Several pathohistological classification systems exist for the diagnosis of gastric cancer.Many studies have investigated the correlation between the pathohistological characteristics in gastric ...cancer and patient characteristics,disease specific criteria and overall outcome.It is still controversial as to which classification system imparts the most reliable information,and therefore,the choice of system may vary in clinical routine.In addition to the most common classification systems,such as the Laurén and the World Health Organization(WHO)classifications,other authors have tried to characterize and classify gastric cancer based on the microscopic morphology and in reference to the clinical outcome of the patients.In more than 50 years of systematic classification of the pathohistological characteristics of gastric cancer,there is no sole classification system that is consistently used worldwide in diagnostics and research.However,several national guidelines for the treatment of gastric cancer refer to the Laurén or the WHO classifications regarding therapeutic decision-making,which underlines the importance of a reliable classification system for gastric cancer.The latest results from gastric cancer studies indicate that it might be useful to integrate DNA-and RNA-based features of gastric cancer into the classification systems to establish prognostic relevance.This article reviews the diagnostic relevance and the prognostic value of different pathohistological classification systems in gastric cancer.
Thermal ablative therapies are standard treatments for localized hepatocellular carcinoma (HCC). In addition to local tumor destruction, ablation leads to abscopal effects in distant lesions most ...likely mediated by an anti-tumor immune response. Although microwave ablation (MWA) is increasingly substituting other ablative techniques, its systemic immunostimulatory effects are poorly studied. We analyzed tumor-specific immune responses in peripheral blood of HCC patients after thermal ablation with regard to T cell responses and disease outcome. While comprehensive flow cytometric analyses in sequential samples of a prospective patient cohort (
n
= 23) demonstrated only moderate effects of MWA on circulating immune cell subsets, fluorospot analyses of specific T cell responses against seven tumor-associated antigens (TTAs) revealed de-novo or enhanced tumor-specific immune responses in 30% of patients. This anti-tumor immune response was related to tumor control as Interferon-y and Interleukin-5 T cell responses against TAAs were more frequent in patients with a long-time remission (> 1 year) after MWA (7/16) compared to patients suffering from an early relapse (0/13 patients) and presence of tumor-specific T cell response (IFN-y and/or IL-5) was associated to longer progression-free survival (27.5 vs. 10.0 months). Digital image analysis of immunohistochemically stained archival HCC samples (
n
= 18) of patients receiving combined MWA and resection revealed a superior disease-free survival of patients with high T cell abundance at the time of thermal ablation (37.4 vs. 13.1 months). Our data demonstrates remarkable immune-related effects of MWA in HCC patients and provides additional evidence for a combination of local ablation and immunotherapy in this challenging disease.
Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia in clinical practice and is known to be associated with significant morbidity and mortality. Previous studies suggested a link ...between inflammation and AF by findings of increased inflammatory markers in AF patients. However, it has not been finally clarified whether inflammation is a systemic or a local phenomenon reflecting an active inflammatory process in the heart. To address this subject, human left atrial appendage tissues were obtained from 10 patients who underwent cardiac surgery and subjected to immunohistochemical analysis. The number of inflammatory CD3-positive T cells significantly increased from patients with sinus rhythm to paroxysmal AF and persistent AF, respectively. Interestingly, in patients with persistent AF, these cells were frequently arranged in small clusters. Subsequently, the number of inflammatory CD3-positive T cells decreased and was significantly lower in patients with permanent AF than in patients with persistent AF. Inflammatory CD20-positive B cells could only be detected very occasionally in all AF subgroups and were not locatable in patients with SR. Hence, our data emphasize the potential prominent role of the cellular component of the immune system in the development and perpetuation of AF.
MicroRNAs are small noncoding RNAs that regulate gene expression by targeting messenger RNAs (mRNAs) through translational repression or RNA degradation. Many fundamental biological processes are ...modulated by microRNAs, and an important role for microRNAs in carcinogenesis is emerging. Because understanding the pathogenesis of viral‐associated hepatocellular carcinomas is important in developing effective means of classification, prognosis, and therapy, we examined the microRNA expression profiles in a large set of 52 human primary liver tumors consisting of premalignant dysplastic liver nodules and hepatocellular carcinomas by quantitative real‐time polymerase chain reaction. All patients were infected with hepatitis C, and most had liver cirrhosis. Initially, the accessibility of microRNAs from formalin‐fixed paraffin‐embedded archival liver tissue by real‐time polymerase chain reaction assays was shown. Subsequently, target parenchyma from routinely processed tissue was macrodissected, RNA was extracted, and reverse transcription followed by quantitative real‐time polymerase chain reaction was performed. Relative quantification was performed by the 2−ΔΔCt method with normal livers as a calibrator. In order to obtain a comprehensive microRNA gene expression profile, 80 microRNAs were examined in a subset of tumors, which yielded 10 up‐regulated and 19 down‐regulated microRNAs compared to normal liver. Subsequently, five microRNAs (miR‐122, miR‐100, miR‐10a, miR‐198, and miR‐145) were selected on the basis of the initial results and further examined in an extended tumor sample set of 43 hepatocellular carcinomas and 9 dysplastic nodules. miR‐122, miR‐100, and miR‐10a were overexpressed whereas miR‐198 and miR‐145 were up to 5‐fold down‐regulated in hepatic tumors compared to normal liver parenchyma. Conclusion: A subset of microRNAs are aberrantly expressed in primary liver tumors, serving both as putative tumor suppressors and as oncogenic regulators. (HEPATOLOGY 2008.)
