Worse Tumor Grade Research Articles

Development and external validation of a nomogram for predicting the effect of tumor size on survival of patients with perihilar cholangiocarcinoma

BackgroundThe effect of tumor size on account of long-term survival results in perihilar cholangiocarcinoma (PCCA) patients has remained a controversial debate. It is urgent necessary to identify the optimal cutoff value of tumor size in PCCA and integrate tumor size with other prognostic factors into a nomogram to improve the predictive accuracy of prognosis of patients with PCCA.MethodsThree hundred sixty-three PCCA patients underwent surgical resection were extracted from the Surveillance, Epidemiology and End Results (SEER) database. X-tile program was used to identify the optimal cutoff value of tumor size. A nomogram including tumor size was established to predict 1-, 3- and 5-year cancer-specific survival (CSS) based on the independent risk factors chosen by Kaplan-Meier methods and multivariable cox regression models. The precision of the nomogram for predicting survival was validated internally and externally.ResultsPCCA patients underwent surgical resection were classified into 1–19 mm, 20–33 mm and ≥ 34 mm subgroups based on the optimal cutoff for tumor size in terms of CSS. And we noticed that more larger tumor size group had worse tumor grade, advanced T stage, more positive regional lymph nodes and more frequent vascular invasion. The nomogram according to the independent factors was well calibrated and displayed better discrimination power than 7th Tumor-Node-Metastasis (TNM) stage systems.ConclusionsThe results demonstrated that the larger tumor size of PCCA was, the worse survival would be. The proposed nomogram, which outperforms the conventional TNM staging system, showed relatively good performance and could be considered as convenient individualized predictive tool for prognosis of PCCA patients.

MiRNA-520c-3p accelerates progression of nasopharyngeal carcinoma via targeting RAB22A.

[This retracts the article DOI: 10.3892/ol.2019.11144.].

Creatine Mediated Crosstalk between Adipocytes and Cancer Cells Regulates Obesity-Driven Breast Cancer

Obesity is a major risk factor for adverse outcomes in breast cancer; however, the underlying molecular mechanisms have not been elucidated. To investigate the role of crosstalk between mammary adipocytes and neoplastic cells in the tumor microenvironment, we performed transcriptomic analysis of cancer cells and adjacent adipose tissue in a murine model of obesity-accelerated breast cancer and identified glycine amidinotransferase (Gatm) in adipocytes and Acsbg1 in cancer cells as required for obesity-driven tumor progression. Gatm is the rate-limiting enzyme in creatine biosynthesis, and deletion in adipocytes specifically attenuated obesity-driven tumor growth. Similarly, inhibition of creatine import into cancer cells by knockdown of the creatine transporter (Slc6a8) reduced tumor growth in obesity. In parallel, breast cancer cells in obese animals markedly upregulated the fatty acyl-CoA synthetase, Acsbg1, driving creatine-dependent tumor progression. Analyses of human breast tumors revealed that increased Slc6a8 and Acsbg1 expression were significantly associated with worse tumor grade and that increased Slc6a8 expression was associated with reduced survival in triple negative breast cancer.These findings reveal key nodes in the crosstalk between adipocytes and cancer cells in the tumor microenvironment necessary for obesity-dependent breast cancer progression.

MiRNA-520c-3p accelerates progression of nasopharyngeal carcinoma via targeting RAB22A.

Biological function of microRNA-20c-3p (miRNA-520c-3p) in the progression of nasopharyngeal carcinoma (NPC) and the potential mechanism were investigated. Relative level of miRNA-520c-3p in NPC tissues and adjacent normal tissues was determined by quantitative real-time polymerase chain reaction (qRT-PCR). Particularly, miRNA-520c-3p level in NPC with different tumor stages and tumor sizes was examined. Subsequently, miRNA-520c-3p level in nasopharyngeal epithelial cells and NPC cells was detected. The potential influence of miRNA-520c-3p on the proliferative ability and cell cycle progression of NPC cells were evaluated through cell counting kit-8 (CCK-8) and flow cytometry. The target gene of miRNA-520c-3p was verified by dual-luciferase reporter gene assay. Regulatory role of miRNA-520c-3p/RAB22A in the malignant progression of NPC was identified. miRNA-520c-3p was downregulated in NPC tissues and cell lines. Its level was lower in NPC with worse tumor grade and larger tumor size. Overexpression of miRNA-520c-3p suppressed the proliferative ability and arrested cell cycle in G0/G1 phase. RAB22A was confirmed to be the downstream target of miRNA-520c-3p. In NPC tissues and cell lines, RAB22A remained in higher abundance relative to controls. Overexpression of RAB22A reversed the inhibitory effects of overexpressed miRNA-520c-3p on proliferative ability and cell cycle progression of NPC cells. miRNA-520c-3p is downregulated in NPC, which accelerates the malignant progression of NPC by targeting RAB22A.

