Expression of Hedgehog signalling molecules in microcystic adnexal carcinoma.

BACKGROUND: Microcystic adnexal carcinoma (MAC) is a rare skin neoplasm that has not been characterized on a molecular basis. AIM: To assess expression profiles of Hedgehog (HH) signalling molecules in MAC and control tumours. METHODS: Immunohistochemistry was performed for Sonic Hedgehog (SHH), Indian Hedgehog (IHH), Patched 1 (PTCH1) and Smoothened (SMO) on patient MAC tissue (n = 26) and control tumour tissue, including syringoma (SyG; n = 11), trichoepithelioma (TE; n = 11) and basal cell carcinoma (BCC; n = 12) tissues. RESULTS: Patched 1 and SMO immunoreactivity was significantly higher in BCC than in SyG, TE or MAC (P < 0.001 and P < 0.03, respectively). The highest IHH expression was observed in BCC and TE compared with SyG and MAC (P < 0.04). Notably, the highest SHH protein expression was observed in SyG compared with MAC, TE and even BCC (P < 0.001). In patients with MAC, SMO immunoreactivity significantly (r = 0.51; P < 0.01) correlated with PTCH1 expression. Further correlation studies did not show significant associations between the HH expression markers assessed (P > 0.05). CONCLUSION: Our results indicate that alterations of the HH signalling are unlikely to play a major role in the pathogenesis of MAC, which is in contrast to the morphologically similar BCC and TE. Our observation provides additional information to the limited molecular pathology knowledge on this rare tumour.

Left-sided laterality of Merkel cell carcinoma in a German population: more than just sun exposure.

BACKGROUND: Lateral distribution of cancer has been observed previously. Most evident is this laterality in ultraviolet (UV)-induced skin cancer, based on an unequally distributed UV exposure. OBJECTIVES: The aim of this study was to explore whether patients from Germany also show asymmetrical lateral distribution of Merkel cell carcinoma (MCC). METHODS: In total, 115 patients with MCC were studied for laterality of the primary tumour. Correlation of clinical variables with lateral distribution of MCC was investigated as well. RESULTS: In 64/115 (55.7%) patients, primary tumours were present on the left side, in 37/115 (32.2%) on the right side, and in 14/115 (12.2%) in the midline (P < 0.0001). Excluding the latter localization occurrence of left-sided MCCs (64 of 101/63.4%) was significantly (P = 0.0072) more often observed (1.73-fold) when compared to right-sided tumours (37 of 101/36.6%). The excess of left-sided tumours was found on the head with a left-right ratio of 1.8, trunk of 8, arm of 1.2, and leg of 1.8. There was no significant association between laterality and gender, age, MCPyV status, and anatomic localization of primary tumours including the occurrence in sun-exposed sites. CONCLUSIONS: Occurrence of left-sided MCCs was significantly more often observed when compared to right-sided tumours. Laterality was not associated with tumour presentation at chronically ultraviolet-exposed sites. Hence, the reason for laterality in MCC remains obscure, but likely goes beyond UV exposure.

Prognostic relevance of high atonal homolog-1 expression in Merkel cell carcinoma.

BACKGROUND: It has recently been reported that atonal homolog 1 (ATOH1) gene is down-regulated in Merkel cell carcinoma (MCC) and thus may represent a tumor suppressor gene. OBJECTIVES: We aimed to test for ATOH1 gene mutations and expression levels in MCC tissues and cell lines. METHODS: Genomic DNA isolation and amplification via PCR was successfully performed in 33 MCCs on formalin-fixed paraffin-embedded tissue and three MCC cell lines, followed by Sanger sequencing of the whole ATOH1 gene to detect genomic aberrations. ATOH1 mRNA levels were determined by RT-PCR. Immunohistochemistry of ATOH1 was performed to quantify protein expression in tumor samples and cell lines. RESULTS: Neither in any of the 33 MCC tissue samples nor in the three cell lines ATOH1 mutations were present. ATOH1 was expressed in all lesions, albeit at different expression levels. Univariate analysis revealed that the total immunohistology score significantly correlated with the occurrence of tumor relapse (r = 0.57; P = 0.0008). This notion was confirmed in multivariate analysis suggesting that ATOH1 expression is a potential independent predictor for tumor relapse in MCC patients (P = 0.028). MCC-related death also correlated with ATOH1 expression (r = 0.4; P = 0.025); however, ATOH1 expression did not retain its predictive value in the regression model. CONCLUSIONS: In contrast to anecdotal reports ATOH1 expression is not lost by genetic alterations in MCC. However, protein expression of ATOH1 is increased in advanced MCC indicating that ATOH1 is involved in MCC progression.

[Basal cell carcinoma and rare form variants]. / Das Basalzellkarzinom und seine seltenen Formvarianten.

Basal cell carcinomas are the most common primary cutaneous malignant neoplasms. The diagnosis of basal cell carcinoma represents a common and routine task for pathologists and dermatopathologists. The aim of this review is the clinical and histopathological presentation of the most common subtypes of basal cell carcinoma. Furthermore, the rare variants of basal cell carcinoma and their differential diagnoses are also discussed.

