Holger G. Hass

Signet Ring Cell Carcinoma of the Stomach Is Significantly Associated with Poor Prognosis and Diffuse Gastric Cancer (Lauren’s): Single-Center Experience of 160 Cases

Aim: The aim of this study was to evaluate survival rates and treatment response in stage I–IV gastric cancer in relation to tumor stage (TNM), histology, Lauren’s classification and tumor localization. Patients and Methods: Clinical and histopathological data of 160 patients with stage I–IV gastric cancer were analyzed in this retrospective, single-center study. Results: Most patients (73.1%) showed an advanced or metastatic tumor stage (III/IV). The median 3-year overall survival (OS) was 20 ± 16.8 months and correlated significantly with tumor stage (I: OS 30.6 ± 15 months vs. IV: 10.4 ± 9.3 months; p < 0.0001). Stage III/IV tumors were significantly more often poorly differentiated (G3; p = 0.011) and located in the corpus region. Signet ring cell (SRC) cancers were found in a larger proportion of these tumors when compared with locally limited gastric cancers (43.1% vs. 16.3%; p = 0.002). SRC tumors occurred predominantly in women and younger patients and histology was significantly more often of the diffuse subtype according to Lauren (7.5% vs. 63.2%; p < 0.0001) and poorly differentiated (G3 in 95% vs. 73%; p = 0.001). Conclusions: SRC gastric cancer correlates with poor histopathological criteria and poor prognosis when compared with other histological subtypes. These observations underline the need for more effective treatment in addition to standard approaches.

Thyroid Disorders and Occurrence of Nonorgan-specific Autoantibodies (nosa) in Patients With Chronic Hepatitis C Before and During Antiviral Induction Therapy With Consensus Interferon (interferon Alfacon-1)

Background and Aim Thyroid disorders represent a common side effect of antiviral therapy in patients with chronic hepatitis C (CHC). However, there is strong evidence for a higher prevalence of thyroidal antibodies (TA) and nonorgan-specific autoantibodies (NOSA) even before interferon (IFN) administration. Here, we report for the first time on the distribution and occurrence of TA and NOSA before, during, and after treatment with daily high-dosed IFN alfacon-1 [consensus IFN (CIFN)]. Methods Thyrotropin (TSH) levels and antibodies to different autoantigens were analyzed in 217 patients with CHC (29.8% females) who were treated with CIFN induction therapy (27 or 18 μg q.d.). Results Pretreatment abnormal TSH levels (TSH>3.0 mU/L or <0.4 mU/L) were detected in 15.6% and occurred significantly more often in females (24.6%; P=0.018). TA could be detected only in 2.6%, NOSA in up to 29.9% (47.4% females vs. 24.2% males). During CIFN induction therapy, low TSH levels were detected in 14.1% whereas elevated TSH levels occurred later (week 48) in up to 15.5%, again preferentially in females (42%, P=0.005). In 1.4% of all patients, treatment had to be discontinued because of symptomatic hyperthyroidism. TAs were detected in 10.5% (30.5% females) and NOSA up to 58% during CIFN treatment. Conclusions During CIFN induction therapy, alterations in TSH levels and an increased prevalence of TA and NOSA are quite common, especially in females. Clinically relevant symptoms occur, however, only in a small number (1.4%). Thus, treatment with daily and high-dose CIFN does not appear to increase the incidence of (severe) thyroidal or other autoimmune disorders compared with standard IFN in patients with CHC.

Overexpression of Tumor-Associated Trypsin Inhibitor (SPINK1/TATI) in Hepatitis C-Associated Hepatocellular Carcinoma: Potential Implications for Viral Hepatocarcinogenesis

