Presence Of Lymphatic Invasion Research Articles

C-Reactive Protein to Albumin Ratio in Colorectal Cancer: A Meta-Analysis of Prognostic Value.

Background:The relationship between pretreatment C-reactive protein to albumin ratio (CAR) and colorectal cancer (CRC) prognosis has been extensively studied in various tumors. However, little is known on CAR and its association with prognosis in CRC. This study aims to investigate the prognostic value of pretreatment CAR in CRC.Methods:We conducted a systematic search of MEDLINE, EMBASE, and Cochrane Library databases for eligible studies evaluating the associations of CAR with survival and/or clinicopathology of CRC. Overall survival (OS), disease-free survival (DFS), relapse-free survival (RFS), and clinicopathological features were synthesized and compared.Results:Nine studies including 3431 patients were analyzed in this meta-analysis. Pooled results showed that elevated pretreatment CAR was associated with poor OS (pooled hazards ratio [HR]: 2.18, 95% confidence interval [CI]: 1.70-2.78, P < .001) and DFS/RFS (pooled HR: 2.36, 95% CI: 1.40-3.98, P < .001). Moreover, elevated pretreatment CARs were correlated with male patients, large tumor diameter, late III-IV tumor node metastasis stage tumors, high serum carcinoembryonic antigen and carbohydrate antigen 19-9, and presence of lymphatic invasion and venous invasion.Conclusion:Elevated pretreatment CAR could be an adverse prognostic indicator in patients with CRC.

Prognostic Significance of Increased Expression of Annexin A10 (ANXA10) in Serous Epithelial Ovarian Cancer.

BackgroundEpithelial ovarian cancer (EOC) is a gynecological malignancy that is associated with high mortality. Annexin A10 (ANXA10) is variably expressed in several types of human malignancy, but its role and clinical significance in EOC remain unknown. This study aimed to investigate the role of ANXA10 in EOC cells in vitro and to study the association between the protein expression levels of the ANXA10 in tumor tissue from patients with serous EOC and clinical outcome.Material/MethodsThe expression of ANXA10 was studied in 118 cases of serous EOC and in the ovarian cancer cell lines, SKOV-3, HO9810, HO8910PM, and OVCAR3 with immunohistochemistry and Western blot. Correlation between ANXA10 expression and clinicopathological variables and patient outcome were evaluated, including with Kaplan-Meier survival curves, univariate analysis with the log-rank test, and the multivariate analysis with the Cox-regression model.ResultsANXA10 was expressed by cells in the ovarian cancer cell lines. Patients with low expression and high expression of ANXA10 were 61.86% (73/118) and 38.14% (45/118), respectively. High expression of ANXA10 was correlated with poor response to chemotherapy (P=0.034), the presence of lymphatic invasion (P=0.043), and the International Federation of Gynecology and Obstetrics (FIGO) advanced stage (P=0.033), which were all associated with lower survival rates of serous EOC. Increased expression of ANXA10 was identified as an independent prognostic biomarker of serous EOC (HR=1.73; 95% CI, 1.01–2.98; P=0.046).ConclusionsIncreased expression of ANXA10 was an independent prognostic marker in patients with serous EOC.

Abstract 4898: Clinical application of quantitative multiplex mass spectrometry-based proteomics in predicting clinical outcomes in locally advanced rectal cancer

