The Role of PROX1 in Neoplasia: A Key Player Often Overlooked.

The human PROX1 gene (Prospero homeobox gene 1) is a member of the homeobox transcription factor family. PROX1 plays a key role in the development of the lymphatic system and is primarily used as a lymphatic vessel marker. However, as the accumulating evidence indicates that PROX1 is also implicated in the tumorigenesis of various cancer types, the scientific community has attempted to elucidate its complicated function in neoplasia pathogenesis, as well as its utility in cancer diagnosis, prognosis, and therapy. PROX1 has been shown to participate in the complex molecular mechanisms affecting tumorigenesis and has been associated with a plethora of clinicopathological parameters, including tumor stage and patients' overall survival. Depending on the specific organ affected, PROX1 has exhibited both tumor-promoting and tumor-suppressing properties, with its inhibition and reactivation representing possible novel therapeutic interventions, respectively. Moreover, researchers have reported PROX1 as a useful tool in the fields of diagnosis and prognosis assessment. The current study aims to summarize and present the existing data that render PROX1 a novel and useful diagnostic and prognostic biomarker, as well as a possible therapeutic target.

Exosomes on Endometrial Cancer: A Biomarkers Treasure Trove?

Endometrial cancer (EC) is one of the main causes of cancer-related death among women. In the last decade, the incidence of EC is on the rise, and the relative 5-year survival remains unchanged. This creates a dire need for new diagnostic and therapeutic approaches that can only result from a deeper understanding of the pathogenesis of the disease. In this direction, exosomes are under heavy research, with two main aims: to identify the potential diagnostic and prognostic markers and to develop technologies based on their use as therapeutic vectors targeting EC cells. Exosomes are widely available in all bodily fluids and are sources of ideal biomarkers for liquid biopsies. They are extracellular vesicles containing DNA, RNA, lipids, and proteins, which they transfer between cells, serving multiple functions and being implicated in both the physiological processes and the pathogenesis of diseases. Of all the biomolecules contained in exosomes, microRNAs (miRNAs) seem to have the most clinical utility in the diagnosis and treatment of EC. Exosomal miRNAs mediate the communication between EC cells, cancer-associated fibroblasts (CAFs), and tumor-associated macrophages (TAMs) and have a pivotal role in the tumor cells' proliferation, epithelial to mesenchymal transition (EMT), and the formation of a tumor microenvironment. They participate in many processes that are tied to carcinogenesis and cancer progression, and they are therefore considered as attractive therapeutic targets. Here, we review the functions of exosomes in EC, focusing on potential biomarkers of diagnostic and prognostic significance or potential therapeutic use.

Two Needle Passes Achieve Similar Diagnostic Yield Compared to Three Passes Regarding Diagnosis of Solid Pancreatic Lesions in Endoscopic Ultrasound-Guided Fine Needle Aspiration.

Current guidelines advocate 3-4 passes with a fine-needle aspiration (FNA) to achieve high rates of diagnostic samples for malignancy when performing endoscopic ultrasound (EUS)-guided sampling of solid pancreatic lesions, in the absence of on-site cytologic evaluation. The aim of this study is to compare 2 vs. 3 needle passes in EUS-FNA for solid pancreatic lesions in terms of incremental diagnostic yield and to identify factors associated with the procedure's outcome. In this retrospective study, 2 passes of EUS-FNA were found to have similar diagnostic yield compared to 3 passes for the diagnosis of solid pancreatic masses, suggesting that there might be no significant incremental tissue yield when 3 passes are performed.

Imaging and Cytopathological Criteria Indicating Malignancy in Mucin-Producing Pancreatic Neoplasms: A Series of 68 Histopathologically Confirmed Cases.

