROR)-γ, recently described to be essential for differentiation of Tregs and Th17 cells, were evaluated by real time RT-PCR. Results: Between October 2009 and October 2010, 27 patients with clinical stage I NSCLC were enrolled consecutively. Among them, twenty patients (thirteen men, seven women, mean age 67.6 years) pathologically staged as N0 were analyzed. Eight patients had squamous cell carcinoma and twelve patients had adenocarcinoma. The expression of Foxp3 in the tumor mass was increased in adenocarcinoma compared to squamous cell carcinoma (P=0.05). The Foxp3 expression and Treg cells in the tumor mass were not significantly associated with recurrence. However, Foxp3 expression and Treg cells’ presence in SLNs were significantly increased in patients with recurring disease compared to nonrecurring disease (P=0.03 and P=0.01, respectively). The number of Th17 cells in tumor mass was decreased in patients with recurring pN0 disease compared to those with non-recurring disease (P=0.04). ROR-γ expression and Th17 cells presence in SLNs were not related with recurrence. Conclusion: The results of this study suggest that the increased number of Treg cells in SLNs and decreased number of Th17 cells in tumor mass might be a promising indicator of recurrence. Citation Format: Chan Kwon Park, Seung Joon Kim. Differential expression of regulatory T cells and Th17 cells are indicative of tumor recurrence in pN0 stage I lung cancer patients [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2018 Nov 27-30; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(4 Suppl):Abstract nr B70.

Prognostic utility of serial 18F-FDG-PET/CT in patients with locally advanced rectal cancer who underwent tri-modality treatment.

This study explored the value of serial 18-fludeoxyglucose-positron emission tomography (18F-FDG-PET/CT) in predicting disease-free survival (DFS) in locally advanced rectal cancer (LARC) treated with neoadjuvant chemoradiation (NCRT) and surgery. We prospectively studied 46 patients with LARC who underwent NCRT and surgery. 18F-FDG-PET/CT scans were performed at three time-points before surgery (pre-NCRT-PET1, during NCRT-PET2 and following completion of NCRT-PET3). The following semi-quantitative PET parameters were analysed at each time point: maximum standardized uptake value (SUVmax), SUVmean, metabolic tumour volume (MTV) and tumour lesion glycolysis (TLG). Absolute and percentage changes in these parameters were analysed between time points. Statistical analysis consisted of median tests, Cox regression and Kaplan-Meier analysis for DFS. The median follow-up time was 24 months. A reduction in PET parameters showed statistically significant differences for patients with recurrence compared to those without; percentage changes in MTV between PET1 and PET3 (cut-off: 87%, p = 0.023), percentage changes in TLG between PET1 and PET3 (cut-off: 94%, p = 0.02) and absolute change in MTV PET1 and PET2 (cut-off: 10.25, p = 0.001).An absolute reduction in MTV between PET1 and PET3 (p=0.013), a percentage reduction in TLG between PET1 and PET2 (p=0.021), SUVmax and SUVmean at PET2 (p = 0.01, p = 0.027 respectively)were also prognostic indicators of recurrence.MTV percentage change between PET1 and PET2 and SUVmean percentage change between PET1 and PET3 were also trending towards significance (p = 0.052, p = 0.053 respectively). Serial 18F-FDG-PET/CT is a potentially reliable non-invasive method to predict recurrence in patients with LARC. Volumetric parameters were the best predictors. This could allow risk-stratification in patients who may benefit from conservative management. This paper will add to the literature in risk-stratifying patients with LARC based on prognosis, using 18F-FDG-PET/CT. This may improve patient outcomes by selecting suitable candidates for conservative management.

Development of Novel Prognostic Prediction Models including the Prognostic Nutritional Index for Patients with Colorectal Cancer after Curative Resection.

Objectives: It has been reported that there is an association between the nutritional condition and the prognosis of cancer. Here, we evaluated the relation between the prognostic nutritional index (PNI) and colorectal cancer (CRC). Methods: A total of 184 patients with CRC who underwent curative surgery from October 2011 to December 2012 at the Osaka University Hospital were investigated. According to the median PNI value of our data set, patients were classified into a high-PNI (≥46) group and a low-PNI (<46) group. The relationship between the PNI and the disease-free survival (DFS) and overall survival (OS) was analyzed by a Cox regression model. Results: A low PNI was significantly associated with poor DFS (P = 0.006) and OS (P < 0.001). A multivariate analysis showed that low PNI, venous invasion (present), and tumor location (rectum) were independent risk factors for recurrence. Low PNI, advanced age, and venous invasion were found to be independent risk factors for mortality. Using these clinicopathological factors, we developed nomograms to predict DFS and OS. The concordance index was 0.828 for DFS and 0.756 for OS. Conclusions: A low PNI is a prognostic indicator for recurrence and mortality in CRC. Nomograms constructed by clinicopathological factors including the PNI can provide individual prognostic outcomes.