Gadoxetic acid-enhanced MRI as a predictor of recurrence of HCC after liver transplantation.

To investigate the value of preoperative gadoxetic acid-enhanced MRI for tumor staging and recurrence prediction of hepatocellular carcinoma (HCC) after primary liver transplantation (LT). This multicenter retrospective study included 122 recipients who underwent living donor LT (LDLT) for untreated HCC and pre-transplant gadoxetic acid-enhanced MRI from January 2009 to December 2013. Disease-free survival (DFS) was evaluated. Milan criteria, tumor grade, and microvascular invasion (MVI) were analyzed on the pathological examination of the explanted liver. The 1-, 3-, 5-, and 7-year DFS rates were 93.3%, 90.7%, 88.9%, and 86.1%, respectively. In the multivariable analysis, independent predictors of HCC recurrence were "beyond the Milan criteria" (hazard ratio [HR], 3.54; 95% confidence interval [CI], 1.13-11.12; p = 0.030) and peritumoral hypointensity on hepatobiliary phase (HBP) (HR, 18.30; 95% CI, 4.33-77.34; p < 0.001). Pre-transplant MRI yielded a 90.2% accuracy to categorize the Milan criteria when compared with the explanted liver. Peritumoral hypointensity on HBP was significantly associated with a worse tumor grade (p = 0.010) and MVI (p < 0.001). The 5-year DFS rate in patients with "beyond the Milan criteria" but the absence of peritumoral hypointensity on HBP was not different from that in patients "within the Milan criteria" (92.2% vs. 92.9%, p = 0.438). Pre-transplant gadoxetic acid-enhanced MRI may assist in the HCC recurrence risk prediction. • Lesions beyond the Milan criteria and peritumoral hypointensity on hepatobiliary phase (HBP) were independent predictors of HCC recurrence. • Peritumoral hypointensity on HBP significantly associated with a worse tumor grade and microvascular invasion.

MicroRNA-449b-5p Suppresses Proliferation, Migration, and Invasion of Osteosarcoma by Targeting c-Met.

BackgroundThe aim of this study was to clarify the biological function of microRNA-449b-5p in the progression of osteosarcoma (OS) and to define the underlying mechanism.Material/MethodsRelative levels of microRNA-449b-5p in OS tissues and cell lines was determined by quantitative real-time polymerase chain reaction (qRT-PCR). The correlation between microRNA-449b-5p level and pathological characteristics of OS patients was analyzed by chi-square test. Kaplan-Meier analysis was used for survival analysis of OS patients based on their expression level of microRNA-449b-5p. Regulatory effects of microRNA-449b-5p on cellular behaviors of OS cells were evaluated by cell counting kit-8 (CCK-8) and Transwell assay. The binding relationship between microRNA-449b-5p and c-Met was verified through dual-luciferase reporter gene assay, and their interaction in OS progression was further examined through a series of rescue experiments.ResultsMicroRNA-449b-5p was expressed at low levels in OS. Lower levels of microRNA-449b-5p were seen in OS tissues with worse tumor grade or histological differentiation. OS patients with low levels of microRNA-449b-5p had worse overall survival relative to those with high level of microRNA-449b-5p. Overexpression of microRNA-449b-5p markedly attenuated proliferative, migratory, and invasive abilities of OS cells. C-Met is the downstream target of microRNA-449b-5p, and its level was inhibited in OS cells overexpressing microRNA-449b-5p. Importantly, c-Met partially rescued the inhibitory effects of microRNA-449b-5p on behavior of OS cells.ConclusionsMicroRNA-449b-5p is downregulated in OS, which alleviates the malignant progression of OS by targeting c-Met.