To evaluate the histopathologic response to neoadjuvant therapy in esophageal adenocarcinoma according to impact on prognosis and to suggest a classification for clinical routine.
Measures of ...histopathologic response to neoadjuvant treatment of esophageal cancer such as Mandard tumor regression grading focus on the effect on the primary tumor. Although lymph node infiltration is of significant prognostic importance, this criterion is mostly not included in the response classifications.
A total of 370 patients (89% males, median age: 61 years) with neoadjuvant radiochemotherapy (40 Gy, 5-FU, cisplatin) or chemotherapy (MAGIC or FLOT) for cT3, Nx, M0 esophageal adenocarcinoma were included in the analysis. All patients had undergone transthoracic en bloc esophagectomy, with a median of 27 resected lymph nodes and a R0-resection rate of 92%. Histopathologic regression grading differentiated major or minor response according to less or more than 10% vital cells in the primary tumor. The lymph nodes were classified as ypN0 or ypN+.
From the patients with R0 resection and M0 category, 3 groups with significantly different 5-year survival rates (5-YSR) could be differentiated: 1. Major response and ypN0 (n=100) with 5-YSR of 64% 2. Either major response and ypN+ (n=34) 5-YSR 42% or minor response and ypN0 (n=84) 5-YSR 44%, together 42% 5-YSR 3. Minor response and ypN+ (n=111) and 5-YSR of 18%.
A combined classification of primary tumor regression and lymph node status in 3 grades represents a simple and reproducible prognostic classification of the effect of neoadjuvant treatment in esophageal adenocarcinoma.
Background & Aims The progression of liver fibrosis in patients with chronic hepatitis C (CHC) is important to decide on the treatment of the virus. As liver biopsy and liver stiffness measurement ...for staging of fibrosis present limitations, circulating levels of miR-122 have been suggested as a novel biomarker to predict the extent of liver injury. We evaluated the potential of miR-122 as an indicator of fibrosis progression in CHC infection and performed, for the first time, a comprehensive analysis of hepatic and circulating miR-122 levels in patients with CHC. Methods Patients with well-documented CHC infection were selected from the database of HepNet, the German-Competence-Network on Viral Hepatitis. All patients underwent blood sampling and liver biopsy with grading of inflammation and staging of fibrosis. RNA was extracted from 84 liver biopsies and 164 serum samples of CHC patients. miR-122 levels in liver and serum samples were quantified by real-time PCR normalized to RNU6 or spiked-in RNA, respectively. Results Hepatic levels of miR-122 decreased significantly with the severity of fibrosis ( p = 0.001). In addition, circulating miR-122 levels correlated negatively with increasing stages of fibrosis, although the inverse correlation was moderate due to a two-phase miR-122 pattern during fibrosis progression. Thus, circulating miR-122 levels decreased in patients with severe fibrosis (F3, F4), while at early stages with distinct fibrotic structures (F2) and high inflammatory activity, miR-122 serum levels were elevated. Conclusions We conclude that during progression of fibrosis less miR-122 is released into the blood stream due to the loss of liver cells and the decrease of hepatic miR-122 levels. Although the release of circulating miR-122 possibly mirrors acute liver injury, in chronic liver disease and fibrosis, the loss of liver cells and the decreased hepatocellular miR-122 expression render miR-122 an inappropriate marker, when exclusively used for interpretation of fibrosis progression.
Chronic infection with hepatitis C (HCV) is a major risk factor in the development of cirrhosis and hepatocellular carcinoma. Lipid metabolism plays a major role in the replication and deposition of ...HCV at lipid droplets (LDs). We have demonstrated the importance of LD-associated proteins of the perilipin family in steatotic liver diseases. Using a large collection of 231 human liver biopsies with HCV, perilipins 1 and 2 have been localized to LDs of hepatocytes that correlate with the degree of steatosis and specific HCV genotypes, but not significantly with the HCV viral load. Perilipin 1- and 2-positive microvesicular steatotic foci were observed in 36% of HCV liver biopsies, and also in chronic hepatitis B, autoimmune hepatitis and mildly steatotic or normal livers, but less or none were observed in normal livers of younger patients. Microvesicular steatotic foci did not frequently overlap with glycogenotic/clear cell foci as determined by PAS stain in serial sections. Steatotic foci were detected in all liver zones with slight architectural disarrays, as demonstrated by immunohistochemical glutamine synthetase staining of zone three, but without elevated Ki67-proliferation rates. In conclusion, microvesicular steatotic foci are frequently found in chronic viral hepatitis, but the clinical significance of these foci is so far not clear.
