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The progesterone receptor (PR) has been increasingly well described as an important mediator of the pathogenesis and progression of breast cancer. The aim of this study was to assess the role of PR status as a prognostic factor in addition to other well-established prognostic factors. Data from five independent German breast cancer centers were pooled. A total of 7,965 breast cancer patients were included for whom information about their PR status was known, as well as other patient and tumor characteristics commonly used as prognostic factors. Cox proportional hazards models were built to compare the predictive value of PR status in addition to age at diagnosis, tumor size, nodal status, grading, and estrogen receptor (ER) status. PR status significantly increased the accuracy of prognostic predictions with regard to overall survival, distant disease-free survival, and local recurrence-free survival. There were differences with regard to its prognostic value relative to subgroups such as nodal status, ER status, and grading. The prognostic value of PR status was greatest in patients with a positive nodal status, negative ER status, and low grading. The PR-status adds prognostic value in addition to ER status and should not be omitted from clinical routine testing. The significantly greater prognostic value in node-positive and high-grade tumors suggests a greater role in the progression of advanced and aggressive tumors.

Profiles of gene transcription have begun to delineate the molecular basis of ovarian cancer, including distinctions between carcinomas of differing histology, tumor progression and patient outcome. However, the similarities and differences among the most commonly diagnosed noninvasive borderline (low malignant potential, LMP) lesions and invasive serous carcinomas of varying grade (G1, G2 and G3) have not yet been explored. Here, we used oligonucleotide arrays to profile the expression of 12 500 genes in a series of 57 predominantly stage III serous ovarian adenocarcinomas from 52 patients, eight with borderline tumors and 44 with adenocarcinomas of varying grade. Unsupervised and supervised analyses showed that LMP lesions were distinct from high-grade serous adenocarcinomas, as might be expected; however, well-differentiated (G1) invasive adenocarcinomas showed a strikingly similar profile to LMP tumors as compared to cancers with moderate (G2) or poor (G3) cellular differentiation, which were also highly similar. Comparative genomic hybridization of an independent cohort of five LMP and 63 invasive carcinomas of varying grade demonstrated LMP and G1 were again similar, exhibiting significantly less chromosomal aberration than G2/G3 carcinomas. A majority of LMP and G1 tumors were characterized by high levels of p21/WAF1, with concomitant expression of cell growth suppressors, gadd34 and BTG-2. In contrast, G2/G3 cancers were characterized by the expression of genes associated with the cell cycle and by STAT-1-, STAT-3/JAK-1/2-induced gene expression. The distinction between the LMP-G1 and G2–G3 groups of tumors was highly correlated to patient outcome ( χ 2 for equivalence of death rates=7.681189; P =0.0056, log-rank test). Our results are consistent with the recent demonstration of a poor differentiation molecular ‘meta-signature’ in human cancer, and underscore a number of cell-cycle- and STAT-associated targets that may prove useful as points of therapeutic intervention for those patients with aggressive disease.

Background Estrogen receptor alpha ( ERa/ESR1 ) expression is regulated by alternative splicing. Its most frequently detectable exon7 skipping isoform ( ERaD7 ) is a dominant negative variant. Elevated expression of ERaD7 was already detected in endometrial cancer (EC), while its potential prognostic significance has not been characterized so far. Exon7 contains potential binding sites for the two functional splicing regulatory opponents, HNRNPG and HTRA2-BETA1 known to trigger opposite effects on EC outcome. This study served to elucidate the influence of HNRNPG and HTRA2-BETA1 on ERa exon7 splicing regulation and the impact of ERaD7 concentration on type 1 EC outcome. Methods Functional in vitro experiments for HNRNPG and HTRA2-BETA1 in regard to the regulatory impact on endogenous and exogenous ERaD7 splicing were performed. Additionally, real-time PCR determined mRNA levels of ERaD7 , HNRNPG and HTRA2-BETA1 in 116 type 1 EC patients. Results HNRNPG and HTRA2-BETA1 were found to be specific regulators of ERa exon7 splicing. While HTRA2-BETA1 promoted exon7 inclusion, HNRNPG antagonized this effect by inducing exon7 skipping (p = 0.004). ERaD7 was detected in 71 out of 116 type 1 EC specimens. Statistical analyses revealed an inverse correlation between ERaD7 mRNA levels and tumor grading (p = 0.029), FIGO stage (p = 0.033) as well as lymph node metastases (p = 0.032), respectively. Furthermore, higher ERaD7 expression could be correlated to an improved disease-specific survival (p = 0.034). Conclusions Our study demonstrates antagonistic regulatory effects of HNRNPG and HTRA2-BETA1 on ERa exon7 splicing with potential impact on type 1 EC clinical outcome due to the consecutively variable expression levels of the ERa isoform D7 .