OBJECTIVES: This study aims to evaluate the performance of clinical, imaging, and cytopathological criteria in the identification of high-grade dysplasia/carcinoma (HGD/Ca) in pancreatic mucin-producing cystic neoplasms. METHODS: Sixty-eight consecutive, histopathologically confirmed mucin-producing cystic neoplasms, evaluated by endoscopic ultrasound-guided fine-needle aspiration, were enrolled; specifically, 39 branch duct intraductal papillary mucinous neoplasms (BD-IPMNs), 21 main duct IPMNs, and 8 mucinous cystic neoplasms. The associations between HGD/Ca in histopathology and findings of endoscopic ultrasound and cytology, demographic, lifestyle, and clinical parameters were evaluated, separately in IPMNs and mucinous cystic neoplasms. RESULTS: Age 65 years or more was associated with HGD/Ca in IPMNs. In BD-IPMNs, cyst diameter 3 cm or greater (sensitivity, 68.8%; specificity, 65.2%), a mural nodule (sensitivity, 56.3%; specificity, 78.3%), main pancreatic duct diameter 5 to 9 mm (sensitivity, 50.0%; specificity, 87.0%), and suspicious cytology (sensitivity, 81.3%; specificity, 100%) signaled the presence of HGD/Ca. Similarly, in main duct IPMNs, suspicious cytology predicted HGD/Ca with high sensitivity (88.9%) and excellent specificity (100%). Regarding cytopathological criteria, in BD-IPMNs, HGD/Ca was associated with a high nuclear/cytoplasmic ratio, background necrosis, presence of papillary structures, hypochromatic nuclei, hyperchromatic nuclei, and major nuclear membrane irregularities (thickening and/or indentations). CONCLUSIONS: Clinical, imaging, and cytopathological criteria are useful in the identification of HGD/Ca in IPMNs.

Elevated Hu-Antigen Receptor (HuR) Expression is Associated with Tumor Aggressiveness and Poor Prognosis but not with COX-2 Expression in Invasive Breast Carcinoma Patients.

Hu-antigen R (HuR), a RNA-binding protein, is considered to play a crucial role in tumor development and progression by stabilizing or regulating a group of cellular mRNAs of cancer-related genes, such as cyclooxygenase-2 (COX-2). The present study aimed to evaluate the clinical significance of HuR and COX-2 expression in invasive breast carcinoma. HuR and COX-2 protein expression was assessed immunohistochemically on paraffin-embedded breast cancer tissue sections obtained from 121 patients and was statistically analyzed with clinicopathological parameters, estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2), as well as with tumor cells' proliferative capacity and overall and disease-free patients' survival. High HuR expression was positively associated with larger tumor size and advanced disease stage (p = 0.0234 and p = 0.0361, respectively), being more frequently observed in ER negative cases (p = 0.0208). High COX-2 expression was negatively associated with histological (p < 0.0001) and nuclear (p = 0.0033) grade and tumor cells' proliferative rate (p = 0.0015), being more frequently observed in luminal-A compared to other molecular subtypes (p = 0.0221). High HuR expression was associated with poor overall and disease-free patients' survival at both univariate (log-rank test, p = 0.0092 and p = 0.0004, respectively) and multivariate (Cox-regression analysis, p = 0.0223 and p = 0.0004, respectively) level. On the other hand, high COX-2 expression was associated with favorable overall and disease-free patients' survival merely at univariate level (log-rank test, p = 0.0389 and p = 0.0154, respectively). HuR expression was not associated with COX-2 expression (Spearman R = 0.1489, p = 0.1032). The present data support evidence that HuR is associated with tumor aggressiveness and poor prognosis in breast carcinoma, reinforcing its potential as promising therapeutic target in this type of neoplasia.

The Goodness-of-fit of the Fractal Dimension as a Diagnostic Factor in Breast Cancer.

A large number of studies have found that the fractal dimension increases with the progression towards pathological or more pathological states, but there are also studies that have demonstrated the opposite relationship. In this study, we calculate the nuclear box-counting fractal dimension of 109 malignant, 113 benign, and 80 normal isolated breast cells in order to investigate its possible diagnostic importance. We computed the fractal dimension and its goodness-of-fit (i.e., the r-squared value that describes how well the regression line fits the set of the measurements) for two different sets of box size lengths. The statistical analysis did not confirm an important diagnostic potential of the nuclear fractal dimension of isolated breast cells. However, the goodness-of-fit did display a diagnostic potential. The r-squared value may be able to serve as a complementary diagnostic parameter.

Filaggrin and Periostin Expression Is Altered in Eosinophilic Esophagitis and Normalized With Treatment.

