STAT3 expression, activity and functional consequences of STAT3 inhibition in esophageal squamous cell carcinomas and Barrett's adenocarcinomas.

Signal transducer and activator of transcription 3 (STAT3) is altered in several epithelial cancers and represents a potential therapeutic target. Here, STAT3 expression, activity and cellular functions were examined in two main histotypes of esophageal carcinomas. In situ, immunohistochemistry for STAT3 and STAT3-Tyr705 phosphorylation (P-STAT3) in esophageal squamous cell carcinomas (ESCC, n=49) and Barrett's adenocarcinomas (BAC, n=61) revealed similar STAT3 expression in ESCCs and BACs (P=0.109), but preferentially activated P-STAT3 in ESCCs (P=0.013). In vitro, strong STAT3 activation was seen by epidermal growth factor (EGF) stimulation in OE21 (ESCC) cells, whereas OE33 (BAC) cells showed constitutive weak STAT3 activation. STAT3 knockdown significantly reduced cell proliferation of OE21 (P=0.0148) and OE33 (P=0.0243) cells. Importantly, STAT3 knockdown reduced cell migration of OE33 cells by 2.5-fold in two types of migration assays (P=0.073, P=0.015), but not in OE21 cells (P=0.1079, P=0.386). Investigation of transcriptome analysis of STAT3 knockdown revealed a reduced STAT3 level associated with significant downregulation of cell cycle genes in both OE21 (P<0.0001) and OE33 (P=0.01) cells. In contrast, genes promoting cell migration (CTHRC1) were markedly upregulated in OE21 cells, whereas a gene linked to tight-junction stabilization and restricted cell motility (SHROOM2) was downregulated in OE21 but upregulated in OE33 cells. This study shows frequent, but distinct, patterns of STAT3 expression and activation in ESCCs and BACs. STAT3 knockdown reduces cell proliferation in ESCC and BAC cells, inhibits migration of BAC cells and may support cell migration of ESCC cells. Thereby, novel STAT3-regulated genes involved in ESCC and BAC cell proliferation and cell migration were identified. Thus, STAT3 may be further exploited as a potential novel therapeutic target, however, by careful distinction between the two histotypes of esophageal cancers.

[Maxillary ameloblastoma extending into the sinonasal tract]. / Expansion eines Ameloblastoms in den sinunasalen Trakt.

Maxillary ameloblastomas can extensively expand into the paranasal sinuses or even the nasal cavity due to a slow growth pattern. Sinusitis is rarely the first tumor-related complaint. Due to the various growth forms of ameloblastomas the challenging histological differential diagnosis includes several other odontogenic as well as benign and malignant non-odontogenic tumors, e.g. tumors from the mucosa of the paranasal sinuses, salivary glands and Rathke's pouch. Despite the radical surgical approach a complete resection with wide margins cannot always be achieved. Maxillary ameloblastomas show the highest recurrence rates.

Polymorphisms in methionine synthase (A2756G) and cystathionine beta-synthase (844ins68) and susceptibility to carcinomas of the upper gastrointestinal tract.

PURPOSE: Folate deficiency is considered to increase the risk for the development of malignant tumors such as prostate and colorectal cancer. Methionine synthase (MTR) and cystathionine ss-synthase (CBS) are enzymes that play a central role in folate metabolism, thereby affecting DNA methylation and synthesis. A single A-->G substitution at nucleotide 2756 of the MTR and a 68 bp CBS insertion polymorphism in exon 8 have been associated with decreased enzyme activity. The purpose of this study is to compare the association of the MTR A2756G polymorphism and CBS insertion polymorphism with susceptibility to carcinomas of the upper gastrointestinal tract. METHODS: Using the restriction fragment length polymorphism (RFLP)-PCR, the prevalence of MTR A2756G and CBS insertion polymorphism was determined in healthy controls (n = 257) and in patients with esophageal squamous cell carcinoma (ESCC) (n = 263), Barrett's esophagus-associated esophageal adenocarcinoma (BC) (n = 89), cardiac carcinoma (CC) (n = 144), or gastric carcinoma (GC) (n = 221) from German Caucasian subjects. RESULTS: No significant difference in MTR A2756G genotype distribution was observed between controls (A/A 66.9%, A/G 29.8%, G/G 3.3%) and patients with ESCC (A/A 61.7%, A/G 36.3%, G/G 2.1%), BC (A/A 69.2%, A/G 26.9%, G/G 3.9%), CC (A/A 51.8%, A/G 44.6%, G/G 3.6%), or GC (A/A 73.4%, A/G 20.9%, G/G 5.7%). Similarly, the CBS genotype (I: allele with 68 bp insertion; N: allele without insertion) distribution among German patients with ESCC (N/N 86.8%, I/N 13.2%), BC (N/N 90.2%, I/N 9.8%), CC (N/N 90.1%, I/N 9.9%) or GC (N/N 91.3%, I/N 8.7%) was not different from healthy controls (N/N 90.4%, I/N 9.6%). The gene allele constellation I/I was not present. CONCLUSIONS: The current study suggests that there is no association between MTR A2756G polymorphism and the CBS (844ins68) insertion polymorphism and cancer of the upper gastrointestinal tract.

[Prognostic and predictive impact of protein expression profiling in high risk breast cancer patients treated with high-dose chemotherapy]. / Prognostische und prädiktive Bedeutung von Proteinexpressions-Profilen in einer Hochrisiko-Mammakarzinomsubgruppe aus der WSG AM01 phase III-Studie (Hochdosis-Chemotherapie versus konventionelle dosis-dichte Chemotherapie).