Background Neoadjuvant chemotherapy (NC) is an established therapy in breast cancer, able to downstage positive axillary lymph nodes, but might hamper their detectibility. Even if clinical observations suggest lower lymph node yield (LNY) after NC, data are inconclusive and it is unclear whether NC dependent parameters influence detection rates by axillary lymph node dissection (ALND). Methods We analyzed retrospectively the LNY in 182 patients with ALND after NC and 351 patients with primary ALND. Impact of surgery or pathological examination and specific histomorphological alterations were evaluated. Outcome analyses regarding recurrence rates, disease free (DFS) and overall survival (OS) were performed. Results Axillary LNY was significantly lower in the NC in comparison to the primary surgery group (median 13 vs. 16; p < 0.0001). The likelihood of incomplete axillary staging was four times higher in the NC group (14.8% vs. 3.4%, p < 0.0001). Multivariate analyses excluded any influence by surgeon or pathologist. However, the chemotherapy dependent histological feature lymphoid depletion was an independent predictive factor for a lower LNY. Outcome analyses revealed no significant impact of the LNY on local and regional recurrence rates as well as DFS and OS, respectively. Conclusion NC significantly reduces the LNY by ALND and has profound effects on the histomorphological appearance of lymph nodes. The current recommendations for a minimum removal of 10 lymph nodes by ALND are clearly compromised by the clinically already established concept of NC. The LNY of less than 10 by ALND after NC might not be indicative for an insufficient axillary staging.

Cervical uterine cancer is the second most frequent female cancer worldwide and a substantial burden for low-income societies and the patients themselves. Understanding the molecular mechanisms of metastasis permits the development of therapies that limit tumor progression, as well as providing health and social benefits. Pathomorphology is still the basis of research and a reference standard for molecular analysis. The aim of our study was to research and critically evaluate clinical trials that use new oncological approaches for node-positive cervical cancer to gain an insight into the molecular mechanisms of tumor metastasis. Inclusion criteria: node-positive disease at baseline; at least a first phase clinical study comprising adult female patients; novel clinical approach (e.g., radiotherapy, immunotherapy, targeted therapy, vaccines, radiosurgery); histologic measurement of treatment efficacy (preferably lymph node ultrastaging); and publications in English language only. Information sources: US Clinical trials registry, EU Clinical trials register, ISRCTN registry, and Ovid, EBSCO and Cochrane Collaboration databases. Access dates: from January 2010 to April 2018. Exclusions: Abstracts that did not meet the inclusion criteria or with unreliable data. We collected complete data (e.g., the entire publication associated with included abstracts, heterogeneity examination of individual studies, and validity measurement of the statistical methods used). Results were analyzed in relation to the most recent understanding of the pathogenesis of cervical cancer metastasis. We proposed a possible direction for drug treatment of epithelial tumors based on the mechanisms of metastasis.

Breast cancer is the leading cause of cancer death in women and the second most common cancer worldwide after lung cancer. The remarkable heterogeneity of breast cancers influences numerous diagnostic, therapeutic, and prognostic factors. Triple-negative breast carcinomas (TNBCs) lack expression of HER2 and the estrogen and progesterone receptors and often contain lymphocytic infiltrates. Most of TNBCs are invasive ductal carcinomas (IDCs) with poor prognosis, whereas prognostically more favorable subtypes such as medullary breast carcinomas (MBCs) are somewhat less frequent. Infiltrating T-cells have been associated with an improved clinical outcome in TNBCs. The prognostic role of γδ T-cells within CD3(+) tumor-infiltrating T lymphocytes remains unclear. We analyzed 26 TNBCs, 14 IDCs, and 12 MBCs, using immunohistochemistry for the quantity and patterns of γδ T-cell infiltrates within the tumor microenvironment. In both types of TNBCs, we found higher numbers of γδ T-cells in comparison with normal breast tissues and fibroadenomas. The numbers of infiltrating γδ T-cells were higher in MBCs than in IDCs. γδ T-cells in MBCs were frequently located in direct contact with tumor cells, within the tumor and at its invasive border. In contrast, most γδ T-cells in IDCs were found in clusters within the tumor stroma. These findings could be associated with the fact that the patient's prognosis in MBCs is better than that in IDCs. Further studies to characterize these γδ T-cells at the molecular and functional level are in progress.