Abstract Background: Neoadjuvant chemoradiotherapy (CRT) using 5-fluorouracil (5-FU) is a standard treatment for locally advanced rectal cancer (LARC) to improve clinical outcomes. The pathologic responses after neoadjuvant CRT is a major prognostic factor, thus identification of good or poor responder in advance is important. This study is to find candidate predictive biomarkers for CRT and prognosis in LARC patients using quantitative mass spectrometry (MS). Materials and methods: 86 patients with stage II/III LARC, received neoadjuvant CRT consisting of 5-FU/leucovorin followed by surgery were included. 14 proteins potentially associated with 5-FU activity or prognosis were evaluated in archived formalin-fixed, paraffin-embedded pre- and post-CRT tumor tissues using MS: DHFR, DPYD, EGFR, hENT1, Her2, MET, OPRT, p16, TK1, TYMP, TYMS, UCK1, UCK2, UPP1. Tumor regression grade (TRG) after CRT was assessed by Dworak criteria: 0, no regression; 1, dominant tumor mass with obvious fibrosis; 2, dominant fibrotic changes with few tumor cells; 3, very few tumor cells; 4, no tumor cells. Results: TGR was 0 in 2 (2.3%), 1 in 30 (34.9%), 2 in 23 (26.7%), 3 in 20 (23.3%), and 4 in 11(12.8%) patients. Major regression (TRG 2/3/4) was associated with high TK1 (P = 0.040), low TYMS (P = 0.037), p16 (P = 0.055), and UPP1 (P = 0.028) levels. Among the pre-CRT parameters, low CEA level (&amp;lt;5ng/mL, P = 0.013), clinical stage II (P&amp;lt;0.001), tumor differentiation (good, P = 0.052), low EGFR level (&amp;lt;200amol/ug, P=0.006), undetectable TYMS level (P = 0.070) were associated with longer recurrence-free survival (RFS). Among the post-CRT parameters, major pathologic response (P = 0.001), and the absence of lymphatic (P&amp;lt;0.001)/ vascular (P= 0.025)/ perineural invasion (P = 0.001) was associated with longer RFS. For 71 patients with available paired pre- and post-CRT tissues, the changes of protein expression were calculated. The pre-CRT/post-CRT ratio of DHFR (&amp;gt;1.1), Her2 (&amp;lt;1.25), MET (≥0.8), p16 (&amp;lt;2), TK1 (≥0.9) showed trend toward long RFS. Multivariate analysis showed that the presence of lymphatic invasion (HR=3.07; 95% CI, 1.35-7.01; P = 0.008) and pre-CRT high EGFR level (≥200amol/ug; HR=2.23; 95% CI, 1.03-4.83; P = 0.042) were significantly associated with shorter RFS. The presence of lymphatic invasion (P=0.005), positive pre-CRT TYMS level (P = 0.008), and high CEA level (P = 0.015) were significantly related to short survival. Conclusions: Quantitative MS-based proteomics can facilitate the identification of predictive biomarkers of CRT responses and prognosis in LARC patients. Citation Format: Ho Jung An, Ji-Han Jung, Byoung Yong Shim, Hyung Soon Park, Hyeon-Min Cho, Hyung-Jin Kim, Ri Na Yoo, Sung Hwan Kim, Jonghoon Lee, Kang-Moon Lee, Dae Bum Kim, Ji Min Lee. Clinical application of quantitative multiplex mass spectrometry-based proteomics in predicting clinical outcomes in locally advanced rectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4898.

Rac GTPase-Activating Protein 1 (RACGAP1) as an Oncogenic Enhancer in Esophageal Carcinoma

Purpose: Rac GTPase-activating protein 1 (RACGAP1) is associated with cell proliferation, and there is much evidence of its oncogenic role. This study investigated the clinical importance and functional role of RACGAP1 in esophageal carcinoma (EC). Methods: A total of 81 EC patients were enrolled in the study. We assessed the immunohistochemical score of EC tissues and adjacent normal esophageal mucosae, and then performed multiple cell function tests by means of in vitro experiments to elucidate the functional role of RACGAP1 using RNA interference technology in EC cell lines. Results: RACGAP1 was significantly overexpressed in EC tissues compared with the adjacent normal esophageal mucosae (p < 0.0001). Moreover, RACGAP1 overexpression was significantly correlated with poor overall survival (p = 0.032) and disease-free survival (p = 0.012) in EC patients. High RACGAP1 expression was also significantly correlated with the presence of lymphatic invasion (p = 0.012), vessel invasion (p = 0.003), and advanced TNM (tumor-node-metastasis) stage (p = 0.046) in EC patients. In vitro analysis demonstrated that RACGAP1 was involved in the proliferation, tumorigenicity, invasion, migration, and anoikis resistance in EC cells. Conclusions: RACGAP1 plays a pivotal role in EC development, suggesting that it could be used as an indicator of prognosis in EC patients.

Spread through air spaces is an independent predictor of recurrence in stage III (N2) lung adenocarcinoma.

Spread through air space (STAS) is recognized as a pattern of invasion in lung adenocarcinoma and has been reported to be a predictor of recurrence and survival in patients with early-stage lung adenocarcinoma. However, this parameter has not been studied well in stage III (N2) lung adenocarcinoma. In this study, we evaluated the association between STAS invasion patterns and recurrence and survival in stage III (N2) lung adenocarcinoma. We retrospectively reviewed data from 76 patients at University of Tokyo with stage III (N2) lung adenocarcinoma who underwent surgery from August 1998 to December 2013. Statistical analysis was performed to determine the impact of STAS invasion clinicopathological features and clarify the relationship between this pattern of invasion and survival. Tumour STAS was observed in 46 of 76 patients (60.5%) and was significantly associated with the presence of lymphatic invasion (P < 0.001), papillary components (P < 0.001) and micropapillary components (P < 0.001). STAS was also significantly associated with recurrence (5-year recurrence-free probability: 19.0% vs 46.1%, P < 0.05). Univariate analyses showed that STAS was a significant risk factor for recurrence (hazard ratio 1.94, 95% confidence interval 1.07-3.51; P = 0.029). The presence of STAS invasion pattern is a significant risk factor for recurrence in stage III (N2) lung adenocarcinoma.