The prognostic and predictive impact of protein expression profiles was analyzed in high-risk breast cancer patients who had previously been shown to benefit from high-dose chemotherapy (HDCT) in comparison to dose-dense chemotherapy (DDCT). Using tissue microarrays, the expression of 34 protein markers was evaluated in 236 patients who had received either HDCT or DDCT (in the WSG AM01 trial). 1) 24 protein markers of the initial panel of 34 markers were sufficient to identify five profile clusters by K-means clustering: luminal A (27%), luminal B (12%), HER-2 (21%), basal-like (13%) cluster and a so called 'multiple marker negative'=MMN cluster (27%) characterized by the absence of specifying markers. 2) After DDCT, HER-2 and basal-like groups had significantly worse event-free survival (EFS) (HR 3.6 (95% CI, 1.65-8.18; p = 0.001) and HR 3.7 (95% CI, 1.68-8.48); p < 0.0001), respectively) when compared to both luminal groups. 3) After HDCT, the hazard ratio was 1.5 (95% CI, 0.76-3.05) for EFS in the HER-2 subgroups and 1.1 (95% CI, 0.37-3.32) in the basal-like subgroups which indicates a better outcome for patients in the HER-2 and basal-like subgroups who received HDCT. Protein expression profiling in high-risk breast cancers identified 5 subtypes, which differed with respect to survival and response to chemotherapy: In contrast to luminal A and B subtypes, HER-2 and basal-like subgroups had a significant predictive benefit from HDCT when compared to DDCT.

C-kit expression in high-risk breast cancer subgroup treated with high-dose or conventional dose-dense chemotherapy.

The proto-oncogene c-kit is known to be expressed in poorly differentiated breast cancer. In this study, we retrospectively evaluated the prognostic and predictive impact of c-kit in a high risk subgroup of breast cancer patients (>9 axillary node metastases) who received high-dose (HDCT) or dose-dense (DDCT) conventional chemotherapy and correlated these findings with the expression of the basal-type markers CK5 and CK 17, estrogen (ER) and progesterone (PR) receptor, Her-2/neu and MIB 1. C-kit, CK5, CK17, ER, PR, Her-2/neu and MIBI expression was evaluated immunohistochemically using tissue microarrays containing breast cancer samples from 236 patients who were randomized to the WSG AM01 trial (median follow-up of 60 months). There was a significant overall survival (OS) benefit for patients receiving HDCT compared to DDCT (p = 0.027). C-KIT expression was found in 12 % of all breast cancers and correlated with a poorer OS in multivariate analysis (p = 0.051). Furthermore, c-kit correlated with high grade (p = 0.019), CK5- and CK17-positivity (p <0.0001 and p = 0.001, respectively) and ER- and PR-negativity (p = 0.04 and p = 0.008, respectively). In contrast to CK5 and CK17, patients with c-kit positive breast cancers revealed no benefit from high-dose chemotherapy. These findings underline that c-kit expression represents an independent negative prognostic marker in high-risk breast cancer. Correlation with CK5 +/CK17+ and ER-/PR-suggests that c-kit positive carcinomas are at least partly of basal-type.

Adrenal pheochromocytoma with contralateral cortisol-producing adrenal adenoma: diagnostic and therapeutic management.

There is evidence for a close interrelation between the adrenomedullary and adrenocortical tissues, and there are well-characterized models of their paracrine interaction. To contribute to the studies of systemic interactions between these tissues, we studied a 52-year-old female patient with a pheochromocytoma and a contralateral cortisol-producing adenoma. Due to a misunderstanding, she presented to her family doctor to have an inherited kidney disease ruled out. An adrenal mass was discovered incidentally by ultrasound. A computerized tomography of the abdomen revealed bilateral adrenal masses. Due to excess catecholamine secretion, bilateral pheochromocytomas based on multiple endocrine neoplasia syndrome were suspected. Laboratory work-up, selective adrenal venous sampling and magnetic resonance imaging studies established the diagnosis of a pheochromocytoma in the right-hand adrenal gland and a cortisol-producing adenoma on the left. Simultaneous bilateral laparoscopic subtotal adrenalectomy was performed. Immunohistochemistry showed positive staining against chromogranin A in a histological specimen obtained from the right-hand adrenal gland, while the left was negative; the left-hand adrenal gland stained positive against the ACTH receptor (MC2R) while the right was negative. Genetically, the patient was negative for MEN2, von Hippel-Lindau disease, and mutations in subunits B, C, and D of the succinate dehydrogenase gene. Although presence of bilateral adrenal adenomas or bilateral adrenal pheochromocytomas in certain inherited disorders are possible, this rare case of an adrenal pheochromocytoma combined with a contralateral cortisol-producing adrenal adenoma may further underline the wide range of complex interactions between the two endocrine systems.

[Histopathological diagnosis of Barrett's mucosa and associated neoplasias. Results of a consensus conference of the Working Group for "Gastroenterological Pathology of the German Society for Pathology" on 22 September 2001]. / Histopathologische Diagnostik der Barrett-Schleimhaut und ihrer Neoplasien. Ergebnisse einer Konsensus-Konferenz der Arbeitsgemeinschaft "Gastroenterologische Pathologie der Deutschen Gesellschaft für Pathologie" am 22. September 2001 in Erlangen.

There are a number of difficulties regarding the diagnosis of Barrett's mucosa and the varying grades of neoplasia that may be associated with it. It was therefore the aim of a consensus conference of the "Working Group for Gastroenterological Pathology within the German Society of Pathology" to achieve standardization regarding the following issues: definition and diagnostic criteria for Barrett's mucosa and its discrimination from intestinal metaplasia of the cardia, diagnostic criteria for intraepithelial neoplasia, number of biopsies necessary to establish the diagnosis, significance of additional immunohistochemical and/or molecular biological methods as well as importance of a second opinion in the diagnosis of intraepithelial neoplasia.