To evaluate the dependency of the sensitivity of (11)Ccholine positron emission tomography/computed tomography (PET/CT) for detecting and localizing primary prostate cancer (PCa) on tumor ...configuration in the histologic specimen.
Forty-three patients with biopsy-proven PCa were included. They underwent radical prostatectomy within 31 days after (11)Ccholine PET/CT. The transaxial image slices and the histologic specimens were analyzed by comparing the respective slices. Maximum standardized uptake values (SUV(max)) were calculated in each segment and correlated with histopathology. The tumor configuration in the histologic specimen was grouped as: I, unifocal; II, multifocal; III, rind-like shaped; IV, size <5 mm. Data analysis included the investigation of detection of PCa by SUV(max), the assessment of the influence of potential contributing factors on tumor prediction, and the evaluation of whether SUV could discriminate cancer tissue from benign prostate hyperplasia (BPH), prostatitis, HGPIN (high-grade prostate intraepithelial neoplasm), or normal prostate tissue. General estimation equation models were used for statistical analysis.
Tumor configuration in histology was classified as I in 21 patients, as II in 9, as III in 5, and as IV in 8. The prostate segment involved by cancer is identified in 79% of the patients. SUV(max) was located in the same side of the prostate in 95% of patients. Tumor configuration was the only factor significantly negatively influencing tumor prediction (P < 0.001). PCa-SUV(max) (median SUV(max) = 4.9) was not significantly different from BPH-SUV (median SUV(max) = 4.5) and prostatitis-SUV (median SUV(max) = 3.9), P = 0.102 and P = 0.054, respectively.
The detection and localization of PCa in the prostate with (11)Ccholine PET/CT is impaired by tumor configuration. Additionally, in our patient population, PCa tissue could not be distinguished from benign pathologies in the prostate.
We previously identified in a single-center study a 76-gene prognostic signature for lymph node-negative (LNN) breast cancer patients. The aim of this study was to validate this gene signature in an ...independent more diverse population of LNN patients from multiple institutions.
Using custom-designed DNA chips we analyzed the expression of the 76 genes in RNA of frozen tumor samples from 180 LNN patients who did not receive adjuvant systemic treatment.
In this independent validation, the 76-gene signature was highly informative in identifying patients with distant metastasis within 5 years (hazard ratio, HR, 7.41; 95% CI, 2.63 to 20.9), even when corrected for traditional prognostic factors in multivariate analysis (HR, 11.36; 95% CI, 2.67 to 48.4). The actuarial 5- and 10-year distant metastasis-free survival were 96% (95% CI, 89% to 99%) and 94% (95% CI, 83% to 98%), respectively, for the good profile group and 74% (95% CI, 64% to 81%) and 65% (53% to 74%), respectively for the poor profile group. The sensitivity for 5-yr distant metastasis-free survival was 90%, and the specificity was 50%. The positive and negative predictive values were 38% (95% CI, 29% to 47%) and 94% (95% CI, 86% to 97%), respectively. The 76-gene signature was confirmed as a strong prognostic factor in subgroups of estrogen receptor-positive patients, pre- and postmenopausal patients, and patients with tumor sizes 20 mm or smaller. The subgroup of patients with estrogen receptor-negative tumors was considered too small to perform a separate analysis.
Our data provide a strong methodologic and clinical multicenter validation of the predefined prognostic 76-gene signature in LNN breast cancer patients.
Background
Preoperative chemotherapy has been shown to improve outcome of patients with adenocarcinoma of the esophagogastric junction (AEG) and gastric cancer (GC), and histopathologic response has ...been identified as an independent prognostic parameter in these patients. A recent meta-analysis has identified patients with AEG as benefiting more from preoperative chemotherapy than patients with GC. The aim of this retrospective analysis was to prove these findings in an experienced single-center large patient cohort because there are currently no recruiting prospective clinical trials.
Methods
In a single center, 551 patients underwent preoperative platin-based chemotherapy followed by oncologic surgery for locally advanced AEG and GC. Pretherapeutic clinical parameters were correlated with histopathologic response to preoperative chemotherapy.
Results
Histopathologic response (<10% of residual tumor) was found in 130 patients (24%) and was significantly correlated with overall survival (
P
< 0.0001). Tumor localization at the esophagogastric junction (GE junction), lower baseline cT stage, and baseline cN0 stage were significantly associated with histopathologic response (
P
= 0.034,
P
= 0.015, and
P
= 0.002, respectively). In subgroup analyses, the latter two predictive parameters were confirmed only for AEG (
n
= 378) but not for other GC (
n
= 173). AEG patients who were pretherapeutically staged as having cT3/4, cN0 disease (
n
= 73) were identified as the subgroup with the highest rate of histopathologic response (48%).
Conclusions
AEG is more likely to respond to preoperative chemotherapy than GC, a finding that might help identify patients who would benefit from preoperative chemotherapy.
A recent study presented first evidence that a single nucleotide polymorphism (SNP) at codon 388 of fibroblast growth factor receptor 4 (FGFR4) gene, causing a transmembrane domain missense mutation ...(Gly388Arg), is associated with disease outcome in node-positive breast cancer. This article addresses the clinical relevance of this SNP, FGFR4 genotype, phenotype, and HER2 regarding patient outcome and influence of adjuvant systemic therapy in a substantial primary breast cancer collective (n = 372; median follow-up, 94.5 months).