Management and outcomes among patients with sarcomatoid hepatocellular carcinoma: A population‐based analysis

Few data are available regarding the management and outcomes among patients with sarcomatoid hepatocellular carcinoma (HCC) due to its rarity. Patients diagnosed with sarcomatoid HCC from 2004 through 2015 were identified in the National Cancer Data Base. Overall survival (OS) was calculated among patients with sarcomatoid versus conventional HCC using a 1:3 propensity score matching based on sex, age, and American Joint Committee on Cancer (AJCC) stage of disease. The final analytic cohort included 104 patients with sarcomatoid HCC and 312 patients with conventional HCC. Patients with sarcomatoid HCC more often had a larger median tumor size (8.5cm vs 5.4cm; P<.001) and poorly or undifferentiated tumors (52.9% vs 13.8%; P<.001) compared with patients who hadconventional HCC. 5-year OS was worse among patients with sarcomatoid versus conventional HCC (5.7% vs 30.1%; P<.001). Subgroup analysis demonstrated worse 5-year OS among patients with sarcomatoid versus conventional HCC among patientstreated with eithercurative-intent or palliative therapies. Stage-specific subgroup analysis indicated a worse OS amongpatients with AJCC stage I, stage II, or stage III sarcomatoid HCC. On multivariable analysis, uninsured status, advanced AJCC stage (stage III/stage IV), and histological sarcomatoid subtype were independentlyassociated with worse outcomes (all P<.05). Sarcomatoid HCC is a very rare variant of HCC, which wasassociated with larger tumor size and worse tumor grade on presentation. On propensity score matched analyses that controlled for known confounding factors, patients with sarcomatoid HCC hada worse stage-for-stage long-term survival compared with patients who had conventional HCC.

The Impact of Tumor Location on Resection and Survival for Pancreatic Ductal Adenocarcinoma

BackgroundDifferences in clinical staging and survival among pancreatic head, body, and tail cancers are not well defined. We aim to identify the prognostic relevance of primary tumor location in patients undergoing treatment for pancreatic ductal adenocarcinoma (PDAC). Materials and methodsThe National Cancer Database was used to identify patients with PDAC from 1998 to 2011 (n = 175,556). Patients were categorized by primary tumor site into head (67.5%, n = 118,343), body (15.5%, n = 27,218), and tail (17.0%, n = 29,885) groups. Univariate and Cox regression analyses were used to determine covariates associated with overall survival (OS). ResultsPatients with head PDAC presented with earlier stage disease (39.2% Stage I/II versus 19.7% versus 16.0%, P < 0.001) and underwent resection more often (27.9% versus 10.7% versus 17.0%, P < 0.001) than those with body or tail tumors. Of surgically resected PDAC, those localized to the head had advanced pathologic stage (84.8% stage II/III versus 66.6% versus 65.6%, P < 0.001), higher nodal positivity (64.9% versus 45.8% versus 45%, P < 0.001), and worse tumor grade (35.9% poorly differentiated versus 29.5% versus 27.8%, P < 0.001). Despite increased utilization of adjuvant therapies (54.4% versus 45.6% versus 42.0%, P < 0.001), patients with head PDAC had inferior OS compared with those with body and tail tumors (P < 0.001). ConclusionsWhen examining patients with PDAC undergoing resection, tumor localization to the head is associated with improved resectability because they present earlier. Of resected PDACs, however, those localized to the head have worse OS compared with body and tail tumors. This discrepancy may represent a combination of lead time and selection biases and biologic differences between tumor sites.