Survival rate of 10 years among women with breast cancer: a historic cohort from 2000-2014

Breast cancer is a public health problem due to its high incidence, morbidity and mortality. The analysis of survival for this disease contributes to the description of behavior and prognostic factors. The scope of this article is to investigate survival for 10 years after diagnosis and the prognostic factors of women with breast cancer admitted to the Unified Health System Mastology Service in Joinville, State of Santa Catarina, between 2000 and 2014. A historical cohort study with data from the medical records and death certificates of 1,321 women, of whom 471 were considered eligible under the minimum follow-up criteria of 10 years (n = 288), and/or death before this period (n = 183). Survival analysis using the Kaplan-Meier model, the Log-Rank test and the Cox regression model was conducted. Overall survival at 10 years was 41% (CI 95%, 36.1%-45.0%). The risk of 10-year mortality stratified by tumor staging was higher among women with lymphatic invasion and staging II, and staging III, at 60 years or older. The findings suggest that the presence of lymphatic invasion, advanced age and intermediate/advanced staging of the disease can be considered indicators of a worse prognosis for breast cancer.

Central Nervous System Failure in Korean Breast Cancer Patients with HER2-Enriched Subtype: Korean Radiation Oncology Group 16-15 Multicenter Retrospective Study.

PurposeThe purpose of this study was to evaluate the risk of central nervous system (CNS) failure in Korean patients with human epidermal growth factor receptor 2 (HER2)-enriched breast cancer treated with surgery followed by postoperative radiotherapy (RT).MethodsA total of 749 patients from eight institutions were enrolled in this study. All of them underwent surgery followed by postoperative RT from 2003 to 2011; 246 (32.8%) received neoadjuvant chemotherapy and 649 (81.7%) received adjuvant chemotherapy. Adjuvant trastuzumab was administered to 386 patients (48.6%).ResultsThe median follow-up duration was 84 (range, 8–171) months. The 7-year disease-free and overall survival rates were 79.0% and 84.2%, respectively. On multivariate analysis, mastectomy, nodal involvement, and presence of lymphatic invasion were correlated with poor overall survival (p = 0.004, 0.022, and 0.011, respectively), whereas T stage and lymphatic invasion were associated with disease-free survival (p = 0.018 and 0.005, respectively). Regarding CNS failures, 30 brain metastases, 2 leptomeningeal metastases, and 8 brain and leptomeningeal metastases were noted. The 7-year CNS relapse-free survival rates in patients receiving and not receiving trastuzumab were 91.2% and 96.9%, respectively (p = 0.005). On multivariate analysis, the administration of adjuvant trastuzumab was the only prognostic factor in predicting a higher CNS failure rate (hazard ratio, 2.260; 95% confidence interval, 1.076–4.746; p = 0.031).ConclusionAdjuvant trastuzumab was associated with higher CNS failure rate in Korean patients with HER2-enriched breast cancer. Close monitoring and reasonable approaches such as CNS penetrating HER2 blockades combined with the current standard therapy could contribute to improving intracranial tumor control and quality of life in patients with CNS metastasis from HER2-enriched breast cancer.

Phospho-Sphingosine Kinase 1 Expression in Lymphatic Spread of Esophageal Squamous Cell Carcinoma

BackgroundLymphatic spread is the main mode of progression of esophageal squamous cell carcinoma (ESCC). Sphingosine-1-phosphate (S1P) is a pleiotropic bioactive lipid mediator, which produced by sphingosine kinase 1 (SphK1) activated by phosphorylation. The SphK1-S1P axis has a crucial role in lymphangiogenesis. However, the significance of phospho-SphK1 (pSphK1) in the progression of ESCC has not been fully investigated. Materials and methodsWe evaluated pSphK1 expression in 92 surgically resected tumor tissues of ESCC by the immunohistochemistry. Fifty-nine (64%) patients with moderate or strong expression and 33 (36%) with negative or weak expression were classified in the pSphK1-high and pSphK1-low groups, respectively. ResultsHigher pathological N category (pN) was more frequently observed in the pSphK1-high group (P < 0.01). The median number of lymph node metastasis (pSphK1-high: 2 versus pSphK1-low: 0; P < 0.01), the proportion of patients with lymphatic invasion (69% versus 18%; P < 0.01) and that with intramural metastasis (27% versus 3%; P < 0.01) were significantly higher in the pSphK1-high group. The presence of lymphatic invasion (odds ratio [OR] 5.63; P < 0.01) and pN1–3 (OR 3.26; P = 0.04) were independently associated with high pSphK1 expression. The 5-y overall survival rate of the pSphK1-high group was significantly lower than that of the pSphK1-low group (50.8% versus 67.3%; P = 0.01). High pSphK1 expression was not identified as a significant independent prognostic factor. ConclusionsWe provide the first evidence of the association between high expression of pSphK1 and both lymphatic spread and patient outcomes in ESCC.