Reproducibility of image-based analysis of cerebral aneurysm geometry and hemodynamics: an in-vitro study of magnetic resonance imaging, computed tomography, and three-dimensional rotational angiography.

BACKGROUND AND STUDY AIMS: Image-based computational fluid dynamics (CFD) provides a means for analysis of biofluid mechanical parameters of cerebral aneurysms. This may enable patient-specific rupture risk analysis and facilitate treatment decisions. Application of different imaging methods may, however, alter the geometrical basis of these studies. The present study compares geometry and hemodynamics of an aneurysm phantom model acquired by means of magnetic resonance imaging (MRI), computed tomography (CT), and rotational angiography (3DRA). MATERIALS AND METHODS: The phantom model of a basilaris artery aneurysm was fabricated based on data generated by CT angiography. This model underwent imaging by means of CT, MRI, and 3DRA. We compared the geometrical reconstructions using the original dataset with those obtained from CT, MRI, and 3DRA. Similarly, CFD analyses were performed using the four reconstructions (3DRA, MRI, CT, and original dataset). RESULTS: MRI and the 3DRA-based reconstructions yield mean reconstruction errors of 0.097 mm and 0.1 mm, which are by a factor of 2.5 better than the CT reconstruction. The maximal error for the aneurysm radius (7.11 mm) measurement was found in the 3DRA reconstruction and was 3.8% (0.28 mm). A comparison of calculated time-averaged wall shear stress (WSS) shows good correlations for the entire surface and, separately, for the surface of the aneurysmal sack. The maximal error of 8% of the mean WSS calculation of the whole surface was found for the CT reconstruction. The calculations of the aneurysmal sack mean WSS from the MRI reconstruction were estimated to have a maximal error of 7%. CONCLUSION: All three imaging techniques (CT, MRI, 3DRA) adequately reproduce aneurysm geometry and allow meaningful CFD analyses.

[Cutaneous malignant peripheral nerve sheath tumor in neurofibromatosis type 1]. / Kutaner maligner peripherer Nervenscheidentumor bei Neurofibromatose Typ 1.

Patients with neurofibromatosis have an increased risk of developing malignant tumors in comparison to the general population. We describe a woman who developed a malignant peripheral nerve sheath tumor in a pre-existing neurofibroma.

[Juvenile hyaline fibromatosis]. / Juvenile hyaline Fibromatose.

Juvenile hyaline fibromatosis is a rare autosomal recessive disease of the connective tissue. We present the case of a 6-year-old normal mental developed boy with confluent pearly papules behind the ears and in the paranasal folds, firm nodules of the scalp, the back and metaphalangs, and severe gingival hypertrophy.

[Extrafacial granuloma eosinophilicum]. / Extrafaziales Granuloma eosinophilicum.

Three patients with a rare extrafacial granuloma eosinophilicum are presented. Lesions were localized on the scalp, the upper back or the upper arm. Only one patient had a typical facial granuloma eosinophilicum at the same time. Diagnosis was established by histopathology. The histopathological findings vary with the age of the lesion. Early lesions are characterized by a vasculitis with many eosinophils separated by a Grenz zone from epidermis and follicular structures. With time the inflammation changes and hyalin fibrosis takes place.

[Dermatohistology laboratory]. / Dermatohistologisches Labor.

Dermatohistology plays an essential role in the diagnosis of cutaneous tumors and inflammatory skin diseases. In order to practice dermatohistology properly, one needs not only a well-equipped laboratory but also properly trained dermatohistologists and laboratory technicians. We discuss the establishment of a dermatohistology laboratory. The technical procedures involved in making slides, ranging from traditional H & E stains, through special stains, immunohistochemistry and molecular-biological techniques, are viewed. The importance of clinical-histologic correlation and the limitations of pure histologic diagnostics are demonstrated with illustrative cases.

Palmar atypical lipomatous tumour with spindle cell features (well-differentiated spindle cell liposarcoma): a rare neoplasm arising in an unusual anatomical location.

Lipomatous tumours, both benign and malignant, arising on the hands are uncommon. We present a rare atypical lipomatous tumour with spindle cell features (synonym: well-differentiated spindle cell liposarcoma) arising on the left palm of a 54-year-old male patient. The neoplasm presented as a long-standing, exophytic neoplasm measuring 9 x 9 cm. The well-circumscribed neoplasm was completely excised, and margins were tumour free. Histologically, the neoplasm showed features closely resembling spindle cell lipoma, being composed of mature adipocytic cells associated with bland, neuroid spindle cells staining positively for CD34. However, focally, atypia of adipocytic and stromal cells as well as scattered lipoblasts were noted, and immunohistochemical stainings showed focal overexpression of MDM 2 and CDK4. Aypical lipomatous tumour with spindle cell features may arise very rarely in palmar location and has to be distinguished from a number of benign and malignant mesenchymal neoplasms.