Co-Detection of miR-21 and TNF-α mRNA in Budding Cancer Cells in Colorectal Cancer.

MicroRNA-21 (miR-21) is upregulated in many cancers including colon cancers and is a prognostic indicator of recurrence and poor prognosis. In colon cancers, miR-21 is highly expressed in stromal fibroblastic cells and more weakly in a subset of cancer cells, particularly budding cancer cells. Exploration of the expression of inflammatory markers in colon cancers revealed tumor necrosis factor alpha (TNF-α) mRNA expression at the invasive front of colon cancers. Surprisingly, a majority of the TNF-α mRNA expressing cells were found to be cancer cells and not inflammatory cells. Because miR-21 is positively involved in cell survival and TNF-α promotes necrosis, we found it interesting to analyze the presence of miR-21 in areas of TNF-α mRNA expression at the invasive front of colon cancers. For this purpose, we developed an automated procedure for the co-staining of miR-21, TNF-α mRNA and the cancer cell marker cytokeratin based on analysis of frozen colon cancer tissue samples (n = 4) with evident cancer cell budding. In all four cases, TNF-α mRNA was seen in a small subset of cancer cells at the invasive front. Evaluation of miR-21 and TNF-α mRNA expression was performed on digital slides obtained by confocal slide scanning microscopy. Both co-expression and lack of co-expression with miR-21 in the budding cancer cells was noted, suggesting non-correlated expression. miR-21 was more often seen in cancer cells than TNF-α mRNA. In conclusion, we report that miR-21 is not linked to expression of the pro-inflammatory cytokine TNF-α mRNA, but that miR-21 and TNF-α both take part in the cancer expansion at the invasive front of colon cancers. We hypothesize that miR-21 may protect both fibroblasts and cancer cells from cell death directed by TNF-α paracrine and autocrine activity.

Identification of a nine-gene panel as a prognostic indicator for recurrence with muscle-invasive bladder cancer.

Bladder cancer is one of the most common and highly recurrent cancers worldwide. Recurrence-associated genes may potentially predict cancer recurrence. We aimed to construct a recurrence-associated gene panel to improve the prognostic prediction of bladder cancer. Based on DNA sequencing and clinical data from the TCGA-BLCA project, we identified 10 potential driver genes significantly associated with recurrence of bladder cancer. We performed multivariable logistic regression analysis to construct an optimized recurrence prediction model with nine recurrence-associated genes (EME1, AKAP9, ZNF91, PARD3, STAG2, ZFP36L2, METTL3, POLR3B, and MUC7) and clinical information as the independent variables. The area under the receiver operating characteristic (ROC) curve was 0.80 in this model, much higher than that of the baseline model (AUC = 0.73) and the same trend was also validated in its subset. Decision curve analysis also revealed that there is a significant net benefit gained by adding nine genes mutation to the baseline model. Furthermore, Kaplan-Meier survival analysis showed that eight out of the nine genes (excluding MUC7) had good effects on the overall prognosis of patients. This nine-gene panel will most likely be a useful tool for prognostic evaluation and will facilitate the personalized management of patients with bladder cancer.

Prognosis and treatment outcomes of central neurocytomas: clinical interrogation based on a single center experience.

Central neurocytoma (CN) is a very rare neuronal neoplasm. The clinical implications of the potential prognostic factors for these lesions, including tumor atypia, have therefore not been clarified. Forty CN patients were enrolled and reclassified as typical or atypical in accordance with an MIB-1 labeling index (LI) of above and below 2%. We classified our retrospective study cohort as 21 (52.5%) typical and 19 (47.5%) atypical CN cases. No significant differences were found in terms of sex, mean age, mean tumor size or tumor location between these groups. Recurrences occurred in 2 (9.5%) typical and 6 (33.3%) atypical cases. The typical CN 2-,3- and 5-year PFS rates were 100%, 100%, 92.3%, and those for the atypical group were 93.8%, 78.1%, 65.1%, respectively (p = 0.02). The PFS rates did not statistically differ by treatment modality (gross total resection alone, subtotal resection (STR) alone and STR plus radiation therapy (RT) or radiosurgery (RS)) either in the whole cohort (p = 0.75) or in the typical CN and atypical CN subgroups (p = 0.45 and 0.98, respectively). An atypical histology was the only prognostic indicator of recurrence by univariate analysis (hazard ratio: 5.40, p = 0.04). An atypical lesion (MIB-LI > 2%) is an important prognostic indicator in CN. The clinical implications of the extent of resection for CN patients are still debatable. The use of STR plus RT or RS may be a viable treatment strategy for CN but different therapeutic and follow-up approaches for atypical CN will be needed.

