[Transcription factors in tumor diagnosis]. / Transkriptionsfaktoren in der Tumordiagnostik.

Transcription factors are a heterogeneous group of DNA-binding proteins that regulate the transcription of distinct genes. Due to their cell-type specificity and cell lineage restriction, numerous transcription factors have been established in recent years as excellent, sensitive, and specific immunohistochemical tumor markers. As compared to other cytoplasmic and membranous differentiation markers, the nuclear immunolocalization of transcription factors is often more stably preserved. Therefore, cell lineage-specific transcription factors can be detected even in poorly differentiated metastatic tumors. However, for their reliable diagnostic use, detailed knowledge is required on their expression profiles, which are often more complex than initially assumed.CDX2 is a sensitive marker for colorectal adenocarcinomas but is also expressed in upper abdominal adenocarcinomas, mucinous carcinomas of lung and ovary, and midgut neuroendocrine tumors. A higher degree of specificity for colorectal origin is provided by SATB2. TTF-1 is a valuable marker particularly for pulmonary adenocarcinomas, but may also be focally expressed "aberrantly" in abdominal and gynecological adenocarcinomas. GATA3 is found in breast and urothelial carcinomas but also in squamous cell carcinomas. PAX8 is a highly sensitive marker of all subtypes of gynecological adenocarcinomas, renal cell carcinomas, and thyroid carcinomas. Further transcription factors characterized by molecular biology have meanwhile become diagnostically relevant, the number of which is increasing.Principally, for the diagnostic use of transcription factors as immunohistochemical tumor markers, clinical and radiological data as well as conventional histopathology should always be carefully considered and if necessary they should be applied in the context of a marker panel.

The Ebola epidemic and public health response.

INTRODUCTION: An unprecedented global effort has been required to tackle the Ebola outbreak in West Africa. In this paper, we describe the contribution of Public Health England (PHE) in West Africa and the UK. SOURCES OF DATA: Public Health England AREAS OF AGREEMENT: The epidemic has been a humanitarian crisis for the three worst affected countries. PHE contributions have included expertise in outbreak control and microbiology services in West Africa, and UK preparedness for an imported case. AREAS OF CONTROVERSY: National and international systems require change to enhance the response to the next international public health crisis. GROWING POINTS: Legacy planning following the epidemic will be crucial, supporting the recovery of the health and public health systems in West Africa and ensuring that the knowledge gained during this outbreak is put to best use. AREAS TIMELY FOR DEVELOPING RESEARCH: Ongoing PHE-associated research includes efforts to understand the pathogenicity of Ebola virus disease, improve diagnostic capability, explore therapeutic options and develop new vaccines.

Well-differentiated neuroendocrine neoplasia: relapse-free survival and predictors of recurrence after curative intended resections.

BACKGROUND: Resection with curative intention is the cornerstone of treatment in patients with neuroendocrine tumors. A proportion of patients will relapse after R0 resection, but the factors predictive of recurrence are not well understood. METHODS: A database established 1998 at the University Hospital Marburg was queried for all patients with documented R0 resection. Recurrence-free survival and overall survival were estimated using the Kaplan-Meier method. Uni- and multivariate analyses were performed. RESULTS: 180 patients with a median age of 52 years entered the analysis. We observed 77 recurrences after a median time of 2.9 years. 24% of the recurrences occurred later than 5 years after operation. Median recurrence-free survival of the whole cohort was 101 months. In univariate analysis grade by Ki-67, stage, high lymph node ratio and microangioinvasion were significant predictors of recurrence. On multivariate analysis these parameters were confirmed as independent prognostic parameters with stage and microangioinvasion being the most important predictors. CONCLUSIONS: After R0 resection of neuroendocrine tumors, postoperative surveillance should be extended to at least 10 years. Patients with distant metastases and microangioinvasion are at high risk of recurrence. Clinical trials of adjuvant treatment protocols are indicated in these patients.

The feed-forward loop between YB-1 and MYC is essential for multiple myeloma cell survival.