Background:YT521 is a splicing factor involved in alternative splicing regulation of several tumor biological important genes. Two messenger RNA (mRNA) isoforms due to YT521 exon6 alternative splicing exist, with so far unknown functional consequences. Further evidence exists for a direct influence of YT521 expression in tumorigenesis because its mRNA level is changed in tumors compared with physiological tissue. We investigated the potential impact of YT521 expression on tumor biological parameters in endometrial cancer (EC).Methods:Real-time reverse transcription-polymerase chain reaction specifically detecting YT521 exon6-retention and exon6-skipping mRNA isoforms and immunohistochemistry were performed in a cohort of 130 EC tissue samples.Results:Whereas YT521 exon6-retention mRNA was detectable in 86 (66.2%), the exon6-skipping isoform mRNA was expressed in only 8 (6.2%) of all EC samples. On the protein level, 104 (80%) of EC samples showed nuclear expression. The mRNA levels of exon6-skipping isoform were not correlated to any of the clinicopathological parameters of EC. In contrast, YT521 exon6-retention mRNA expression was positively correlated to metastasis (R = 0.196, P = 0.026) and inversely correlated to the protein expression levels (R = −0.205, P = 0.019). In univariate analyses, higher levels of YT521 exon6-retention mRNA were correlated to a poorer progression-free survival (P = 0.003), and this is confirmed by multivariate analyses (P = 0.019). The negative YT521 protein expression was correlated to poorer overall and disease-specific survival (P = 0.036 and P = 0.034), respectively, in univariate analyses. They are also confirmed by multivariate analyses (P = 0.021 and P = 0.010, respectively).Conclusions:We characterized for the first time in a clinical setting a new but rare exon6-skipping mRNA splicing isoform of YT521. Furthermore, we identified YT521 as a potential new independent prognostic factor for patients with EC: the lack of YT521 protein in tumor cells was highly predictive for a poor overall and disease-specific survival and independent from the histological subtypes.

Introduction:The pp125 focal adhesion kinase (FAK) plays a pivotal role in tumor cell signaling. Focal adhesion kinase expression has been linked to tumor cell proliferation, invasion, and metastasis, but data on endometrial cancer are inconclusive.Methods:We assess FAK expression by immunohistochemistry in endometrial cancer for its value to predict patient prognosis.Results:Of 134 endometrial cancer cases, 120 (89%) revealed moderate and strong expressions of FAK, whereas weak expression was found in 14 (11%) tumors. Kaplan-Meier analysis indicated a clear trend toward improved survival rates for patients with endometrial carcinomas weakly expressing FAK, and notably, there was neither lymph node metastasis nor tumor-related death in this patient subgroup. Increased expression of FAK correlated with higher histological tumor grade (P = 0.002), lymphatic vascular space invasion (P = 0.003), and vascular space invasion (P = 0.02). Significant prognostic survival variables were tumor stage (P < 0.01), histological type (P < 0.01), tumor grade (P = 0.028), and pelvic lymph node status (P = 0.035). Multivariate Cox regression analysis identified histological tumor grade as a significant independent predictor of patient survival (hazards ratio, 2.71; P = 0.03).Conclusions:Further studies are warranted to elucidate whether FAK expression analysis is a suitable tool in stratifying patients at different risks of disease progress, and wether FAK might become a new molecular target for endometrial anticancer therapy.

Acute respiratory distress syndrome (ARDS) in young infants is linked with a pulmonary inflammatory response part of which are increased interleukin-8 (IL-8) levels and migration of polymorphonuclear leukocytes (PMNL) into lung tissue. A topical application of an antibody against IL-8 might therefore decrease PMNL migration and improve lung function. Randomized, controlled, prospective animal study. Research laboratory of a university children's hospital. Anesthetized, mechanically ventilated newborn piglets (n=22) underwent repeated airway lavage to remove surfactant and to induce lung inflammation. Piglets then received either surfactant alone (S, n=8), or a topical antibody against IL-8 admixed to surfactant (S+IL-8, n=8), or an air bolus injection (control, n=6). After 6 h of mechanical ventilation following intervention, oxygenation [S 169+/-51 (SD) vs S+IL-8 139+/-61 mmHg] and lung function (compliance: S 1.3+/-0.4 vs S+IL-8 0.9+/-0.4 ml/cmH(2)O/kg; extra-vascular lung-water: S 27+/-9 vs S+IL-8 52+/-28 ml/kg) were worse in the S+IL-8 group because reactive IL-8 production [S 810 (median, range 447-2323] vs S+IL-8 3485 (628-16180) pg/ml; P<0.05) with facilitated migration of PMNL into lung tissue occurred. Moreover, antibody application caused augmented chemotactic potency of IL-8 [linear regression of migrated PMNL and IL-8 levels: S r(2)=0.30 (P=ns) vs S+IL-8 r(2)=0.89 (P=0.0002)]. Topical anti-IL-8 treatment after lung injury increases IL-8 production, PMNL migration, and worsens lung function in our piglet lavage model. This effect is in contrast to current literature using pre-lung injury treatment protocols. Our data do not support anti-IL-8 treatment in young infants with ARDS.