OBJECTIVES: Previous data have suggested that filaggrin (FLG) and periostin (POSTN) genes may be dysregulated in eosinophilic esophagitis (EoE). We aimed to further evaluate the expression patterns of FLG and POSTN proteins in esophageal tissue samples of patients with EoE, as compared to those of patients with gastroesophageal reflux disease (GERD) and normal controls. METHODS: A total of 61 prospectively collected cases, including 40 children with EoE and 21 children with GERD, and a control group of 14 sex- and age-matched healthy children were enrolled. Patients with EoE were treated with skin testing-driven elimination diet and/or corticosteroids. The immunohistochemical expression of FLG and POSTN was evaluated in esophageal biopsies obtained from patients and controls, and the results were correlated with EoE-related clinicopathological parameters. RESULTS: Positive FLG and negative POSTN staining were observed in all esophageal biopsies from normal controls. In contrast, FLG and POSTN stained negative and positive, respectively, in all pretreatment biopsies obtained from patients with EoE, whereas FLG and POSTN stained positive in 57.1% and 95.2% of GERD cases, respectively (P < 0.001). A statistically significant decrease of the proportion of cases with negative FLG and positive POSTN staining was observed from the first (pretreatment) to the second (post-treatment) biopsy in the subgroup of patients with EoE (P < 0.001 in both correlations). CONCLUSIONS: FLG and POSTN expression may be downregulated and upregulated, respectively, in the esophageal mucosa of patients with active EoE, and these changes may be restored with treatment in a significant percentage of cases.

Cytomorphometric study of epithelial cells in normal and cataractous human lenses in relation with hyperglycemia.

The aim of the study is to evaluate and correlate the morphology and cell density of epithelial cells adhering to lens capsule surgically removed from the anterior central region with lens clarity and type of cataract present in patients with or without type 2 diabetes. Capsulorhexis specimens were obtained from patients who had undergone phacoemulsification cataract surgery. All the samples were centrifuged and stained by the aid of Papanicolaou technique and were observed under light microscope. We determinated the mean cell density, the degree of epithelial damage, and morphological indicators of cells such as cell area and the nucleus-plasma ratio. Patients with cataract demonstrated a statistical significant decrease in cell density and an heterogeneous cell picture in which enlarged cells dominated. In addition, type 2 diabetics with cataract had a significantly even lower mean epithelial cell density by the presence of larger cell area with smaller nucleus-plasma ratio. More pronounced alterations in the lens epithelium were correlated not only with the presence of cortical cataract, increased fasting blood sugar, and increased HbA1c but also with the prolonged duration of diabetes and the co-existence of diabetic retinopathy. It seems that density and morphology of the anterior lens epithelial cells determine the lens epithelium damage which is more profound in hyperglycemia and in cortical cataracts. The changes in lens epithelium seem to play an important role in cataractogenesis.

Pregnancy associated breast cancer (PABC): aspects in diagnosis.

Diagnosis of a clinical entity like pregnancy associated breast cancer (PABC) is as demanding and challenging as its rarity. Increasing incidence and controversy that exists in the literature upon prognosis, tumor aggressiveness and underlying mechanisms, highlight the importance of optimizing the diagnostic strategy in women with PABC. Adjustment of standard approach for breast cancer by modifying management methods and options plays key role in decision making. Knowledge of diagnostic modalities and their limitations, in accordance with awareness of physiologic hormone-induced changes of pregnancy and lactation, is the fundamental method of diagnosis in PABC. Thorough triple assessment (history/clinical examination, imaging and cytology/histology) enforces healthcare providers with all essential tools to avoid detrimental delay in diagnosis and to confront with their own hesitation to take action due to limited experience of the disease.

Detection of pAkt protein in imprint cytology of invasive breast cancer: Correlation with HER2/neu, hormone receptors, and other clinicopathological variables.