Expression of phosphorylated sphingosine kinase 1 is associated with diffuse type and lymphatic invasion in human gastric cancer

BackgroundSphingosine-1-phosphate, a pleiotropic bioactive lipid mediator, is an important player in cancer progression. Previous studies suggested that sphingosine-1-phosphate produced by sphingosine kinase 1, which is activated by phosphorylation, plays important roles in the progression of disease and metastasis. The association between phospho-sphingosine-1-phosphate produced by sphingosine kinase 1 and clinical parameters in human gastric cancer have not been fully investigated to date. MethodsWe created phospho-sphingosine-1-phosphate produced by sphingosine kinase expression profiles by immunohistochemistry for 136 patients who underwent operative intervention for gastric cancer in 2007–2009. Phospho-sphingosine-1-phosphate produced by sphingosine kinase expression and compared clinicopathologic factors by univariate and multivariate analyses. ResultsThe univariate analysis revealed that phospho-sphingosine-1-phosphate produced by sphingosine kinase expression was correlated significantly with depth of tumor invasion, lymph node metastasis, distant metastasis, histologic type, and lymphatic invasion. The multivariate analysis revealed that the diffuse type (odds ratio 2.210; 95% confidence interval, 1.045–4.671, P = .038) and the presence of lymphatic invasion (odds ratio 3.697; 95% confidence interval, 1.161–8.483, P = .002) were associated independently with phospho-sphingosine-1-phosphate produced by sphingosine kinase expression in patients with gastric cancer. The 5-year rate of disease-specific survival was 79.3% in patients with phospho-sphingosine-1-phosphate produced by sphingosine kinasephospho-sphingosine-1-phosphate produced by sphingosine kinase-positive expression and 98.3% in those with phospho-sphingosine-1-phosphate produced by sphingosine kinase-negative expression (P = .002). In multivariate analysis, however, high phospho-sphingosine-1-phosphate produced by sphingosine kinase expression was not an independent prognostic factor for disease-specific survival (hazard ratio 5.540; 95% confidence interval, 0.717–42.81, P = .100). ConclusionWe provide the first evidence that diffuse histologic type and lymphatic invasion were independently associated with high phospho-sphingosine-1-phosphate produced by sphingosine kinase expression in gastric cancer patients, indicating a role of sphingosine-1-phosphate in disease progression among patients with gastric cancer. (Surgery 2017;160:XXX-XXX.)

Podoplanin expression in cancer-associated fibroblasts predicts unfavourable prognosis in patients with pathological stage IA lung adenocarcinoma.

Podoplanin expression in cancer-associated fibroblasts (CAFs) has been proposed as an unfavourable indicator in squamous cell carcinoma of the lung, but little is known about its clinical significance in early-stage lung adenocarcinoma. We evaluated the prognostic impact of podoplanin expression in patients with pathological stage (p-stage) IA lung adenocarcinoma as categorised by the 8th edition of the tumour-node-metastasis classification for lung cancer. Immunohistochemical analyses using anti-podoplanin antibody were performed on resected specimens from 158 patients with p-stage IA lung adenocarcinoma. When more than 10% of cancer cells or CAFs showed immunoreactivity with podoplanin, the specimens were classified as podoplanin-positive. Podoplanin-positive status in cancer cells (n = 8) was not correlated with clinicopathological factors or with patient prognosis. Podoplanin-positive status in CAFs (n = 41) was correlated significantly with poorer tumour differentiation (P < 0.001), the presence of lymphatic invasion (P < 0.001) and high-grade (solid and/or micropapillary) components constituting ≥1% of the entire tumour (P < 0.001). The log-rank test showed that podoplanin-positive status in CAFs was associated significantly with shorter disease-free survival (DFS) (P < 0.001) and disease-specific survival (P = 0.015). In Cox's multivariate analysis, podoplanin-positive status in CAFs had the most significant effect on shorter DFS [hazard ratio (HR) = 4.411, P = 0.004], followed by the presence of high-grade components (HR = 3.581, P = 0.013). Podoplanin expression in CAFs could be an independent predictor of increased risk of recurrence in patients with p-stage IA lung adenocarcinoma.