Schistosomiasis (bilharzia) is a neglected tropical disease caused by parasitic flatworms of the genus Schistosoma, with considerable morbidity in parts of the Middle East, South America, Southeast ...Asia, in sub-Saharan Africa, and particularly also in Europe. The WHO describes an increasing global health burden with more than 290 million people threatened by the disease and a potential to spread into regions with temperate climates like Corsica, France. The aim of our study was to investigate the influence of S. mansoni infection on colorectal carcinogenic signaling pathways in vivo and in vitro. S. mansoni infection, soluble egg antigens (SEA) and the Interleukin-4-inducing principle from S. mansoni eggs induce Wnt/β-catenin signaling and the protooncogene c-Jun as well as downstream factor Cyclin D1 and markers for DNA-damage, such as Parp1 and γH2a.x in enterocytes. The presence of these characteristic hallmarks of colorectal carcinogenesis was confirmed in colon biopsies from S. mansoni-infected patients demonstrating the clinical relevance of our findings. For the first time it was shown that S. mansoni SEA may be involved in the induction of colorectal carcinoma-associated signaling pathways.
Esophageal cancer is often diagnosed at an advanced stage. Diagnostic markers are needed for achieving a cure in esophageal cancer detecting and treating tumor cells earlier. In patients with locally ...advanced squamous cell carcinoma of the esophagus (ESCC), we profiled the gene expression of ESCC compared to corresponding normal biopsies for diagnostic markers by genome microarrays. Profiling of gene expression identified 4844 genes differentially expressed, 2122 upregulated and 2722 downregulated in ESCC. Twenty-three overexpressed candidates with best scores from significance analysis have been selected for further analysis by TaqMan low-density array-technique using a validation cohort of 40 patients. The verification rate was 100 % for ESCC. Twenty-two markers were additionally overexpressed in adenocarcinoma of the esophagus (EAC). The markers significantly overexpressed already in earlier tumor stages (pT1-2) of both histological subtypes (
n
= 19) have been clustered in a “diagnostic signature”: PLA2G7, PRAME, MMP1, MMP3, MMP12, LIlRB2, TREM2, CHST2, IGFBP2, IGFBP7, KCNJ8, EMILIN2, CTHRC1, EMR2, WDR72, LPCAT1, COL4A2, CCL4, and SNX10. The marker signature will be translated to clinical practice to prove its diagnostic impact. This diagnostic signature may contribute to the earlier detection of tumor cells, with the aim to complement clinical techniques resulting in the development of better detection of concepts of esophageal cancer for earlier therapy and more favorite prognosis.
•Log odds of positive lymph nodes (LODDS) is an independent risk factor for recurrence.•LODDS is a better predictor than lymph node ratio and N-Classification.•LODDS is able to distinguish prognosis ...between groups without positive lymph nodes.
Log odds of positive lymph nodes (LODDS) has been demonstrated as a very promising staging model for multiple cancer sites, as it avoids singularity and predicts prognosis significantly better than conventional nodal staging and lymph node ratio. However, published studies on the influence of LODDS for patients with OSCC are very seldom.
Retrospective chart review of 499 patients with treatment-naive oral squamous cell carcinoma. Exclusion criteria were neoadjuvant chemoradiotherapy, T4b classification, perioperative death, unresectable disease, synchronous malignancy, follow-up < 3 months and inadequate information to correctly determine nodal yield. Statistical analysis was performed using univariate and multivariate analysis.
A significant correlation was found between locoregional recurrence and pathologic T classification (p=0.030), pathologic N classification p=0.013), extracapsular spread (p=0.034), grading (p=0.021), number of positive lymph nodes (p=0.042), lymph node ratio (p=0.009), LODDS (p=0.007) and treatment strategy (p=0.039). Multivariate analysis indicated lymph node ratio (p=0.029) and LODDS (p=0.015) as independent indicators for locoregional recurrence. Within the analyzed models, Nagelkerke R2 index and Someŕs D showed the strongest discrimination ability for LODDS.
For patients with oral squamous cell carcinoma, log odds of positive lymph nodes and lymph node ratio are independent indicators for locoregional recurrence. LODDS predicts locoregional recurrence better than conventional nodal staging system, lymph node ratio and the number of positive lymph nodes.
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