PURPOSE: Akt is a serine/threonine protein kinase and has emerged as a crucial regulator of widely divergent cellular processes, including apoptosis, proliferation, differentiation, and metabolism. Activation of Akt/protein kinase B has been positively associated with human epidermal growth-factor receptor 2 (HER2)/neu overexpression in breast carcinoma and a worse outcome among endocrine treated patients. The Akt signaling pathway currently attracts considerable attention as a new target for effective therapeutic strategies. We therefore investigated the relationship between activation of Akt and clinicopathologic variables including hormone receptor and HER2/neu status. METHODS: Archival tumor tissues from 100 patients with invasive breast carcinoma were analyzed by immunocytochemistry. This study describes the results of immunocytochemical pAkt expression in breast carcinoma imprints, prepared from cut surfaces of freshly removed tumors. Both nuclear and cytoplasmic expressions were evaluated for pAkt. RESULTS: Nuclear and cytoplasmic positive scores of 72% (72/100) and 42% (42/100), respectively, were found. Coexistence of nuclear and cytoplasmic staining was observed in 32 cases (32/100). Nuclear positive staining correlated with HER2/neu overexpression (P = 0.043) and was significantly associated with positive involvement of axillary lymph nodes (P = 0.013). No correlation was found between cytoplasmic pAkt rate and clinicopathological parameters, estrogen receptor, progesterone receptor or HER2/neu expression. CONCLUSIONS: pAkt expression can be evaluated in cytological material and may add valuable information to current prognostic models for breast cancer. pAkt overexpression appears to be linked with potentially aggressive tumor phenotype in invasive breast carcinoma.

In vitro exposure of NK-92 cells to serum from patients with non-small cell lung cancer impairs their cytotoxicity.

AIM: To investigate the effect of serum from patients with non-small cell lung cancer (NSCLC) on in vitro cytotoxicity of the clonal cell line NK-92. MATERIALS AND METHODS: Twenty-six patients with NSCLC were included in this study. NK-92 cells were incubated in medium supplemented with 25% of each patient's serum (before and after chemotherapy) for 24 h, then washed and tested for cytotoxicity against NK-sensitive K562 targets. RESULTS: The cytotoxicity of NK-92 cells exposed to serum from patients with NSCLC before chemotherapy initiation was significantly reduced compared to that upon incubated with serum from healthy individuals (p<0.001). NK-92 cytotoxicity was further reduced upon exposure to patient's serum after the first and third chemo therapy cycles (p<0.001). CONCLUSION: The results of our in vitro study suggest that serum of patients with NSCLC may exert per se an inhibitory effect on the cytotoxicity of NK-92 cells and this negative regulation may be enhanced with chemotherapy.

Immunohistochemical expression of p53, p63, c-myc, p21(WAF1/cip1) and p27(kip1) proteins in urothelial bladder carcinoma: correlation with clinicopathological parameters.

PURPOSE: To reevaluate the expression levels of p53, p63, c-myc, p21(WAF1/cip1) and p27(kip1) proteins and their potential association with standard clinicopathological parameters, including tumor stage and grade, in urothelial bladder carcinoma (UBC). METHODS: Immunohistochemistry was performed in 100 transurethral resection specimens obtained from prospectively identified patients with primary UBC. RESULTS: Overall, 26, 41 and 75% of the cases showed positive staining for p53, p63 and c-myc, respectively, while p21(WAF1/cip1) and p27(kip1) expression levels were altered in 75 and 88% of the cases, respectively. Positive staining for p53 was associated with increased tumor stage (pT2) (p=0.037), while altered expression of p27(kip1) was strongly associated with male gender (p=0.009). CONCLUSION: The results of our study imply that p53 overexpression may be a useful marker of tumor invasion in UBC. In contrast, we failed to demonstrate any statistically significant correlation between the remaining markers evaluated and tumor stage or grade.

The clinical significance of cytology versus histology-based diagnosis in small cell lung cancer: a retrospective study.

OBJECTIVES: The aim of this study was to investigate the clinical significance of cytology versus histology-based diagnosis among patients diagnosed with small cell lung cancer (SCLC). MATERIALS AND METHODS: Retrospective analysis of medical records of 443 patients with histologically or cytologically confirmed small cell lung carcinoma (SCLC) was performed. All patients received platinum-based chemotherapy regimens. Survival data (overall survival) were compared between patients with histology or cytology-based diagnosis in the overall study population as well as after stratification of patients according to disease stage (limited or extensive) at the time of diagnosis. RESULTS: Distribution of demographics and clinicopathological characteristics among the two groups ("histology" and "cytology") was similar. No statistically significant differences in the survival curves between the "histology" and "cytology" groups were found in the overall study population (log rank test, p=0.237), as well as in the subgroup of patients with limited disease (log rank test, p=0.474). In contrast, patients with histology-based diagnosis had a statistically significant longer survival as compared to those with cytology-based diagnosis in the extensive disease subgroup (log rank test, p=0.031), but this association was not retained after adjusting the analysis for demographics and clinical characteristics via a Cox regression model (HR=1.18, 95% CI: 0.96-1.44, p=0.110). CONCLUSION: The results of our study suggest that the type of diagnostic modality employed (histology or cytology-based) for the establishment of a diagnosis of SCLC may not have a significant effect on the overall survival of patients. Further studies are warranted to further investigate this important, yet rather unexplored, issue.