Y-box binding protein 1 (YB-1) functions as a translational regulator and has been suggested to elevate MYC mRNA translation via an internal ribosome entry segment (IRES) point mutation in multiple myeloma (MM). We show that YB-1-mediated translation of MYC mRNA occurs independently of the reported IRES mutation, as 87 MM patients (n=88) and all tested human MM cell lines (HMCLs) were negative for the mutation. We show for the first time that positive MYC staining predicts YB-1 co-expression in malignant plasma cells and YB-1/MYC co-expression increases from 30% in medullary to 70% in extramedullary MM. YB-1 knockdown in HMCLs reduced both MYC protein levels and MYC mRNA in the polysomal fraction, providing a mechanism by which YB-1 controls MYC translation. MYC transcription of YB-1 is demonstrated in HMCLs as MYC knockdown resulted in reduced YB-1 protein and mRNA levels. Furthermore, MYC activation in non-malignant mouse embryonic fibroblasts (MEFs) increased YB-1 mRNA, clearly indicating that MYC drives YB-1 transcription. Importantly, perturbation of the MYC/YB-1 oncogenic circuit leads to apoptosis in HMCLs. Here, we demonstrate that these two proteins co-regulate each other via combined transcriptional/translational activity establishing their pivotal role in MM cell survival. We therefore suggest that targeting the YB-1/mRNA interaction provides a new strategy for MM drug development.

Successful selective internal radiotherapy (SIRT) in a patient with a malignant solid pseudopapillary pancreatic neoplasm (SPN).

Solid pseudopapillary neoplasms of the pancreas (SPNs, Gruber-Frantz-Tumor) are a rare entity representing 1-5% of all exocrine pancreatic tumors. The pseudocystic lesions preferentially affect young females <30 years, are mostly benign (∼90%) and normally present with unspecific symptoms. We describe the case of a 16-years-old Asian woman that was initially diagnosed with an SPN in the pancreatic head with mesenterial and hepatic metastases. After diagnosis, an extensive tumor resection was performed including pyloric-preserving pancreatic head resection followed by sequential resection of all hepatic metastases. After the patient was diagnosed with a hepatic recurrence and high intrahepatic tumor load, we chose a multimodal procedure and performed a selective internal radiotherapy (SIRT). Four years after SIRT and 10 years after initial diagnosis of metastatic SPN, the patient is in a good condition without any evidence for hepatic recurrence. This case represents a rare clinical course of a malignant and invasive SPN with an exceptionally long survival despite of high initial tumor burden. The selective internal radiotherapy is a suitable approach for inducing long-term remissions of the strongly vascularized liver metastases.

[In situ hybridization in clinical pathology. Significance of polysomy 17 for HER2 determination and genetic tumor heterogeneity in breast cancer]. / In-situ-Hybridisierung in der klinischen Pathologie. Bedeutung der Polysomie 17 für die HER2-Bestimmung und genetische Tumorheterogenität im Mammakarzinom.

The introduction of total genome sequencing led to the confirmation that tumors show substantial genetic heterogeneity. This phenomenon, which describes the presence of different genetic cell clones within a tumor also complicates the diagnostics of HER2. This article gives a review of new knowledge on polysomy 17 and genetic tumor heterogeneity in connection with HER2 determination of breast cancer.

Differential diagnosis of pericardial effusion after stem cell transplantation in acute myeloic leukemia.

The pathology underlying a pericardial effusion in a 24-year-old patient, who had suffered from acute myeloic leukemia 5 years previously and undergone chemotherapy followed by whole body radiation prior to allogeneic stem cell transplantation, could be identified by the careful analysis of pericardial cytology and epicardial biopsy guided by flexible pericardioscopy. Molecular, histological, cytochemical and immunological examination of the effusion and the epicardial biopsy for a viral or bacterial infection despite known CMV reactivation, or an effusion induced by radiation or graft-versus-host reaction, could be ruled out as possible causes of pericardial tamponade. The infiltration of CD 117-positive cells in the biopsied cardiac tissue revealed recurrent acute myeloic leukemia now also affecting the heart and the pericardium. An intrapericardial instillation of 1000 mg triamcinolone acetate at day 1 and 50 mg/m(2) cisplatin at day 3 effectively prevented the recurrence of tamponade, but could not prevent a lethal outcome 3 weeks later.

[Unusual presentation of autoimmune pancreatitis type 1]. / Ungewöhnliche klinische Präsentation einer autoimmunen Pankreatitis Typ 1.