Prognostic Analysis of Clinical and Immunohistochemical Factors for Patients with Spinal Schwannoma

Schwannoma comprises approximately 25% of all spinal tumors, but there is little information published in the literature regarding this subject. Our aim in this study was to discuss diagnostic and prognostic factors for spinal schwannoma. A retrospective study was performed to analyze the clinical and immunohistochemical data of patients with spinal schwannoma surgically treated in our center between 2005 and2013. A total of 524 patients with spinal schwannoma were included in the study. The mean follow-up period was 58.3 months. Forty-eight patients developed recurrence, and 26 died. Findings from the statistical analyses suggested duration of preoperative symptoms, Sridhar classification, tumor size, bone damage, Ki67 labeling index, and S100 expression were different between benign schwannoma and the malignant subtype. Recurrence was associated with resection mode, segments of involvement, pathology grade, CD57 expression, Ki67 labeling index, and S100 expression. The overall survival was closely related with recurrence, location in sacrum, pathology grade, Ki67 labeling index, and P53 expression. Compared with the benign subtype, malignant schwannoma has a shorter duration of preoperative symptoms, larger tumor size, greater Sridhar classification, and poorer prognosis. Total resection can significantly reduce recurrence but not guarantee a better survival, which is associated location and pathology grade. A Ki67 labeling index >5% was not only an index for malignant subtype but also a prognostic indicator for recurrence and poor survival. Moreover, S100-negative was a prognostic indicator for recurrence, whereas P53-positive was associated with a poor prognosis.

Extranodal extension of lymph node metastasis as a prognostic indicator of recurrence and survival in papillary thyroid carcinoma.

Stratification of extranodal extension (ENE) extent has the potential to improve the accuracy of risk estimations in papillary thyroid carcinoma (PTC). This study examined the prognostic importance of nodal factors, including ENE, in PTC patients. This study enrolled 2071 consecutive patients with treatment-naïve PTC who underwent thyroidectomy between 2006 and 2010. Microscopic/macroscopic ENE was determined by pathological and operative findings. Univariate and multivariate analyses were used to identify the relationship of factors with recurrence and survival in all study patients and in the node-positive subset. Of 2071 patients, 975 (47.1%) had positive lymph nodes, and 271 (13.1%) and 70 (3.4%) had microscopic and macroscopic ENE, respectively. During a median follow-up of 96 months, 114 (5.5%) patients had post-treatment recurrence. Multivariate analyses showed that, in all patients, the number of positive nodes, lymph node ratio, ENE status, and ATA risk group were independent variables affecting recurrence (P < 0.05). T4 and macroscopic ENE were independent variables associated with shorter overall survival (P < 0.05). Macroscopic ENE was significantly associated with macroscopic extrathyroidal extension. Macroscopic ENE has a significant adverse impact on recurrence and survival after treatment for PTC. ENE is considered a high risk factor for recurrence.

Abstract P3-05-12: Combination of anti-progranulin (GP88/PGRN) antibody and letrozole inhibits tumor formation of letrozole resistant breast cancer cell lines