Differential transcriptional and protein expression of thyroid-stimulating hormone receptor in ovarian carcinomas.

OBJECTIVE: Thyroid-stimulating hormone (TSH) regulates normal thyroid function by binding to its receptor (thyroid-stimulating hormone receptor -TSHR) that is expressed at the surface of thyroid cells. Recently, it has been demonstrated that TSHR is abundantly expressed in several tissues apart from the thyroid, among them the normal ovarian surface epithelium. The role of TSHR expression outside the thyroid is not completely understood. The current study examines possible alterations of TSHR expression in ovarian carcinomas and its implication in ovarian carcinogenesis. MATERIALS AND METHODS: Quantitative real-time polymerase chain reaction and immunohistochemistry analysis of TSHR expression were performed in 34 ovarian carcinoma specimens and 10 normal ovarian tissues (controls). RESULTS: Significant reduction in TSHR messenger RNA (mRNA) expression was detected in ovarian carcinomas (mean [SD]: 0.518 [0.0934] vs normal, 49.4985 [89.1626]; P < 0.001, Mann-Whitney U test), whereas TSHR protein levels were significantly increased (percentage of positive cells: cancer, 73.55% [20.09%], vs normal, 54.54% [21.14%]; intensity: cancer, 2.52 [0.508], vs normal 1 [0]; P = 0.012, Mann-Whitney U test). No significant differences in TSHR mRNA were found according to history of thyroid disease. CONCLUSIONS: Our study describes for the first time alterations in TSHR expression both at mRNA and protein levels in ovarian carcinomas. The discrepancy between the decreased levels of the TSHR mRNA and the increased protein expression has already been described in thyroid carcinomas and might be due to alterations in its degradation by the ubiquitin system or other unknown mechanisms. Further analysis could elucidate the role of these findings in ovarian carcinogenesis.

Expression of peroxisome proliferator activated receptor-gamma (PPAR-γ) in human non-small cell lung carcinoma: correlation with clinicopathological parameters, proliferation and apoptosis related molecules and patients' survival.

Peroxisome proliferator-activated receptor-γ (PPAR-γ) has currently been considered as molecular target for the treatment of human metabolic disorders. PPAR-γ has also been implicated in the pathogenesis and progression of several types of cancer, being associated with cell differentiation, growth and apoptosis. The present study aimed to evaluate the clinical significance of PPAR-γ expression in non-small cell lung carcinoma (NSCLC). PPAR-γ protein expression was assessed immunohistochemically in tumoral samples of 67 NSCLC patients and was statistically analyzed in relation to clinicopathological parameters, proliferation and apoptosis related molecules and patients' survival. Positive PPAR-γ expression was prominent in 30 (45 %) out of 67 NSCLC cases. PPAR-γ positivity was more frequently observed in squamous cell lung carcinoma cases compared to lung adenocarcinoma ones (p = 0.048). PPAR-γ positivity was significantly associated with bcl-2 positivity (p = 0.016) and borderline with c-myc positivity (p = 0.052), whereas non associations with grade of differentiation, TNM stage, Ki-67, p53, bax proteins' expression and patients' survival were noted. In the subgroup of squamous cell lung carcinoma cases, PPAR-γ positivity was significantly associated with tumor size (p = 0.038), while in lung adenocarcinoma ones with histopathological grade of differentiation (p = 0.026). The present study supported evidence for possible participation of PPAR-γ in the biological mechanisms underlying the carcinogenic evolution of the lung. Although the survival prediction using PPAR-γ expression as a marker seems uncertain, the observed correlation with apoptosis related proteins reinforces the potential utility of PPAR-γ ligands as cell cycle modulators in future therapeutic approaches in lung cancer.

VEGF directly suppresses activation of T cells from ovarian cancer patients and healthy individuals via VEGF receptor Type 2.