HISTORY AND ADMISSION FINDINGS: A-51-year-old man presented with increasingly severe upper abdominal pain, in reduced general state and mild weight loss. Ten years before the patient had undergone a Kausch-Whipple procedure (pancreaticoduodenectomy) for an inflammatory mass in the pancreas, at that time histologically identified as an inflammatory tumour with chronic pancreatitis. Since then he has had repeated episodes of stenosis of the biliary-digestive anastomosis, associated with acute cholangitis. Laboratory findings on admission revealed liver function tests that were moderately (AST, ALT) or markedly elevated (GGT and AP). INVESTIGATIONS: Abdominal ultrasound revealed cuffing of the portal vein and its side-branches with low echogenicity. Magnetic resonance imaging showed periportal edema with irregular bile ducts. Initially the histological examination strongly suggested a peripheral malignant T-cell lymphoma. However, subsequent examination revealed a chronic IgG4-associated, lymphoplasmatic sclerosing inflammation of the biliary tract. TREATMENT AND COURSE: Histological re-examination of the 10-year-old pancreatic resection specimens also showed severe lymphoplasmatic infiltrates suggesting a pancreatic manifestation of an IgG4-associated systemic disease (ISD), known nowadays as an type 1 autoimmune pancreatitis (AIP). Based on the initial diagnosis of an invasive periphere malignant T-cell lymphoma of the liver a pre-phase treatment with vincristine, prednisolone followed by one cycle of CHOEP were administered. This resulted in complete remission of the patient's symptoms. Once the true diagnosis had been revised this treatment was immediately stopped. Since the patient remained symptom-free, the initially elevated laboratory parameters returned to normal and a remission of low echogenicity cuffing of the portal vein was observed and no further steroid treatment was administered. Ursodesocycholic acid was then given as the only drug, to prevent any further episodes of cholangitis. CONCLUSIONS: Autoimmune pancreatitis continues to be frequently unrecognized in clinical practice. But because it responds well to corticosteroids, this clinical entity should be considered in the differential diagnosis of unclear inflammatory changes and strictures of the pancreatic and biliary tracts or even, if necessary, looked for retrospectively in resected pancreas specimens.

CD44: survival and metastasis in chondrosarcoma.

OBJECTIVE: Recent studies have shown abnormal expression of CD44s and some of its isoforms in many human malignancies, but little is known about the presence of CD44 in chondrosarcoma. In this study the expression of CD44s and two variant isoforms was evaluated. It was assumed that abnormalities in these receptor proteins may be associated with clinical outcome of the patients. METHOD: Thirty paraffin-embedded chondrosarcoma samples were immunostained with monoclonal antibodies for CD44s, CD44v5 and CD44v6. Two independent examiners who were unaware of the clinical status of the patients evaluated the immunohistochemical results. The percentage of CD44-positive cells was scored semiquantitatively. A rate of higher than 10% was considered as overexpression. RESULTS: Among the 30 patients (median age 50 years) there were 22 conventional chondrosarcomas, two dedifferentiated chondrosarcomas, two extraskeletal chondrosarcomas, and one periostal, mesenchymal, clear cell and myxoid chondrosarcoma each. In the immunochemistry staining overexpression (>10% of cells) of CD44s was shown in 56.7% (17 of 30), of CD44v5 in 43.3% (13 of 30) and of CD44v6 in 6.7% (two of 30) of the tumors. Four grade III chondrosarcomas (80%) and 10 (71.4%) grade II chondrosarcomas showed overexpression for CD44s, whereas CD44s was overexpressed in only three (27.3%) grade I chondrosarcomas. Cox regression suggests overexpression of CD44s to be an additional prognostic marker for chondroid bone tumors independent of grading and other covariates. CONCLUSIONS: Overexpression of CD44s correlated significantly with metastatic potential and with poorer survival in patients with chondrosarcoma. CD44s might be an independent additional marker, but small sample size remains to be considered.

Differentiation between thyroidal and ectopic calcitonin secretion in patients with coincidental thyroid nodules and pancreatic tumors - a report of two cases.

Although elevated blood levels of calcitonin are considered highly indicative for the presence of medullary thyroid carcinomas, they may be observed in patients with chronic kidney disease or in consequence of ectopic calcitonin production. We report two patients who presented with excessively elevated calcitonin levels. Diagnostic work-up revealed a single thyroid nodule and a pancreatic tumor with ectopic calcitonin secretion in both of them. On the basis of these case reports, the diagnostic work flow and management in case of clearly elevated calcitonin levels are described and discussed.

[The initial CUP situation and CUP syndrome: pathological diagnostics]. / Initiale CUP-Situation und CUP-Syndrom: Pathologische Diagnostik.

