[Mesenchymal tumors of the mediastinum]. / Mesenchymale Tumoren des Mediastinums.

Mesenchymal neoplasms of the thymus and mediastinum account for only 2 % of neoplasms of the mediastinum and are therefore very rare. With very few exceptions the histology, immunohistochemistry and (based on current knowledge) molecular biology of mediastinal soft tissue tumors are not different from their counterparts in other organs. Characteristic features are more concerned with clinical epidemiological and therapeutic aspects as well as the multitude of possible differential diagnoses. With the exception of organ-specific tumors, such as gastrointestinal stromal tumors (GIST), virtually all entities encountered in peripheral soft tissues can also arise in the mediastinum. Primary mediastinal soft tissue sarcomas (STS) must be distinguished from secondary radiation-induced STS after irradiation, e. g. for breast cancer and Hodgkin's lymphoma and from STS arising as somatic type malignancies in mediastinal germ cell tumors.

Loss of FUBP1 expression in gliomas predicts FUBP1 mutation and is associated with oligodendroglial differentiation, IDH1 mutation and 1p/19q loss of heterozygosity.

AIMS: The Far Upstream Element [FUSE] Binding Protein 1 (FUBP1) regulates target genes, such as the cell cycle regulators MYC and p21. FUBP1 is up-regulated in many tumours and acts as an oncoprotein by stimulating proliferation and inhibiting apoptosis. Recently, FUBP1 mutations were identified in approximately 15% of oligodendrogliomas. To date, all reported FUBP1 mutations have been predicted to inactivate FUBP1, which suggests that in contrast to most other tumours FUBP1 may act as a tumour suppressor in oligodendrogliomas. METHODS: As no data are currently available concerning FUBP1 protein levels in gliomas, we examined the FUBP1 expression profiles of human glial tumours by immunohistochemistry and immunofluorescence. We analysed FUBP1 expression related to morphological differentiation, IDH1 and FUBP1 mutation status, 1p/19q loss of heterozygosity (LOH) as well as proliferation rate. RESULTS: Our findings demonstrate that FUBP1 expression levels are increased in all glioma subtypes as compared with normal central nervous system (CNS) control tissue and are associated with increased proliferation. In contrast, FUBP1 immunonegativity predicted FUBP1 mutation with a sensitivity of 100% and a specificity of 90% in our cohort and was associated with oligodendroglial differentiation, IDH1 mutation and 1p/19q loss of heterozygosity (LOH). Using this approach, we detected a to-date undescribed FUBP1 mutation in an oligodendroglioma. CONCLUSION: In summary, our data indicate an association between of FUBP1 expression and proliferation in gliomas. Furthermore, our findings present FUBP1 immunohistochemical analysis as a helpful additional tool for neuropathological glioma diagnostics predicting FUBP1 mutation.

EGFR mutational status in a large series of Caucasian European NSCLC patients: data from daily practice.

BACKGROUND: The prognosis of metastatic non-small cell lung cancer (NSCLC) is still poor. Activating epithelial growth factor receptor (EGFR) mutations are important genetic alterations with dramatic therapeutical implications. Up to now, in contrast to Asian populations only limited data on the prevalence of those mutations are available from patients with Caucasian and especially European ethnicity. METHODS: In this multicentre study, 1201 unselected NSCLC patients from Southern Germany were tested in the daily clinical routine for EGFR mutation status. RESULTS: Activating EGFR mutations were found in 9.8% of all tumours. Mutations in exons 18, 19 and 21 accounted for 4.2%, 61.9% and 33.1% of all mutations, respectively. Non-smokers had a significantly higher rate of EGFR mutations than smokers or ex-smokers (24.4% vs 4.2%; P<0.001). Non-lepidic-non-mucinous adenocarcinomas (G2) accounted for 45.5% of all activating EGFR mutations and 3.5% of all squamous cell carcinomas were tested positive. Thyroid transcription factor 1 protein expression was significantly associated with EGFR mutational status. CONCLUSION: These comprehensive data from clinical routine in Germany add to the knowledge of clinical and histopathological factors associated with EGFR mutational status in NSCLC.

[Lymphocytic esophagitis: an entity to be excluded in chronic inflammatory diseases of the esophagus]. / Lymphozytäre Ösophagitis: Eine Ausschlussdiagnose in der Diagnostik chronischer Ösophagitiden.

Lymphocytic esophagitis is a rare, ill-defined inflammatory disease of the esophagus and is characterized by an increased number of intraepithelial lymphocytes. Up to now no distinct clinical symptom or endoscopic finding could be linked to histopathological changes. Hence lymphocytic esophagitis remains a diagnosis by exclusion after ruling out other possible causes of esophageal intraepithelial lymphocytosis.