Abstract 5729: Loss of USP10 and p14ARF protein expression is associated with poor prognosis patients with small intestinal adenocarcinoma

Abstract Ubiquitin Specific Peptidase 10 (USP10) is a member of the ubiquitin-specific protease family and its related pathways are apoptosis, autophagy and DNA damage. P14ARF is encoded by an alternative reading frame within the INK4a/ARF locus at chromosome 9p21, which is related with cell cycle arrest and apoptosis. Recently, ablation of USP10 prevented c-myc induced cellular senescence by destabilization of p14ARF and p53, and accelerated hyper-proliferation and transformation of normal cells, suggesting USP10 have a crucial role in oncogenes induced senescence by keeping the stability of p14ARF and p53, key regulator of cellular senescence. However, knowledge on the clinical and prognostic significance of USP10 and p14ARF expression in patients with small intestine adenocarcinoma is limited. In the present study, we investigated the prognostic significance of USP10 and p14ARF by immunohistochemistry. 195 of resected small intestine adenocarcinomas were retrieved from 22 South Korean institutions by Korean Small Intestinal Cancer Study Group. Tissue microarrays were constructed using formalin-fixed paraffin-embedded specimen. 70 (35.9 %) out of 195 patients showed immunoreactivity for USP10 and 124 (63.6 %) showed loss of immunoreactivity for USP10. 120 (61.5 %) of 195 patients were immunopositive for p14ARF and 75 (38.5 %) patients showed loss of immunoreactivity for p14ARF. Loss of USP 10 was correlated with male predominancy (p=0.014), higher pT stage (p=0.044), presence of lymphatic invasion (p=0.033), absences of sporadic adenoma (p=0.024) and absences of peritumoral dyplasia (p=0.019). On multivariate survival analysis, loss of USP10 expression was independent poor prognostic factor ( HR=3.04, 95% CI= 1.79-5.18, p &amp;lt; 0.001) and also both loss of USP10 and p14ARF expressions showed similar result ( HR=3.76, 95% CI= 1.93-7.23, p &amp;lt; 0.001) while loss of p14ARF was not an independent prognostic factor ( p= 0.587). Our findings indicate that loss of USP10, associated with loss of p14ARF protein expression, could be poor prognostic factors in small intestine adenocarcinoma. Citation Format: Joon Seon Song, Hanbyoul Cho, Joon-Yong Chung, Ilseon Hwang, Hee Jin Lee, Seung-Mo Hong, Stephen M. Hewitt. Loss of USP10 and p14ARF protein expression is associated with poor prognosis patients with small intestinal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5729. doi:10.1158/1538-7445.AM2017-5729

Expression of TLR4 in Non-Small Cell Lung Cancer Is Associated with PD-L1 and Poor Prognosis in Patients Receiving Pulmonectomy.

Currently, the effect of inflammation on tumorigenesis and progression has been widely noted. As a member of pattern recognition receptors, toll-like receptor 4 (TLR4) plays a pivotal role in tumor immune microenvironment and has been increasingly investigated. In the present study, we evaluated TLR4 expression and its association with programmed cell death ligand 1 (PD-L1) in non-small cell lung cancer (NSCLC) tissues and assessed the predicting value of TLR4 on postoperative outcome. A total of 126 NSCLC patients receiving complete pulmonary resection and systematic lymph node dissection between April 2008 and August 2014 were enrolled. All the patients had integrated clinicopathological records and follow-up data. TLR4 and PD-L1 expression on NSCLC samples were determined by immunohistochemistry, and serum soluble TLR4 (sTLR4) levels were measured by enzyme-linked immunosorbent assay. Results showed that TLR4 expression level in cancer tissue was significantly higher than that in para-cancer tissue. Elevated TLR4 expression was significantly associated with histological type (adenocarcinoma higher than squamous cell carcinoma, P = 0.041), increased clinical TNM stage (P < 0.001), and presence of lymphatic invasion (P < 0.001). Besides, TLR4 expression level in cancer samples was inversely correlated with serum sTLR4 level in patients with early-stage NSCLC (r = −0.485, P = 0.003). TLR4 expression level was also positively correlated with the PD-L1 expression level (r = 0.545, P < 0.0001). Multivariate analysis showed that expression level of TLR4 was an independent prognostic factor and TLR4 overexpression indicated a poor overall survival and disease-free survival. Taken together, we conclude that expression of TLR4 in lung cancer is associated with PD-L1 and could predict the outcome of patients with NSCLC receiving pulmonary resection for cancer.