The role of vascular endothelial growth factor (VEGF) in tumor angiogenesis is well characterized; nevertheless, it is also a key element in promoting tumor evasion of the immune system by downregulating dendritic cell maturation and thus T cell activation. We sought to investigate the possible direct effect of VEGF on T cell activation and through which type of VEGF receptor (VEGFR) it exerts this effect. Circulating T cells from healthy donors and ovarian cancer patients were expanded in cultures with anti-CD3 and IL-2 with or without VEGF for 14 days, and the number of T cells was assessed. Cultured T cells were also tested for their cytotoxic activity in a standard 4-hr (51) Cr-release assay, and the expression of VEGFRs 1, 2 and 3 was assayed by flow cytometry, immunocytochemistry and Western blotting. To assess the ability of activated T cells to secrete VEGF, levels in culture supernatants were measured by enzyme linked immunosorbent assay. The addition of VEGF in cultures significantly reduced T cell proliferation in a dose-dependent manner. Protein expression studies demonstrated that CD3(+) T cells express VEGFR-2 on their surface upon activation. Experiments with anti-VEGFR-2 antibodies showed that the direct suppressive effect of VEGF on T cell proliferation is mediated by VEGFR-2. We also showed that VEGF significantly reduced the cytotoxic activity of T cells and that activated T cells secrete VEGF in the culture environment. Overall, our study shows that T cells secret VEGF and expresses VEGFR-2 upon activation. VEGF directly suppresses T cell activation via VEGF receptor type 2.

Primary hepatic neuroendocrine tumor with exophytic growth: report of a case with diagnosis by fine needle aspiration biopsy.

BACKGROUND: Primary hepatic neuroendocrine tumor with exophytic growth is a unique entity. CASE: A 74-year-old man presented to our hospital with abdominal discomfort. Diagnostic imaging procedures revealed a 15 x 10-cm mass in the liver with exophytic growth. The tumor was adjacent to the stomach, and clinical suspicion of gastrointestinal stromal tumor of the stomach was very strong initially. The cytologic and immunocytochemical examination of aspirated material showed features similar to those of neuroendocrine tumor. Systemic staging procedures showed no evidence of metastasis or other primary site. The histopathologic results of the excised tumor confirmed the cytologic diagnosis. CONCLUSION: Primary neuroendocrine tumor with exophytic growth is a rare entity and can be diagnosed with cytology and immunocytochemistry.

Study of T lymphocytes infiltrating peritoneal metastases in advanced ovarian cancer: associations with vascular endothelial growth factor levels and prognosis in patients receiving platinum-based chemotherapy.

INTRODUCTION: The presence of CD3(+) tumor-infiltrating lymphocytes (TILs) has been found to correlate with improved survival in epithelial ovarian cancer, but the association of TIL subpopulations with clinical outcome remains controversial. We performed a prospective analysis of TIL subpopulations from patients with epithelial ovarian cancer and their activation status and studied their association with prognosis. METHODS: Flow cytometric analysis was performed on TIL subpopulations isolated from 45 fresh ovarian tumor specimens, obtained during surgery, after mechanical dissociation and enzymatic degradation. Vascular endothelial growth factor and tumor necrosis factor alpha levels in ascites and serum were measured by enzyme-linked immunosorbent assay. RESULTS: Significantly increased numbers of CD56(+) cells (natural killer and natural killer-like T cells; P = 0.045), activated CD4(+)HLA-DR cells (P = 0.046), and activated CD8(+)CD25(+) cells (P = 0.028) were found in serous and endometrioid carcinomas compared with mucinous and clear cell carcinomas. A high percentage of CD4(+)CD25(hi) cells (regulatory T cells) and activated CD4(+)HLA-DR cells significantly associated with improved median overall survival (not reached vs 35 months [P = 0.0241] and not reached vs 35 months [P = 0.0144], respectively) and median progression-free survival (30 months vs 14 months [P = 0.0819] and 30 months vs 13 months [P = 0.0479], respectively). Vascular endothelial growth factor ascites levels were inversely correlated with CD14(+) (rho = -0.529, P = 0.001), whereas HLA-DR8(+)CD8 lymphocytes were inversely correlated with both ascites and serum vascular endothelial growth factor levels (rho = -0.494, P = 0.006, and rho = -0.586, P = 0.037, respectively). CONCLUSIONS: The presence of regulatory T cells and activated CD4(+) cells within the tumor microenvironment is associated with improved overall and progression-free survival in patients with ovarian cancer.