Polymerase chain reaction restriction fragment length polymorphism analysis of germ-line polymorphism was performed in uninvolved lymph nodes; FGFR4 and HER2 expression were assessed immunohistochemically in tissue microarrays.
In 51% of patients, homo- or heterozygous Arg388 allele was present. No correlation existed between FGFR4 genotype and expression or HER2 status. In node-negative patients, FGFR4 genotype was not correlated with disease outcome. In node-positive patients, however, FGFR4 Arg388 was significantly associated with poor disease-free survival (DFS; P = .02) and overall survival (OS; P = .04). Notably, this association seems to be attributable to relatively poor therapy response in Arg388 carriers, reflected in their significantly shorter DFS (P = .02) and OS (P = .045) among patients receiving adjuvant systemic therapy. It is also seen as a significant interaction term in a multivariate proportional hazards model with Arg388 carriers having only about half as much benefit from adjuvant systemic therapy as wild-type carriers.
According to this study, FGFR4 Arg388 genotype is a marker for breast cancer progression in patients with adjuvant systemic therapy, particularly chemotherapy, and thus may indicate therapy resistance.
Glucose regulated proteins (GRPs) are main regulators of cellular homeostasis due to their role as molecular chaperones. Moreover, the functions of GRPs suggest that they also may play important ...roles in cancer biology. In this study we investigated the glucose regulated proteins GRP78 (BiP) and GRP94 (GP96) in a series of human esophageal adenocarcinomas to determine their implications in cancer progression and prognosis.
Formalin-fixed, paraffin-embedded tissues of primary resected esophageal (Barrett) adenocarcinomas (n = 137) and corresponding normal tissue were investigated. mRNA-gene expression levels of GRP78 and GRP94 were determined by quantitative real-time RT-PCR after mRNA extraction. Protein expression analysis was performed with immunohistochemical staining of the cases, assembled on a tissue micorarray. The results were correlated with pathologic features (pT, pN, G) and overall survival.
GRP78 and GRP94 mRNA were expressed in all tumors. The relative gene expression of GRP78 was significantly higher in early cancers (pT1m and pT1sm) as compared to more advanced stages (pT2 and pT3) and normal tissue (p = 0.031). Highly differentiated tumors showed also higher GRP78 mRNA levels compared to moderate and low differentiated tumors (p = 0.035). In addition, patients with higher GRP78 levels tended to show a survival benefit (p = 0.07). GRP94 mRNA-levels showed no association to pathological features or clinical outcome.GRP78 and GRP94 protein expression was detectable by immunohistochemistry in all tumors. There was a significant correlation between a strong GRP78 protein expression and early tumor stages (pT1m and pT1sm, p = 0.038). For GRP94 low to moderate protein expression was significantly associated with earlier tumor stage (p = 0.001) and less lymph node involvement (p = 0.036). Interestingly, the patients with combined strong GRP78 and GRP94 protein expression exclusively showed either early (pT1m or pT1sm) or advanced (pT3) tumor stages and no pT2 stage (p = 0.031).
We could demonstrate an association of GRP78 and GRP94 mRNA and protein expression with tumor stage and behaviour in esophageal adenocarcinomas. Increased expression of GRP78 may be responsible for controlling local tumor growth in early tumor stages, while high expression of GRP78 and GRP94 in advanced stages may be dependent from other factors like cellular stress reactions due to glucose deprivation, hypoxia or the hosts' immune response.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Protein tyrosine kinases (PTKs) play a critical role in the manifestation of cancer cell properties, and respective signaling mechanisms have been studied extensively on immortalized tumor cells. To ...characterize and analyze commonly used cancer cell lines with regard to variations in the primary structure of all expressed PTKs, we conducted a cDNA-based sequence analysis of the entire tyrosine kinase transcriptome of 254 established tumor cell lines. The profiles of cell line intrinsic PTK transcript alterations and the evaluation of 155 identified polymorphisms and 234 somatic mutations are made available in a database designated "Tykiva" (tyrosine kinome variant). Tissue distribution analysis and/or the localization within defined protein domains indicate functional relevance of several genetic alterations. The cysteine replacement of the highly conserved Y367 residue in fibroblast growth factor receptor 4 or the Q26X nonsense mutation in the tumor-suppressor kinase CSK are examples, and may contribute to cell line-specific signaling characteristics and tumor progression. Moreover, known variants, such as epidermal growth factor receptor G719S, that were shown to mediate anticancer drug sensitivity could be detected in other than the previously reported tumor types. Our data therefore provide extensive system information for the design and interpretation of cell line-based cancer research, and may stimulate further investigations into broader clinical applications of current cancer therapeutics.