A multi-institutional analysis on neuroendocrine liver metastasis from pancreatic neuroendocrine tumors

Objective: Neuroendocrine tumors typically arise from pancreatic (PNET) vs. gastrointestinal or thoracic origins (non-PNET). The impact of primary tumor site on long-term prognosis following resection of neuroendocrine liver metastasis (NELM) remains poorly defined. The objective of the study was to define the association of primary tumor location on prognosis of patients undergoing hepatic resection for NELM. Methods: Between 1990 and -2014, 421patients who underwent resection of NELM were identified from a multi-institutional database. Clinicopathological characteristics, operative details, and outcomes were stratified by location of the primary tumor (PNETvs non-PNET). A propensity score matched analysis was utilized to assess the impact of primary tumor location on long-term survival. Results: Overall, 197(46.8%) patients had NELM from a PNET primary while 224 (53.2% had a non-PNET primary (small bowel, n=145; rectal, n=10; bronchial, n=22; other, n=47). The extent of liver involvement was comparable among PNET vs. non-PNET patients (>50%: 70.6% vs. 76.3%, respectively; P=0.19). Patients with PNET and NELM were, however, more likely to have extrahepatic disease (5.6%) compared with non-PNET patients (12.9%) (P=0.01). At the time of surgery, most patients underwent a minor resection (<3 segments) (PNET, 63.8% vs. non-PNET, 60.3%; P=0.46). On final pathology, patients with a primary PNET were more likely to have NELM characterized as moderate- or poorly-differentiated (P=0.005). Post-operatively, patients with a history of primary PNET were less likely to receive somatostatin-analog/targeted adjuvant therapy than non-PNET patients (15.2% vs. 29.9%, respectively; P<0.001). Patients with PNET+NELM had a worse disease-free (DFS) and overall survival (OS) compared with patients who had non-PNET+NELM (DFS: PNET, 36.2% vs. non-PNET55.2%; OS: PNET, 69.5% vs. non-PNET 83.4%; both P<0.01). However, after propensity score matching, while the presence of extrahepatic disease and tumor grade were associated with DFS (extrahepatic disease: HR 2.12; 95% CI, 1.19–3.75; P=0.010; tumor grade: HR 1.91; 95% CI, 1.43–2.55; p<0.001)and OS (extrahepatic disease: HR 3.09; 95% CI, 1.65–5.79; P<0.001; tumor grade: HR 1.76; 95% CI, 1.25–2.48; P=0.001), primary tumor location was not associate with long-term outcomes (DFS: HR 0.92, 95% CI, 0.60–1.42; OS: HR 0.93. 95% CI, 0.58–1.49; both P>0.05). Conclusion: PNET patients present with NELM with extra-hepatic disease and worse tumor grade. On propensity matched analysis factors such as extra-hepatic disease and tumor grade, but not primary tumor location, were associated with prognosis.

Caveolin-1 is Associated with Tumor Progression and Confers a Multi-Modality Resistance Phenotype in Pancreatic Cancer.

Caveolin-1 (Cav-1) is a 21 kDa protein enriched in caveolae, and has been implicated in oncogenic cell transformation, tumorigenesis, and metastasis. We explored roles for Cav-1 in pancreatic cancer (PC) prognostication, tumor progression, resistance to therapy, and whether targeted downregulation could lead to therapeutic sensitization. Cav-1 expression was assessed in cell lines, mouse models, and patient samples, and knocked down in order to compare changes in proliferation, invasion, migration, response to chemotherapy and radiation, and tumor growth. We found Cav-1 is overexpressed in human PC cell lines, mouse models, and human pancreatic tumors, and is associated with worse tumor grade and clinical outcomes. In PC cell lines, disruption/depletion of caveolae/Cav-1 reduces proliferation, colony formation, and invasion. Radiation and chemotherapy up-regulate Cav-1 expression, while Cav-1 depletion induces both chemosensitization and radiosensitization through altered apoptotic and DNA repair signaling. In vivo, Cav-1 depletion significantly attenuates tumor initiation and growth. Finally, Cav-1 depletion leads to altered JAK/STAT, JNK, and Src signaling in PC cells. Together, higher Cav-1 expression is correlated with worse outcomes, is essential for tumor growth and invasion (both in vitro and in vivo), is responsible for promoting resistance to therapies, and may serve as a prognostic/predictive biomarker and target in PC.