Abstract The 88 kDa glycoprotein GP88 (Progranulin, PCDGF, acrogranin) is the largest member of the granulin/epithelin family of growth modulators identified as a driver of tumorigenesis. GP88 (PGRN) was also shown to be overexpressed in invasive ductal carcinoma (IDC)whereas it was negative in benign tumors and normal mammry epithelial tissue, thereby establishing GP88 as a therapeutic and diagnostic target in breast cancer (BC). Our laboratory has developed validated tools to measure GP88 in tumor biopsies and biological fluids as well as blocking its action. WE showed that GP88 was secreted and detected in the serum of BC patients at an increased level when compared to healthy subjects. Pathological studies with 530 cases of ER+ IDC with clinical outcomes showed that GP88 tumor expression was an independent prognostic indicator of recurrence in early stage BC patients. Training study followed by an independent validation study demonstrated that high GP88 tissue expression (GP88 3+) was associated with a 4-fold increase in risk of recurrence at 5 years. A neutralizing anti-GP88 antibody AG1 was expressed in a high yield CHO cell line was developed. The present study examined the effect of AG1 in letrozole resistant cell line AGLetR developed by long term selection in letrozole supplemented medium. This cell line showed decreased letrozole responsiveness in vivo and therefore constituted an excellent model for investigating letrozole resistance in vitro as well as in vivo. Here we report the results of studies investigating the effect of various doses of AG1 on LetR tumor development in combination with letrozole for AGLetR. We show that treatment with AG1 (10 mg/kg i.p.) in combination with letrozole was efficient to maintain long term responsiveness and inhibit tumor growth. Letrozole alone (5mg/kg) was unable to inhibit tumor growth and showed a doubling of tumor volume. Interestingly, long term combination treatment lead to tumor regression and inhibited tumor growth. These data suggest that inhibiting GP88 could provide a novel and alternative therapeutic strategy for patients with resistance to anti-estrogen therapy, being tamoxifen or letrozole. This works is supported by 2R44CA124179, HHSN 261201200060C, and HHSN2612014400C from NCI. Citation Format: Serrero G, Dong J, Yue B, Hicks D, Hayashi J. Combination of anti-progranulin (GP88/PGRN) antibody and letrozole inhibits tumor formation of letrozole resistant breast cancer cell lines. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P3-05-12.

Use of Cytokeratin-19 Concentration to Assess Early Recurrence and Prognosis of Hepatitis B Virus-Related Hepatocellular Carcinoma following Radical Resection in Patients with a Low Serum Alpha-Fetoprotein Concentration.

Cytokeratin 19 (CK-19) is a prognostic indicator of recurrence and metastasis of hepatocellular carcinoma (HCC) following radical resection. To investigate the role of CK-19 in assessment of early recurrence and prognosis in patients with hepatitis B virus (HBV)-related HCC following radical resection. In total, 235 patients with HBV-related HCC (age, 15–82 years; mean age, 54 ± 10 years) undergoing radical resection were screened for inclusion from January 2005 to December 2010. Malignant tissues and adjacent non-malignant tissues were sampled during surgery, and CK-19 and Ki-67 expression was determined by tissue microarray and immunohistochemistry. CK-19 mRNA levels in 30 randomly selected frozen HCC specimens were examined by reverse transcription polymerase chain reaction from January 2011 to June 2011. Correlations of CK-19 and Ki-67 expression with tumor recurrence, metastasis, disease-free survival (DFS), and overall survival (OS) were analyzed. Elevated CK-19 expression was correlated with early recurrence (P = 0.001), shorter DFS (P = 0.001), and reduced OS (P = 0.010). CK-19 expression was correlated with the Ki-67 index (P = 0.037), histological differentiation (P = 0.016), focal number (P = 0.044), and blood vessel tumor embolism (P = 0.002). Patients with metastasis within 1 year exhibited stronger CK-19 expression than did patients without metastasis (P < 0.05). Furthermore, early recurrence was associated with elevated CK-19 mRNA levels (χ2 = 5.761, P = 0.016).When confirmed by a low alpha-fetoprotein concentration (<400 μg/L), CK-19 expression in surgical biopsy specimens taken from patients with HCC during radical resection is an additional valuable indicator of early recurrence, distant metastasis, and poor prognosis in HBV-positive patients.

Diffusion-weighted magnetic resonance imaging of thymoma: ability of the Apparent Diffusion Coefficient in predicting the World Health Organization (WHO) classification and the Masaoka-Koga staging system and its prognostic significance on disease-free survival.