Abstract P2-01-12: Development of prediction model for omission of sentinel lymph node biopsy in T1 breast cancer

Abstract INTRODUCTION Axillary sentinel lymph node (SLN) biopsy is a standard method for axillary nodal staging in the treatment of breast cancer. However, along with the trends to SLN performed only without additional axillary lymph node dissection, it's time to be considered omission of SLN for selective patients. We developed a prediction model to assess the negative probability of sentinel lymph node metastasis, specifically focus on the patients with clinical T1 breast cancer. METHODS and MATERIALS The study group consisted of 513 consecutive patients with clinical T1 breast cancer, who had undergone primary surgery between 2007 and 2012. The clinicopathologic factors and imaging modalities including breast ultrasound (US), magnetic resonance imaging (MRI), chest computed tomography (CT), and positron emission tomography (PET) were evaluated. Patients who fulfilled our inclusion criteria were randomized into experimental and validation set by 3:1 ratio. In the experimental group (n = 256), multivariate logistic regression analysis was used to analyze the association of each variable with the likelihood of SLN metastases. A prediction model was developed based on the patients in the experimental group and was validated with internal patient cohorts. RESULTS Of the 513 patients, 119 (23.1%) were found to have SLN metastases. In univariate analysis, presence of lymphovascular invasion (P &amp;lt; 0.001) and suspicious finding of preoperative image studies (US, PET, and MRI, P &amp;lt; 0.001) were independent positive predictors of SLN metastases. In multivariate analysis of experimental group, estrogen receptor status (P = 0.012), presence of lymphatic invasion (P &amp;lt; 0.001), and suspicious finding of preoperative image studies (US, PET, and MRI, P &amp;lt; 0.001) were each associated with involvement of SLN. A prediction model based on this analysis consists of 9 rows including 6 variables (age, estrogen receptor status, presence of lymphatic invasion, and results of preoperative US, PET or CT, MRI). The sum of assigned points for all six variables made corresponding value of negative probability of SLN metastasis. The accuracy of prediction model applied to the validation group, as measured by the area under the receiver operating curve was 0.789. CONCLUSIONS The prediction model developed here may be a useful tool to assess SLN involvement for clinical T1 breast cancer patients. And prospective study for additional validation of the prediction model is currently in preparation, exploring the possibility of SLN biopsy omission. Citation Format: Cho JN, Song EJ, Lee MH, Jung S-Y, Lee S, Kang H-S, Sim SH, Park IH, Lee KS, Kim YJ, Kim S-K, Kwon Y, Nam B-H, Lee ES. Development of prediction model for omission of sentinel lymph node biopsy in T1 breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P2-01-12.

Lymphatic invasion and angiotropism in primary cutaneous melanoma

Access of melanoma cells to the cutaneous vasculature either via lymphatic invasion or angiotropism is a proposed mechanism for metastasis. Lymphatic invasion is believed to be a mechanism by which melanoma cells can disseminate to regional lymph nodes and to distant sites and may be predictive of adverse outcomes. Although it can be detected on hematoxylin- and eosin-stained sections, sensitivity is markedly improved by immunohistochemistry for lymphatic endothelial cells. Multiple studies have reported a significant association between the presence of lymphatic invasion and sentinel lymph node metastasis and survival. More recently, extravascular migratory metastasis has been suggested as another means by which melanoma cells can spread. Angiotropism, the histopathologic correlate of extravascular migratory metastasis, has also been associated with melanoma metastasis and disease recurrence. Although lymphatic invasion and angiotropism are not currently part of routine melanoma reporting, the detection of these attributes using ancillary immunohistochemical stains may be useful in therapeutic planning for patients with melanoma.

Association of RAB5 overexpression in pancreatic cancer with cancer progression and poor prognosis via E-cadherin suppression.

Pancreatic cancer is a common type of cancer with poor prognosis worldwide. Postoperative survival depends on the existence of metastasis. Elucidation of the mechanism underlying cancer progression is important to improve prognosis. The RAS-associated protein RAB5 activates intracellular membrane trafficking, and RAB5 expression is correlated to progression and epithelial mesenchymal transition in various cancers.The expression of RAB5 and E-cadherin in 111 pancreatic cancer samples was investigated by immunohistochemical staining, and the relationship among RAB5 expression, clinicopathological factors, and E-cadherin expression was assessed. Furthermore, RAB5 suppression analysis by siRNA was performed to determine the roles of RAB5 in morphological change, proliferation potency, cell migration ability, and invasiveness of the pancreatic cancer cell line.High RAB5 expression correlated with the presence of lymphatic invasion and venous invasion and low E-cadherin expression. Patients with high RAB5 expression had a poorer prognosis than those with low RAB5 expression. RAB5 suppression in pancreatic cancer cells enhanced E-cadherin expression; changed cell morphology from spindle to round; and inhibited proliferation, invasion, and cell migration.RAB5 contributes to poor prognosis and progression in pancreatic cancer patients. It may be a promising candidate for individualized therapy in refractory pancreatic cancer.

The C-Reactive Protein to Albumin Ratio as a Predictor of Severe Side Effects of Adjuvant Chemotherapy in Stage III Colorectal Cancer Patients.