Background: The molecular pathomechanisms leading to hepatitis C virus (HCV)-induced hepatocarcinogenesis remain unclear. This study investigated the molecular pathways and key genes underlying HCV-positive hepatocellular carcinoma (HCC) using gene expression profiling. Methods: Oligonucleotide arrays (Affymetrix HU133A) were used to determine and compare the tissue-specific gene expression profiles in 39 cases of HCV-positive or -negative HCC and non-malignant liver tissue. The expression values of the most overexpressed genes were validated by real-time polymerase chain reaction (RT-PCR). Results: 837 genes or expressed sequence tags (ESTs) were significantly differently expressed in HCV-positive HCC versus healthy tissue: 414 were upregulated and 423 were downregulated (p < 0.05; > 2-fold change in ≥ 70% of the samples). A specific gene expression profile for HCV-positive HCC was obtained using 2-dimensional cluster analysis and was confirmed using supervised neuronal network modeling. The most consistently overexpressed gene coded for serine protease inhibitor Kazal-type 1 (SPINK1)/tumor-associated trypsin inhibitor (TATI) (median fold change, 19.7; significantly overexpressed in 90% of the samples). SPINK1/TATI was coregulated with matrix metalloproteinases (MMPs) and their natural inhibitors (tissue inhibitors of metalloproteinases (TIMPs)). Conclusions: Gene expression profiling identified specific dysregulated molecular pathways and SPINK1/TATI as the most overexpressed gene in HCV-positive HCC. These data highlight the importance of SPINK1/TATI as a tumor marker for HCV-induced HCC and may lead to a better understanding of HCV-induced hepatocarcinogenesis.

Use of Gene Expression Analysis for Discrimination of Primary and Secondary Adenocarcinoma of the Liver

Background: Due to late diagnosis and resistance to chemotherapy, most patients with cholangiocarcinoma have an unfavorable prognosis. Despite the use of immunohistochemistry (IHC) in clinical routine, differentiation between intrahepatic cholangiocarcinoma (ICC) and secondary adenocarcinomas of the liver is frequently not clear, leading to false diagnosis and treatment decisions. Methods: Oligonucleotide microarrays (Affymetrix Hu133A©) were used for gene expression analysis of ICC (n = 11) and secondary adenocarcinomas (colorectal metastases; n = 6). By two-dimensional cluster analysis a specific gene expression profile of these tumors was established and confirmed by real-time polymerase chain reaction and IHC. Results: A total of 338 genes were significantly dysregulated (gene expression/fc ≥2; dysregulation in ≥60%) in both tumor groups. Using two-dimensional cluster analysis a fast, clear, and reproducible differentiation between ICC and colorectal metastases was possible in all cases. As potential biomarkers for differentiation, twelve genes (ICC: KRT7, DBN1, LCTB, LIF, STK17A, PIGF; metastases: TDGF1, HOXA9, TFF3, MYB, ABP1, BCL11A) were detected and will be used for further investigations. Conclusions: A specific gene expression profile for discrimination of primary and secondary adenocarcinoma of the liver could be established. In addition, marker genes for both cancers and their potential use as discrimination markers in clinical routine were also described partially for the first time.

Subclassification and Detection of New Markers for the Discrimination of Primary Liver Tumors by Gene Expression Analysis Using Oligonucleotide Arrays.

Background/Aims The failure to correctly differentiate between intrahepatic cholangiocarcinoma (CC) and hepatocellular carcinoma (HCC) is a significant clinical problem, particularly in terms of the different treatment goals for both cancers. In this study a specific gene expression profile to discriminate these two subgroups of liver cancer was established and potential diagnostic markers for clinical use were analyzed. Methods To evaluate the gene expression profiles of HCC and intrahepatic CC, Oligonucleotide arrays (AffymetrixU133A) were used. Overexpressed genes were checked for their potential use as new markers for discrimination and their expression values were validated by reverse transcription polymerase chain reaction and immunohistochemistry analyses. Results 695 genes/expressed sequence tags (ESTs) in HCC (245 up-/450 down-regulated) and 552 genes/ ESTs in CC (221 up-/331 down-regulated) were significantly dysregulated (p<0.05, fold change >2, ≥70%). Using a supervised learning method, and one-way analysis of variance a specific 270-gene expression profile that enabled rapid, reproducible differentiation between both tumors and non-malignant liver tissues was established. A panel of 12 genes (e.g., HSP90β, ERG1, GPC3, TKT, ACLY, and NME1 for HCC; SPT2, T4S3, CNX43, TTD1, HBD01 for CC) were detected and partly described for the first time as potential discrimination markers. Conclusions A specific gene expression profile for discrimination of primary liver cancer was identified and potential marker genes with feasible clinical impact were described.