To evaluate the usefulness of diffusion-weighted magnetic resonance for distinguishing thymomas according to WHO and Masaoka-Koga classifications and in predicting disease-free survival (DFS) by using the apparent diffusion coefficient (ADC). Forty-one patients were grouped based on WHO (low-risk vs. high-risk) and Masaoka-Koga (early vs. advanced) classifications. For prognosis, seven patients with recurrence at follow-up were grouped separately from healthy subjects. Differences on ADC levels between groups were tested using Student-t testing. Logistic regression models and areas under the ROC curve (AUROC) were estimated. Mean ADC values were different between groups of WHO (low-risk = 1.58 ± 0.20 × 10(-3)mm(2)/sec; high-risk = 1.21 ± 0.23 × 10(-3)mm(2)/sec; p < 0.0001) and Masaoka-Koga (early = 1.43 ± 0.26 × 10(-3)mm(2)/sec; advanced = 1.31 ± 0.31 × 10(-3)mm(2)/sec; p = 0.016) classifications. Mean ADC of type-B3 (1.05 ± 0.17 × 10(-3)mm(2)/sec) was lower than type-B2 (1.32 ± 0.20 × 10(-3)mm(2)/sec; p = 0.023). AUROC in discriminating groups was 0.864 for WHO classification (cut-point = 1.309 × 10(-3)mm(2)/sec; accuracy = 78.1%) and 0.730 for Masaoka-Koga classification (cut-point = 1.243 × 10(-3)mm(2)/sec; accuracy = 73.2%). Logistic regression models and two-way ANOVA were significant for WHO classification (odds ratio[OR] = 0.93, p = 0.007; p < 0.001), but not for Masaoka-Koga classification (OR = 0.98, p = 0.31; p = 0.38). ADC levels were significantly associated with DFS recurrence rate being higher for patients with ADC ≤ 1.299 × 10(-3)mm(2)/sec (p = 0.001; AUROC, 0.834; accuracy = 78.0%). ADC helps to differentiate high-risk from low-risk thymomas and discriminates the more aggressive type-B3. Primary tumour ADC is a prognostic indicator of recurrence. • DW-MRI is useful in characterizing thymomas and in predicting disease-free survival. • ADC can differentiate low-risk from high-risk thymomas based on different histological composition • The cutoff-ADC-value of 1.309 × 10 (-3) mm (2) /sec is proposed as optimal cut-point for this differentiation • The ADC ability in predicting Masaoka-Koga stage is uncertain and needs further validations • ADC has prognostic value on disease-free survival and helps in stratification of risk.

Abstract 2241: MDM2 silencing promotes tumor-initiating cells in osteosarcoma and breast cancer

Abstract Chemotherapy has made remarkable strides in the past century to alleviate tumor burden across most cancer types, yet it remains ineffective at achieving complete tumor remission. To improve chemotherapy efficacy and patient survival, novel drugs will require a greater mechanistic understanding of tumor initiating cell (TIC) regulatory pathways. Intratumoral heterogeneity is a major obstacle for conventional targeted treatment modalities, which select for aggressive phenotypes with acquired drug resistance and TIC enrichment. Here we focus on elucidating the role of Mdm2 in mediating TIC levels in osteosarcoma (MG-63, Saos2) and breast cancer (MDA 231, MDA 468, and BT474) cell lines. We demonstrate Mdm2 silencing by ShRNA results in increased levels of Nanog, Oct4a, and Sox2, and diminished expression of ERα and ERβ by western blot. We observed an increase in the immunophenotypic expression of CD133 in ShMdm2 osteosarcoma and breast cancer cell lines by flow cytometry. Our data provides the first evidence that loss of Mdm2 results in increased TIC population. Further analysis will examine the affects of TIC using small molecular inhibitors to Mdm2. This insight will contribute to the molecular foundations defining the role of Mdm2 in TIC and will determine if targeting Mdm2 therapeutically is a prognostic indicator for recurrence. Citation Format: David J. Olivos, Lindsey D. Mayo. MDM2 silencing promotes tumor-initiating cells in osteosarcoma and breast cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2241. doi:10.1158/1538-7445.AM2015-2241

De Quervain Tendinopathy: Survivorship and Prognostic Indicators of Recurrence Following A Single Corticosteroid Injection