Background/AimsAdjuvant chemotherapy (AC) has been reported to improve the prognosis for patients with Stage III colorectal cancer (CRC). However, some patients experience severe side effects and must stop AC. The C-reactive protein (CRP) to albumin ratio (CAR) is a novel inflammation-based score that could reflect the patient’s general condition. The aim of this study was to evaluate the predictive value of the CAR for side effects of AC in CRC.MethodsA total of 136 CRC patients who received AC were retrospectively analyzed. The patients were subdivided into two groups by the CAR level (CAR ≥0.1, n = 30; CD < 0.1, n = 106).ResultsThe presence of lymphatic invasion, severe side effects, and discontinuation of AC were associated with high CAR levels (p = 0.02, <0.01, and 0.02; respectively). High levels of the Glasgow Prognostic Score (GPS) and the neutrophil to lymphocyte ratio (NLR) appeared to be associated with the CAR (p = 0.04, p<0.01; respectively). Multivariate analysis identified CAR≥0.1 (HR: 7.06, 95% CI: 2.51–19.88, p<0.01) as a significant determinant of severe side effects of AC. CAR had the highest area under the curve (0.79) among several inflammation-based scores.ConclusionThe present study showed that the CAR is a novel and promising inflammation-based score for ≥ grade 3 side effects of AC in node-positive CRC.

High PARP-1 expression is associated with tumor invasion and poor prognosis in gastric cancer.

Poly (adenosine diphosphate-ribose) polymerase 1 (PARP-1) was previously demonstrated to be overexpressed in numerous malignant tumors and associated with invasiveness and poor prognosis. However, the expression of the PARP-1 protein in gastric cancer and its association with clinical outcomes requires further investigation. In the present study, the expression of PARP-1 in 564 gastric cancer tissues and 335 tumor-adjacent control tissues is investigated, using tissue microarray-based immunohistochemistry. PARP-1 expression levels were demonstrated to be significantly higher in gastric cancer tissue samples, as compared with control tissue samples. In gastric cancer, high PARP-1 expression levels were significantly associated with Helicobacter pylori (H. pylori) infection (P=0.032), decreased differentiation (P<0.001), increased depth of invasion (P=0.037), presence of lymphatic invasion (P<0.001), presence of lymph node metastasis (P<0.001), and advanced tumor-node-metastasis (TNM) stage (P=0.015). High PARP-1 expression levels were associated with a significantly shorter overall survival rate (P<0.001) and disease-free survival rate (P=0.001) in patients with gastric cancer, particularly a subset of patients with H. pylori infection or an advanced TNM stage. In addition, univariate analysis indicated that PARP-1 high expression levels were significantly associated with a poor prognosis in gastric cancer. These results suggest that PARP-1 expression may be involved in the progression and prognosis of gastric cancer, particularly H. pylori-positive or advanced-stage gastric cancer.

Correlation Between Cyclo-oxygenase-2 and Vascular Endothelial Growth Factor Expression in Canine and Feline Squamous Cell Carcinomas

Overexpression of cyclo-oxygenase (COX)-2 is involved in tumour growth and spread by modulating the production of angiogenic factors such as vascular endothelial growth factor (VEGF). Expression of COX-2 and VEGF was investigated immunohistochemically in 51 canine and feline cutaneous and non-cutaneous squamous cell carcinomas (SCCs) and the correlation between expression of these molecules and clinicopathological variables was evaluated. COX-2 and VEGF expression was not observed in normal skin keratinocytes. COX-2 overexpression occurred in 53% and 61% of the canine and feline SCCs, respectively. The expression of both markers was higher in cutaneous compared with non-cutaneous SCCs. In both species COX-2 and VEGF expression was correlated with the progression of the disease, but not with the presence of lymphatic invasion, tumour grading or tumour classification in the cutaneous tumours. Further study will be required to understand the role of the COX-2 pathway in angiogenesis in SCC.

Prognostic significance of classified extramural tumor deposits and extracapsular lymph node invasion in T3-4 colorectal cancer: a retrospective single-center study.