"Cancer of unknown primary (site)" (CUP) represents a frequent and often difficult task for diagnostic histopathology. In the initial CUP situation, immunohistochemistry, which is relatively cost-efficient and non-burdensome for the patient, contributes substantially to the targeted search for and identification of the primary tumor. It may be performed in a two-step algorithm (keratins as the first step, group and selective markers as the second step). However, in true CUP syndrome--a heterogeneous disease whose etiology and pathogenesis is still poorly understood--the primary tumor is rarely identified, and the immunohistochemical marker profile is often anomalous. Nevertheless, immunohistochemistry remains the most important special method, aiming at the phenotypical classification and particularly the identification of certain favorable therapy-responsive subsets. Novel methods for subtyping of CUP based on the analysis of gene expression profiles need to be further evaluated before their possible diagnostic application. Future basic and clinical research is required to unravel the still enigmatic tumor biology of the CUP syndrome and to improve the hitherto very unfavorable prognosis by developing new efficient therapy regimens.

Absolute metabolite concentrations calibrated using the total water signal in brain (1)H MRS.

Magnetic resonance spectroscopy (MRS) has been coupled with a multi-echo imaging sequence to determine the relaxation corrected signal areas of the metabolites and the tissue water. Stimulated echo acquisition mode (STEAM) spectra (TE/TM/TR 30/13.7/5000 ms) acquired from gray and white matter voxels in 43 healthy volunteers were fit using LCModel. Corresponding water signals, measured using a multi-echo T(2) imaging sequence, were fit with a Non-Negative Least Squares algorithm. Using this approach the water area could be T(1) and T(2) corrected for all three water compartments: cerebrospinal fluid (CSF), intra- and extra-cellular water, and myelin water. The image-based water measurement is an improvement over spectroscopy methods because it can be more sensitive to water changes in diseased tissue. Metabolite areas were also corrected for relaxation losses. In occipital gray matter, the concentrations of Cho, Cr, and N-acetyl aspartate (NAA) were 1.27 (0.06), 8.9 (0.3), and 9.3 (0.3) mmol/L tissue, respectively and in parietal white matter they were 1.90 (0.05), 7.9 (0.2), and 9.8 (0.2) mmol/L tissue. The Cho and Cr concentrations were different in occipital gray compared to parietal white matter (p < 0.0001 and <0.005, respectively).

[Endovascular treatment of a thoraco-abdominal aortic aneurysm in case of a specific aortitis]. / Endovaskuläre Therapie eines Aneurysma der thorakoabdominellen Aorta bei einer spezifischen Aortitis.

Successful endovascular repair of an aortic aneurysm of the descending thoracic aorta, laying directly cranial of the celiac artery, caused by a spondylodiscitis of the thoracoabdominal spine. While vascular surgeons refused the open resection of the infected aneurysm, endovascular treatment with a stent-graft was performed. Respecting the celiac artery by catheterisation, endovascular treatment was managed without occluding the A. Adamkiewicz. In case of an unknown infection peri- and postoperative treatment was performed of a prolonged antibiotic and corticosteroid therapy. In a follow-up of three months period, there was a complete regression of the inflammatory aneurysm and an improvement of the spondylodiscitis.

Meta-analysis of the prognostic significance of perinodal spread in head and neck squamous cell carcinomas (HNSCC) patients.

To assess the risk factor of capsular rupture for individual prognosis and potential therapeutic decision making, the present meta-analysis elaborated the prognostic significance of perinodal spread in a large group of patients suffering from head and neck squamous cell carcinomas (HNSCC). A review of the published literature was conducted, and fixed and random effects models were applied for estimation of the summarised odds ratio and 95% confidence intervals, including a test for homogeneity of the odds ratios. Study methodology allowed the enrollment of only nine studies of 115 published papers. Excluded studies lacked regarding primary tumour location, number and location of lymph node metastases, values on five-year survival, or adequate follow-up data. A summarised odds ratio of 2.7 leads to the conclusion that perinodal spread negatively impacts the five-year survival. The lower confidence limit of more than 2 also supports the concept that perinodal spread significantly reduces (doubled risk) the five-year-survival. These results support the conclusion that perinodal spread is a significant adverse risk factor for survival in patients with HNSCC.

[The Würzburg polytrauma algorithm. Concept and first results of a sliding-gantry-based computer tomography diagnostic system]. / Der Würzburger Schockraumalgorithmus. Gesamtkonzept und erste Ergebnisse einer "sliding-gantry-basierten" Computertomographiediagnostik.