To determine short- and long-term success rates of a single corticosteroid injection for de Quervain tendinopathy while identifying prognostic indicators for symptom recurrence and repeat intervention. Fifty consecutive patients with de Quervain tendinopathy treated with corticosteroid injections (lidocaine plus triamcinolone acetonide or dexamethasone) were prospectively enrolled. Patients with inflammatory arthritis, carpometacarpal osteoarthritis, or a previous distal radius fracture affecting the symptomatic wrist were excluded. Demographic data and information on existing comorbidities were recorded. Patients were seen in clinic at 6 weeks after injection and contacted at 3, 6, 9, and 12 months following injection to determine symptom recurrence and further intervention. Medical records were also reviewed for this purpose. Kaplan-Meier survival analysis and Cox regression modeling were used to estimate recurrence rates and identify predictors of symptom recurrence and repeat intervention. Fifty wrists in 50 patients (average age, 49 y) were included. One patient was lost to follow-up. Eighty-two percent of patients had resolved symptoms 6 weeks after a steroid injection. Twenty-four patients had a recurrence of symptoms at a median of 84 days after the injection. Eleven patients underwent additional intervention (7 surgical releases and 4 repeat injections) at a median of 129 days (range, 42-365) after the injection. Estimated freedom from symptom recurrence was 52% at 6 and 12 months. Estimated freedom from repeat intervention was 81% at 6 months and 77% at 12 months. Two of 3 patients with a history of trigger finger required subsequent de Quervain surgery. We demonstrated that a single cortisone injection was effective in alleviating symptoms of de Quervain tendinopathy in 82% of patients and that over half remained symptom-free for at least 12 months. All patients with recurring symptoms developed them within the first 6 months. Prognostic IV.

Abstract PR15: The prognostic power of stromal reactivity: An integrated approach to prostate cancer evolution

Abstract Prostate cancer (PCa) is the fifth most common cancer worldwide. Gleason score is the standard metric for defining prostate cancer aggressiveness. Still, prostate cancer is difficult to prognose. Stroma is known to play a major role in tumor progression to malignancy and upon activation (reactive) produces growth factors (GFs) necessary for tissue repair. The prognostic significance of reactive stroma grading in prostate biopsies remains uncertain, except for recurrence in Gleason 7 patients. Moreover, how stromal reactivity and tumor aggressiveness drives progression in PCa remains unclear. To better understand PCa progression, we investigated the interplay between stroma, tumor and microenvironmental heterogeneity in driving PCa aggressiveness. We used an integrated approach combining 7200 simulated prostate cancers over 20 years, 870 prostate cancer patients with 20 years of follow-up (recurrence and death) as well as in-vivo experimentation. We designed a multiscale computational model that incorporates, chemical and physical properties of the microenvironment that modulate the dynamic behavior of hundreds of thousands of cells. This model was simulated on an anatomically reconstructed tissue domain that represents most of the largest segment of the prostate where cancer occurs most frequently (peripheral zone). Each simulated tumor was initiated by seeding a heterogeneous distribution of GF producing tumor cells along with 3 different degrees of reactive stroma. We corroborated our in silico results with whole mount slides from clinical radical prostatectomy specimens. Histopathological analysis included stage, primary and secondary Gleason grades with associated outcomes information. In addition, in vivo experiments were performed combining an initiated epithelial cell line with fibroblasts from patients with pathologically-defined degrees of stromagenesis. The recombinant tissues were grown, stained and the aggressiveness of the tumor was recorded. Our findings reveal that the degree of reactive stroma significantly correlates with the level of aggressiveness of the tumor. Crucially, the degree of stromal reactivity appears to be a significant selection pressure in evolving aggressive tumors. Counter intuitively, a low degree of reactive stroma correlates with a strong selection pressure for higher GF production in the tumor cells - due to the restricted levels of GF found in the microenvironment. This results in a slow progression towards increasingly more aggressive tumor phenotypes. In contrast, a high degree of reactive stroma correlates with a weaker selection pressure for GF producing tumor cells and fast progression - since the GFs are readily accessible to the tumor via the microenvironment. Based on these findings, we conclude that the degree of stromal reactivity is a significant prognostic indicator of recurrence and death for the risk level of low, intermediate and high Gleason grades. For example, Gleason 6 is considered to have a low risk prognosis; however, in cases where the stroma is found to be highly reactive the risk should be considered as high. Patients with Gleason scores 9 or 10 already have a high risk prognosis even when there is a low degree of reactive stroma, but their risk increases even more, when there is a high degree of reactive stroma. In brief, using an integrated computational, experimental and clinical data approach we conclude that the stroma surrounding prostate tumors plays a substantial role in driving PCa evolution toward aggressiveness and prognosis towards higher risk. This abstract is also presented as Poster A66. Citation Format: Ziv Frankenstein, David Basanta, Omar Franco, Douglas Strand, Simon Hayward, Gustavo Ayala, Alexander Anderson. The prognostic power of stromal reactivity: An integrated approach to prostate cancer evolution. [abstract]. In: Abstracts: AACR Special Conference on Cellular Heterogeneity in the Tumor Microenvironment; 2014 Feb 26-Mar 1; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(1 Suppl):Abstract nr PR15. doi:10.1158/1538-7445.CHTME14-PR15