Correlation between chemosensitivity to anticancer drugs and telomerase reverse transcriptase mRNA expression in gastric cancer

BackgroundThe determination of sensitive chemotherapy drugs for gastric cancer (GC) is one of the greatest challenges of adjuvant therapy. Here we evaluated the chemosensitivity of GC to anticancer drugs and the telomerase reverse transcriptase (hTERT) mRNA expression, and investigated the relationship of them.MethodsThe GC cells which were collected from 68 patients with primary GC were primary cultured. The chemosensitivity of GC cells to anticancer drugs was evaluated successfully using the MTT assay for 60 cases of GC cells, and the hTERT mRNA expression was examined in 60 cases of GC tissues and corresponding normal gastric mucosa and 6 cases of chronic superficial gastritis mucosa by in situ hybridization.ResultsTaxol, Cisplatin and 5-Fluorouracil were in general more effective than Adriamycin and Mitomycin for GC cells, and the chemosensitivity to anticancer drugs was associated with tumor histological types and a worse tumor grade. Compared to normal gastric mucosa tissues, hTERT mRNA expression was significantly increased in GC (P<0.05), which was related with a worse differentiation and drug-resistance to 5-Fluorouracil or Adriamycin in GC.ConclusionsThese data demonstrate for the first time that examinations of hTERT mRNA expression as an important factor could be used to select the chemotherapeutic drugs for GC patients.Virtual slidesThe virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1793217009875483

Evaluation of the prognostic and predictive value of p53 and Bcl-2 in breast cancer patients participating in a randomized study with dose-dense sequential adjuvant chemotherapy

To assess the prognostic and predictive significance of p53 and Bcl-2 protein expression in high risk patients with breast cancer treated with dose-dense sequential chemotherapy. From June 1997 until November 2000, 595 patients were randomized to three cycles of epirubicin (E) 110 mg/m2 followed by three cycles of paclitaxel (P) 250 mg/m2 followed by three cycles of 'intensified' CMF (cyclophosphamide 840 mg/m2, methotrexate 47 mg/m2 and fluorouracil 840 mg/m2) or to four cycles of E, followed by four cycles of CMF. p53 and Bcl-2 expression was investigated by immunohistochemistry in 392 and 397 patients respectively. Positive expression of p53 was detected in 104 (26.5%) patients and was significantly associated with negative hormonal status, worse histologic grade, higher incidence of disease relapse and higher rate of death. p53 positive expression was a significant negative predictor of overall survival (OS) (P = 0.002) and disease-free survival (DFS) (P = 0.001). Negative expression of Bcl-2 was detected in 203 (51%) patients and was significantly associated with negative hormonal status. Multivariate analysis revealed that, positive p53 expression, higher number of positive nodes and worse tumor grade were related to significantly poorer OS and DFS. For both treatments, p53 positive expression was a significant negative prognostic factor for OS and DFS while Bcl-2 was not. No predictive ability of p53 status or Bcl-2 status for paclitaxel treatment was evident.

MCM7 amplification and overexpression are associated with prostate cancer progression

The genomic DNA profiles of prostate cancers with aggressive features were compared to the profiles of matched normal DNA to identify genes that are selectively amplified in the cancer cells. One of the identified genes, MCM7, which is a component of the DNA replication licensing complex, has been studied extensively both at the DNA and protein levels in human prostate tissues. Approximately half of the prostate cancer specimens studied showed MCM7 gene amplification, and 60% of the aggressive prostate cancer specimens had increased MCM7 protein expression. Amplification or overexpression of MCM7 was significantly associated with relapse, local invasion and a worse tumor grade. Constitutive expression of MCM7 in a human prostate cancer cell line, DU145, resulted in markedly increased DNA synthesis and cell proliferation compared to vector-only controls, and an increased cell invasion in vitro. Indeed, MCM7 overexpression produced primary tumors 12 times larger than vector-only controls and resulted in a rapid demise of mice bearing those tumors. These studies implicate MCM7, and the DNA replication licensing gene family, in prostate cancer progression, growth and invasion.