BackgroundExtramural tumor deposits (TDs) and extracapsular lymph node involvement (ECLNI) are considered to be poor prognostic factors in patients with T3–4, N0–2, M0 colorectal cancer (CRC). Although TDs are known to have multiple origins and pleomorphic features, the prognostic significances of the different type of TDs have not yet been established.MethodsWe performed a retrospective review of 385 consecutive patients with T3–4, N0–2, M0 CRC who received curative resection at our institution between 2006 and 2012. We classified the TDs into two groups: invasive-type TD (iTD), which is characterized by the presence of lymphatic invasion, vascular invasion, perineural invasion, or undefined cancer cell clusters and nodular-type TD (nTD), which is characterized by a smooth or irregular-shaped tumor nodule other than an iTD. ECLNI was defined as invasion of cancer cells into capsular collagen tissues or adipose tissues beyond the capsular collagen. Multivariate analyses were used to assess the prognostic significance of iTD, ND, and ECLNI for relapse-free survival (RFS), disease-specific survival (DSS), and sites of recurrence.ResultsIn patients without lymph node (LN) metastasis, the incidences of iTD and nTD were both in the range of 2–3 %. Conversely, in patients with LN metastasis, the incidences of iTD, nTD, and ECLNI were 31, 22, and 34 %, respectively. iTD, nTD, and ECLNI were all significant independent adverse factors for RFS in rectal cancer, and were all associated with pT, pN, and LN ratio. iTD was a significant independent adverse prognostic factor for DSS in rectal cancer, metastasis to the liver in colorectal cancer, and distant LN metastasis in colon cancer. ECLNI was a significant independent prognostic factor for RFS in colon cancer.ConclusionsClassifying TDs and assessing ECLNI may help establish significant prognostic factors for patients with T3–4, N0–2, M0 CRC.

Abstract 3131: Prognostic significance of miR-34a and its inverse correlation with c-MET and CDK6 in lung adenocarcinoma

Abstract Background: The microRNA(miR)s affect all aspects of cellular physiology including proliferation, apoptosis, development, aging, and metabolism. miR-34a has tumor suppressive role in various human cancers including non-small cell lung cancer (NSCLC). Recently, various targets of miR-34a including c-MET and G1-phase regulators have been reported in NSCLC cell lines. The aim of this study is to determine whether miR-34a is correlated with c-MET and G1 phase regulators such as cyclin dependent kinase (CDK) 4, CDK6 and cyclin D (CCND)1 in human NSCLC and assess the correlation between miR-34a and clinicopathologic characteristics and recurrence free survival (RFS). Material and Methods: In fresh frozen, paired tumor/normal adjacent tissue samples from 58 NSCLC patients underwent curative resection, expressions of miR-34a and c-MET, CDK4/6, and CCND1 were investigated by quantitative real-time polymerase chain reaction (qRT-PCR) and western blot analysis. Results: There was inverse correlation between miR-34a and c-MET (R = -0.316; P = 0.003) and CDK6 (R = -0.4582; P = 0.004), however, neither CDK4 (P = 0.556) nor CCND1 (P = 0.143). Of 14 patients with low miR-34a, the patients showing high expression of c-MET protein were 12 (85.7%), whereas, in 5 patients with high miR-34a, high expression of c-MET protein was observed in 3 (60.0%). The expression level of miR-34a was significantly lower in the patients with squamous cell histology (P &amp;lt; 0.001) and lymphatic invasion (P = 0.001). The patients expressing high level of miR-34a were significantly associated with a longer RFS (55.6 months; 95% CI, 47.83-63.36 vs 21.6 months; 95% CI, 17.42-25.82, P = 0.020, respectively) for adenocarcinoma subtype. We could not detect any correlation between the c-MET and RFS (P = 0.666), however, adenocarcinoma patients exhibiting low c-MET mRNA and high miR-34a expression had a significantly longer RFS (54.4 months; 95% CI, 44.59-64.20 vs 18.7 months; 95% CI, 8.93-28.42, P = 0.042). Likewise, although CDK6 expression was not associated with RFS (P = 0.601), the adenocarcinomas having low CDK6 mRNA and high miR-34a expression tended to be longer RFS (55.1 months; 95% CI, 46.40-67.73 vs 27.8 months; 95% CI, 23.04-32.56, P = 0.059). In univariate Cox regression analysis, the relative risk (RR) for recurrence for adenocarcinoma patients with low miR-34a expression was 8.1 (95% CI, 1.01-65.58; P = 0.049) as well as with TNM stage, LN involvement, and the presence of lymphatic invasion of 13.6 (95% CI, 2.93-62.64; P = 0.001), 4.2 (95% CI, 1.05-16.76; P = 0.043) and 7.1 (95% CI, 1.46-34.00; P = 0.015), respectively. In multivariate analysis, miR-34a retained its prognostic independency for RFS (RR, 11.5; 95% CI, 1.31-100.68; P = 0.027). Conclusions: We demonstrated the inverse correlation between miR-34a and c-MET and CDK6 in human NSCLC and their prognostic significance for RFS especially in lung adenocarcinoma. Citation Format: Ji Hyung Hong, Kang San Roh, Sung-Suk Suh, Suk Chan Lee, Jae Ho Byun, Myung ah Lee, Jin Hyoung Kang. Prognostic significance of miR-34a and its inverse correlation with c-MET and CDK6 in lung adenocarcinoma. [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 3131. doi:10.1158/1538-7445.AM2015-3131