BACKGROUND: The purpose of this study was to show the practicability of a new algorithm in the management of polytraumatized patients based on Advanced Trauma Live Support (ATLS) and using mobile whole body multislice CT (MMDCT) as the primary imaging system. PATIENTS AND METHODS: A series of 120 trauma patients referred to the Würzburg University Hospital Trauma Emergency Room were categorized into suspected polytrauma and suspected non-polytrauma groups. The polytraumatized patients were investigated using the Würzburg polytrauma-algorithm including whole body multislice CT with a 16-row-scanner. The algorithm is described. The time for the diagnostic procedure was measured and compared with data from the Trauma Registry of the German Society of Trauma Surgery. RESULTS: From 120 patients 78 (66%) underwent whole body CT. The diagnostic procedure was quick with significant advantages especially for cranial and trunk diagnostics. CONCLUSION: The Würzburg polytrauma algorithm worked well. There was excellent cooperation within the interdisciplinary leading team consisting of anaesthesiologists, surgeons, and radiologists. The principles of ATLS could be respected. Mobile whole body multislice CT was an effective tool in the diagnostic evaluation of polytrauma patients.

[Therapeutically options for primary and secondary hepatic malignancies]. / Aktuelle Therapieoptionen bei primären und sekundären Lebermalignomen.

Therapeutically options for the treatment of patients with primary hepatic malignancies have grown in recent years. Apart from liver resection and organ transplantation, representing the only curative strategies for primary hepatic malignancies, a variety of palliative procedures have been introduced. Some of these result in extended patient survival. However, the combination of a malignant disease and an irreversible organ damage remains to be the main problem in the majority of patients with primary liver Cancer. Liver resection is the only curative therapy for patients with isolated hepatic colorectal metastases and can be performed with low morbidity and mortality if a correct indication and a standardized procedure is applied. In case of intrahepatic tumour recurrence re-resection is indicated as long as extrahepatic metastases can be excluded. In patients with primary unresectable metastases a downstaging-chemotherapy, two-stage hepatectomy or portal vene embolization might result in a secondary respectability. Locally ablative procedures are being evaluated at present, in the palliative Situation survival can be prolonged. In the future multimodal therapeutic approaches will dominate the treatment of primary and secondary hepatic malignancies.

Successful treatment of solid-pseudopapillary tumor of the pancreas with multiple liver metastases.

The solid-pseudopapillary tumor (SPT) is a very rare pancreatic neoplasm that predominantly affects young females. About 450 cases have been described in the world literature and approximately 20% of the reported patients were children. The occurrence of SPT with distant metastases in children is extremely rare with only two previously reported cases. We now report a 16-year-old Asian girl with a large SPT and synchronous multiple liver metastases who was successfully treated in a 2-step strategy, including initial pylorus-preserving partial duodenopancreatectomy, right hemicolectomy, resection and allografting of the portal vein and secondary resection of 12 liver metastases. The patient is disease free after a follow-up of 18 months after resection of the primary tumor, suggesting that an aggressive surgical treatment might also be justified for metastasized SPT.

[CUP syndrome: are there advances?]. / CUP-Syndrom: Gibt es Fortschritte?

Metastatic cancer of unknown primary site (CUP syndrome) comprises 2-5% of all solid malignant tumors. One should distinguish between initial CUP (primary tumor later detected) and the true CUP syndrome (primary tumor remains unknown for a patient's lifetime despite thorough diagnostic work-up). For initial CUP, the most important auxiliary diagnostic method is immunohistochemistry, which should be applied in a two-step algorithmic fashion. Firstly, a small marker panel (including certain cytokeratins) yields a preliminary categorization of the tumor. Secondly, selective, organ-specific markers (including recently established markers such as TTF-1 and uroplakin) and further tumor group markers may further subclassify or even identify the primary tumor. Although they are a heterogeneous group, true CUP tumors share some unique biological features such as an early metastatic phenotype and unusual metastasis patterns, and they mostly have a very poor prognosis. Even autopsy reveals the primary site in only 55-80% of cases, most commonly in the lung and pancreas. True CUP tumors, predominantly adenocarcinomas and poorly differentiated carcinomas, may exhibit unusual immunohistochemical phenotypes. Nevertheless, careful histologic and immunohistochemical examination are essential not only for determining the actual tumor immunophenotype but in particular for identifying therapy-responsive subgroups such as neck lymph node CUP, axillary lymph node CUP of females, neuroendocrine CUP, and germ cell tumor CUP of males. For CUP syndrome, future interdisciplinary research efforts are needed, such as gene expression profiling using microarrays. It is thus to be hoped that pathology will contribute to the elucidation of the largely still enigmatic pathogenesis of the CUP syndrome, to improve its diagnosis and classification and, finally, to aid in the development of more specific therapeutic regimens.