[Pathogenesis, classification and diagnosis of necrotizing soft tissue infections]. / Pathogenese, Klassifikation und Diagnose der nekrotisierenden Weichteilinfektionen.

Necrotizing soft tissue infections are caused by a variety of pathogens and may affect different types of soft tissue. Even today mortality and lethality are very high. The primary symptoms of necrotizing soft tissue infections are local pain out of proportion, swelling, erythema and crepitation in cases of subcutaneous gas. A systemic inflammatory response syndrome (SIRS) is often associated. During the last decades early recognition and initiation of an adequate therapy were able to reduce lethality to an average of 20%. The physical examination remains the diagnostic gold standard and may be supported by typical findings of imaging technologies, e.g. subcutaneous gas on x-rays and laboratory tests. After diagnosis an adequate antibiotic and surgical therapy should be performed immediately.

Two malignant tumours in the anterior mediastinum positive for CD5.

To our knowledge, the simultaneous involvement of the anterior mediastinum by a thymic carcinoma and a B-cell chronic lymphocytic leukaemia has not been reported previously. The authors describe the case of a 62-year-old man, suffering from severe bronchitis. Chest x-ray and CT scan showed a mediastinal tumour, resected short-time after diagnosis. First, standard based histological examination revealed a thymic carcinoma admixed by a dense lymphatic infiltrate. Additional immunohistochemical staining for CD5-labelled epithelial thymic carcinoma cells as well as neoplastic B cells and led in combination with blood tests to confirm the diagnosis of the composite occurrence of a thymic carcinoma and a B-cell chronic lymphocytic leukaemia.

An institutional study on thymomas and thymic carcinomas: experience in 77 patients.

BACKGROUND: Thymomas and thymic carcinomas are rare tumors of the anterior mediastinum. A WHO classification was introduced in 1999, which has been updated in 2004. Meanwhile, several retrospective studies have been carried out which have shown the prognostic significance of this classification together with Masaoka's staging system and the extent of surgery. PATIENTS AND METHODS: Between 1983 and 2000, 77 patients (37 male, 40 female) underwent resection of thymomas and thymic carcinomas in our institution. Complete resection was achieved in 57 patients. The median follow-up was 72.6 months. RESULTS: The overall 5-year survival rate was 71.4 %. The factors "histology" and "extent of resection" had the most important impact on survival. However, even among the patients with complete resection, 12 of them suffered a relapse. Among this patient group, the most important factors for disease-free survival were "tumor stage" and "histology". Patients with an incomplete resection had a 5-year survival rate of only 29 % in spite of adjuvant radiation and/or chemotherapy. Due to the high rate of relapse, the poor survival rate found in incompletely resected patients as well as the failure of classical chemotherapy regimens, especially in type B2 and type B3 thymomas and thymic carcinomas, the search for new chemotherapeutic schemes is mandatory. CONCLUSION: Our study shows that there are still encouraging therapeutic options for thymomas and thymic carinomas. Type B2, type B3 thymomas and thymic carcinomas have worse outcomes in spite of adjuvant chemo- and radiotherapies. Especially in patients with incomplete surgical resection the outcome remains poor.

The location of KIT and PDGFRA gene mutations in gastrointestinal stromal tumours is site and phenotype associated.

AIMS: To assess the relation between KIT and PDGFRA mutations and the site of origin, histological phenotype, and pathomorphologically determined risk assessment in gastrointestinal stromal tumours (GISTs). METHODS: A series of 83 clinicopathologically characterised GISTs from 79 patients was analysed for KIT and PDGFRA mutations by polymerase chain reaction amplification, single strand conformation polymorphism analysis, and direct DNA sequencing. RESULTS: KIT or PDGFRA mutations were found in 57 and 11 GISTs, respectively. Most KIT mutations involved exon 11 (46 cases), followed by exon 9 (10 cases). The PDGFRA mutations mostly affected exon 18 (eight cases), followed by exon 12 (three cases). There was a significant association between KIT exon 9 mutations and an intestinal origin of GISTs, and between PDGFRA mutations and gastric origin of the tumours. In addition, the presence of PDGFRA mutations was significantly associated with epithelioid/mixed histology, as was the absence of identified receptor tyrosine kinase mutations. Vice versa, KIT exon 11 mutations were almost exclusively found in spindle cell GISTs. Furthermore, the presence of any KIT and PDGFRA mutations and the presence of KIT mutations alone were significantly associated with high risk/malignant GISTs. CONCLUSIONS: The location of KIT and PDGFRA mutations in GISTs is associated with the site of origin and histological phenotype. Genotyping of GISTs may be a helpful additional parameter in determining the biological profile of these tumours.

Mutational activation of the RAS-RAF-MAPK and the Wnt pathway in small intestinal adenocarcinomas.