Tissues used for clinical diagnostics are mostly formalin-fixed and paraffin-embedded (FFPE) which provides many advantages. However, the quality of the obtained nucleic acids (NA) is reduced and ...this turns out to be a challenge for further molecular analyses. Although the spectrum of analyses of NA extracted from FFPE tissue has increased, the standard operating procedures for NA isolation from old tissue blocks still need to be improved. Here, we compared the efficiency of different NA extraction methods, using FFPE tissues of variable age and origin, with respect to downstream analyses. Our study showed that the phenol–chloroform isoamyl alcohol (PCI) and the commercial Qiagen protocol yielded samples with highest purity. The PCI protocol delivered the longest amplicons even from samples from the 1970s. We developed a short (1 h) tissue lysis procedure that turned out to be highly time- and cost-effective when DNA quality was tested using single and multiplex PCR. Compared to a 1-day lysis-protocol, the amplicons were only 100 bp shorter. In addition, single-copy genes used in daily routine were successfully amplified from long-term stored FFPE samples following 1-h tissue-lysis. The RNA integrity numbers (RIN) determined on RNA isolated from FFPE tissues indicated degraded RNA; however, all RINs were above the generally agreed threshold of 1.4. We showed that, depending on the purpose of the analysis, NA retrieved from FFPE tissues older than 40 years may be successfully used for molecular analysis.
Despite the tendency to regard tumors as a simple mass of cancer cells, tumors have a high degree of complexity that is difficult to access with most analytical methods. Because the cancer tissue ...itself directly contains all information concerning proteomic and genetic changes, it represents the best possible sample material for any molecular research. However, an analytical method should also take advantage of morphological information contained within the cancer tissues, a feat that is not easily possible with methods based on sample homogenization such as conventional mass spectrometry.
Matrix-assisted laser desorption/ionization (MALDI) imaging mass spectrometry represents a method that allows the combination of mass spectrometric analyses with simultaneous histological evaluation to analyze various analytes such as proteins, peptides, lipids, or exogenous and endogenous small molecules. Spatially resolved mass spectrometric measurements are directly taken from a tissue section without destroying it. This combination allows for direct analysis of tumor samples while retaining the morphological information contained within the tissues, making it a very valuable tool in cancer research by complementing other currently used approaches.
In this review, we discuss the position that MALDI imaging mass spectrometry currently occupies in the field of cancer research by showing its fields of application as well as the results and new discoveries that could be obtained using this method.
► MALDI IMS has the unique advantage of combining mass spectrometry with histology. ► MALDI IMS has a wide array of potential applications in cancer research. ► One of the main challenges is the lack of standardized approaches for this technique.
Epithelial-mesenchymal-transition (EMT) is a crucial process during morphogenesis of multi-cellular organisms. EMT not only is a normal developmental process but also plays a role in tumor invasion ...and metastasis. Indeed, molecules involved in EMT, such as the transcription factor and E-cadherin repressor Slug (SNAI2), have recently been demonstrated to be important for cancer cells to down-regulate epithelial markers and up-regulate mesenchymal markers in order to become motile and invasive. Here we summarize major studies focusing on Slug expression in human tumor samples. We review a total of 13 studies involving 1150 cases from 9 different types of tumors. It is becoming clear that this transcription factor plays a role in the progression of some tumor types, including breast and gastric cancer. Interestingly, Slug expression is not always associated with down-regulation of E-cadherin. The mode of action, the signaling pathways involved in its regulation, and the interplay with other EMT regulators need to be addressed in future studies in order to fully understand Slug's role in tumor progression.
Abstract Purpose DNA methylation contributes to carcinogenesis by mediating transcriptional regulation and chromatin remodelling, which may influence the effect of DNA-damaging drugs. We examined the ...prognostic and predictive impact of DNA methyltransferase (DNMT) 1 and 3b expression in gastric carcinomas (GC) treated by neoadjuvant chemotherapy. In vitro , DNMT1 expression and chemosensitivity were investigated for a functional relationship and the DNMT inhibitor decitabine (DAC) was tested as an alternative treatment option. Patients and methods DNMT1/3b expression was analysed immunohistochemically in 127 pretherapeutic biopsies of neoadjuvant (platinum/5-fluorouracil)-treated GC patients and correlated with response and overall survival (OS). Short hairpin RNA technology was used to knockdown DNMT1 in the GC cell line, AGS. The chemosensitivity of GC cell lines to DAC alone and to DAC in combination with cisplatin was analysed by XTT or colony formation assays. Results High DNMT1 and DNMT3b expression was found in 105/127 (83%) and 79/127 (62%) carcinomas, respectively. Patients with low DNMT1 expression demonstrated a significantly better histopathological/clinical response ( P = 0.03/ P = 0.008) and OS ( Plog-rank = 0.001). In vitro , knockdown of DNMT1 caused an increased chemosensitivity towards cisplatin. Combined treatment with cisplatin and DAC showed a synergistic effect leading to increased cytotoxicity in the cisplatin-resistant cell line AGS. Conclusion Low DNMT1 expression defines a subgroup of GC patients with better outcomes following platinum/5FU-based neoadjuvant chemotherapy. In vitro data support a functional relationship between DNMT1 and cisplatin sensitivity. Besides its potential use as a predictive biomarker, DNMT1 may represent a promising target for alternative therapeutic strategies for a subset of GC patients.
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