Treatment decision‐making strategies and influences in patients with localized prostate carcinoma

Patients diagnosed with localized prostate carcinoma need to interpret complicated medical information to make an informed treatment selection from among treatments that have comparable efficacy but differing side effects. The authors reported initial results for treatment decision-making strategies among men receiving definitive treatment for localized prostate carcinoma. One hundred nineteen men treated with radical prostatectomy (44%) or brachytherapy (56%) consented to participate. Guided by a cognitive-affective theoretic framework, the authors assessed differences in decision-making strategies, and treatment and disease-relevant beliefs and affects, in addition to demographic and clinical variables. Approximately half of patients reported difficulty (49%) and distress (45%) while making treatment decisions, but no regrets (74%) regarding the treatment choice they made. Patients who underwent prostatectomy were younger, were more likely to be employed, had worse tumor grade, and had a shorter time since diagnosis (P < 0.01) compared with patients who did not undergo prostatectomy. In multivariate analyses, compared with patients who received radical prostatectomy, patients who received brachytherapy were more likely to say that they chose this treatment because it was "the least invasive" and they "wanted to avoid surgery" (P < 0.0001). In general, patients who received brachytherapy chose this treatment because of quality of life considerations, whereas "cure" and complete removal of the tumor were the main motivations for patients selecting radical prostatectomy. Long-term data are needed to evaluate distress and decisional regret as patients experience treatment-related chronic side effects and efficacy outcomes. Decision-making aids or other interventions to reduce decisional difficulty and emotional distress during decision making were indicated.

A 10-Year Outcomes Evaluation of Mucinous and Signet-Ring Cell Carcinoma of the Colon and Rectum

Most studies examining mucinous or signet-ring cell colorectal cancers are single institution reports. This study used a national cancer registry to analyze the epidemiology and survival outcomes of these two subtypes of colorectal cancer compared with adenocarcinoma tumors. All patients diagnosed with mucinous (n = 16,991), signet-ring cell (n = 1,522), or adenocarcinoma (n = 146,115) colorectal cancer in the Surveillance, Epidemiology, and End Results database (1991-2000) were evaluated. Analyses were performed to obtain age-adjusted incidence rates, stage at presentation, tumor grade, and five-year relative survival for each subtype. Mucinous were slightly more common in females (53.4 percent). Incidence rates per 100,000 persons were: mucinous, 5.5; signet-ring cell, 0.6; and adenocarcinoma 46.6. The annual percent change during ten years was stable for mucinous, increased for signet-ring cell (4.8 percent; P < 0.05), and decreased for adenocarcinoma (-1.1 percent; P < 0.05). Fewer mucinous (18 percent) and signet-ring cell (21 percent) tumors were located in the rectum compared with adenocarcinoma (29 percent). Signet-ring cell presented at later stage (III/IV, 80.9 percent) more often than mucinous (52.8 percent) and adenocarcinoma (49.5 percent), and also had worse tumor grade (high grade: signet-ring cell, 73.5 percent; mucinous, 20.9 percent; adenocarcinoma, 17.5 percent). Relative five-year survival was worse for signet-ring cell than mucinous or adenocarcinoma. We present a large population-based review of colorectal cancer subtypes by analyzing national data from the past decade. Although the incidence of colorectal adenocarcinoma is decreasing in the United States, mucinous and signet-ring cell subtypes are stable and increasing, respectively. Importantly, it seems that the signet-ring cell subtype has worse outcomes, whereas survival rates for mucinous tumors are similar to adenocarcinomas.

S-phase fraction and breast cancer - a decade of experience

During the past decade, more than 300 articles, abstracts, and book chapters have been published about S-phase fraction (SPF) determined by DNA flow cytometry and its clinical utility for patients with breast cancer. However, the use of SPF for making treatment decisions for breast cancer patients remains controversial. After reviewing 273 published articles, we conclude: 1) Despite different techniques and cutpoints, correlations between SPF and other prognostic markers are relatively consistent across studies; higher SPF is generally associated with worse tumor grade, absence of steroid receptors, larger tumors, and positive axillary lymph nodes. 2) Higher SPF is generally associated with worse disease-free and overall survival in both univariate and multivariate analyses; SPF values from laboratories that have conducted validation studies can be used, in combination with other factors, to estimate the prognosis of patients with primary breast cancer. 3) There is considerable variability among laboratories regarding assay methodology, cell-cycle analysis techniques, and cutpoints for classifying and interpreting SPF; use of SPF values from different laboratories is problematic, and there remains a need for standardization of these processes and well-designed confirmation studies. We conclude that measurement of SPF does have clinical utility for patients with breast cancer, but standardization and quality control must be improved before it can be routinely used in community settings.