BACKGROUND: Adenocarcinomas of the small and the large intestine share risk factors and morphological features but both tumor types seem to follow different genetic pathways. The aim of this study on small intestinal carcinomas was to analyze alternative mechanisms of activation of pathways that are typically affected in colorectal cancer. METHODS: Twenty-one sporadic carcinomas were investigated for mutations in KRAS, BRAF, the beta-catenin gene CTNNB1, and the mutational cluster region of APC. Immunohistochemical analysis was performed with a monoclonal antibody for beta-catenin, the transcriptionally active downstream component of wnt signaling. RESULTS: Oncogene mutations were found in 13 (62%) small intestinal adenocarcinomas. Twelve tumors displayed a KRAS mutation, and a novel BRAF mutation at codon 603/604 was seen in one carcinoma without KRAS mutation. One tumor harbored a CTNNB1 mutation consisting of an insertion of 247 nucleotides deriving from chromosome 9. APC mutations were identified in 2 tumors. Immunohistochemistry demonstrated nuclear accumulation of beta-catenin in 5 carcinomas. These carcinomas included the tumor with a CTNNB1 mutation but not those with APC mutations. CONCLUSIONS: Our data show frequent activation of the RAS-RAF-MAPK pathway through mutations of either KRAS or, infrequently, BRAF. Activation of the wnt pathway through accumulation of beta-catenin may have a role in a subset of small intestinal adenocarcinomas but in contrast to colorectal carcinoma, accumulation of beta-catenin is generally not caused by inactivating APC or activating CTNNB1 mutations.

Cystic lymphangioma of the small-bowel mesentery: case report and a review of the literature.

Cystic lymphangioma of the small-bowel mesentery is a rare manifestation of an intraabdominal tumor in elderly patients. We present a case of a small-bowel mesentery lymphangioma, causing fever and chills and present clinical and pathologic features. Furthermore, etiology and differential diagnosis of this tumor are discussed.

Beta-catenin accumulation and mutation of the CTNNB1 gene in hepatoblastoma.

Hepatoblastoma is a rare malignant tumor of the liver that occurs in children at an average age of 2 to 3 years. Epidemiologic studies have shown an increased frequency of this tumor type in families affected by adenomatous polyposis coli. In addition to the epidemiologic data, molecular genetic studies suggest that inactivation of the APC tumor suppressor may be involved in hepatoblastoma tumorigenesis. A major function of APC is the downregulation of beta-catenin, a transcription-activating protein with oncogenic potential. In an ongoing immunohistochemical study of beta-catenin expression in sporadic cases of tumor types that are associated with adenomatous polyposis coli, we observed increased beta-catenin levels in the cytoplasm and in the nuclei of three investigated hepatoblastomas. Sequencing of exon 3 of the beta-catenin gene (CTNNB1) revealed an activating mutation in one of the tumor samples. Our data indicate for the first time that beta-catenin accumulation may play a role in the development of hepatoblastoma and that activating mutations of the beta-catenin gene may substitute biallelic APC inactivation in this tumor type. Genes Chromosomes Cancer 25:399-402, 1999.

Comparison of losses of heterozygosity and replication errors in primary colorectal carcinomas and corresponding liver metastases.

In order to investigate genetic alterations specific to liver metastases of colorectal carcinomas, losses of heterozygosity and replication errors have been compared in 15 cases of primary colorectal carcinoma and in the corresponding metastatic liver tumours. Fifteen microsatellite markers located on 13 different chromosomal arms were used in the study. The LOH patterns of the primary and the metastatic tumours were identical in eight cases and showed differences in seven cases. Areas of deletion predominantly or completely common to the colorectal and the metastatic tumour were detected on chromosomes 5q, 8p, 17p, 18q, and 22q. Preferential loss in metastatic tumours was observed on chromosomal arm 3p. Replication errors were found in four primary tumours and in three of the corresponding secondaries. A replication error phenotype specific to a metastasis was not observed.

Influence of age, comorbidity, type of operation and other variables on lethality and duration of post-operative hospital stay in patients with peptic ulcer. An analysis of 303 surgically treated patients.

Three hundred and three consecutive patients operated on for peptic ulcer for the first time between 1 January 1984 and 31 December 1993 were evaluated in this retrospective study. Eleven variables (Period when operation took place, gender, smoking behaviour, history of former ulcers, ulcerogenic drug intake, ulcer location, epigastric pain, number of blood units substituted, patient's age, type of operation, comorbidity) were investigated regarding their influence on peri- and post-operative mortality and on the length of hospital stay after operation. We found that a high comorbidity score (> 2) and the indication "emergency operation" (vs "elective operation") had an adverse impact on survival. The importance of age was marginal. The duration of post-operative hospital stay in survivors was negatively influenced by age higher than 60 years, more than two red cell units substituted and a high comorbidity score according to Charlson.