Prospective evaluation of the peptide-bound collagen type I cross-links N-telopeptide and C-telopeptide in predicting bone metastases status.

PURPOSE: The objective assessment of bone metastases is currently based on serial changes in skeletal survey. We performed a prospective study to determine whether a correlation exists between the biochemical markers of bone turnover and x-ray evaluation of bone metastases in patients with or without bisphosphonate therapy, and whether bone markers are influenced by extraskeletal disease. PATIENTS AND METHODS: Patients with either bone or extraskeletal metastases were consecutively enrolled and World Health Organization response criteria were applied for both bone and extraosseous disease every 3 to 4 months. Serum levels of bone-specific alkaline phosphatase (B-AP) and C-telopeptide (ICTP) and urine levels of N-telopeptide (NTX) were measured monthly. The data were analyzed by generalized estimation equation regression. RESULTS: We studied 97 patients with bone metastases (52 also with extraskeletal metastases) and 26 with extraosseous disease only. Median time on study was 153 days, and 281 objective evaluations (171 in bone) were performed. With bisphosphonates (49 patients receiving pamidronate and three receiving clodronate), percent change from levels without therapy was 47% for NTX (P <.001) and 69% for B-AP (P =.008). With disease progression in bone, percent change from mean levels during stable disease was 152% for NTX (P <.001) and 144% for ICTP (P <.001) regardless of bisphosphonate therapy. NTX had the highest positive predictive value (71%) for the diagnosis of bone metastases progression. Extraskeletal disease had no significant effect on bone markers. CONCLUSION: Urinary NTX may be a valuable bone marker to assess the antiresorptive effect of bisphosphonate therapy and to evaluate the progression of bone metastases.

Case report: rapid and complete control of idiopathic hypereosinophilia with imatinib mesylate.

In this case report, we report what we believe to be the first case of imatinib mesylate or STI-571 (Novartis) use for treatment of idiopathic hypereosinophilia syndrome (HES). HES is often a fatal illness, damaging the heart, nervous system, lungs, liver, and kidneys. It is often treated with interferon-alpha. In this patient, it was combined with hydroxyurea, and we believe it saved his life. However, he experienced many common side effects, such as a profound intractable headache, severe fatigue, and concentration difficulties. After years on hydroxyurea and interferon-alpha, the severity of these side effects motivated us to try a trial of imatinib mesylate. Its use was followed by an abrupt remission of HES in a few weeks, with no significant side effects.

Inhibition of tumor growth by plasminogen-related protein-B.

BACKGROUND: Various fragments of the fibrinolytic protein plasminogen can act as antiangiogenic factors and inhibit the growth of primary and metastatic tumors in mice. Plasminogen-related gene-B encodes a putative 9 kDa protein virtually identical to the plasminogen N-terminal activation peptide, a 77-amino acid motif that is liberated from the parent plasminogen molecule during conversion to the serine proteinase plasmin. Previous data have documented enhanced transcription of plasminogen-related gene-B in neoplastic tissues. MATERIALS AND METHODS: We have tested the effects of recombinant versions of plasminogen-related protein-B and the plasminogen N-terminal activation peptide on the growth of tumors in mice, employing murine tumor cell lines implanted subcutaneously. RESULTS: The recombinant plasminogen-related protein-B significantly inhibited the growth of primary tumors in mice, while recombinant plasminogen N-terminal activation peptide elicited only a slight inhibition of tumor growth. CONCLUSION: These data suggest that plasminogen-related protein-B may have utility as a novel cancer therapeutic.

Plant adenosine 5'-phosphosulfate reductase is a novel iron-sulfur protein.

Adenosine 5'-phosphosulfate reductase (APR) catalyzes the two-electron reduction of adenosine 5'-phosphosulfate to sulfite and AMP, which represents the key step of sulfate assimilation in higher plants. Recombinant APRs from both Lemna minor and Arabidopsis thaliana were overexpressed in Escherichia coli and isolated as yellow-brown proteins. UV-visible spectra of these recombinant proteins indicated the presence of iron-sulfur centers, whereas flavin was absent. This result was confirmed by quantitative analysis of iron and acid-labile sulfide, suggesting a [4Fe-4S] cluster as the cofactor. EPR spectroscopy of freshly purified enzyme showed, however, only a minor signal at g = 2.01. Therefore, Mössbauer spectra of (57)Fe-enriched APR were obtained at 4.2 K in magnetic fields of up to 7 tesla, which were assigned to a diamagnetic [4Fe-4S](2+) cluster. This cluster was unusual because only three of the iron sites exhibited the same Mössbauer parameters. The fourth iron site gave, because of the bistability of the fit, a significantly smaller isomer shift or larger quadrupole splitting than the other three sites. Thus, plant assimilatory APR represents a novel type of adenosine 5'-phosphosulfate reductase with a [4Fe-4S] center as the sole cofactor, which is clearly different from the dissimilatory adenosine 5'-phosphosulfate reductases found in sulfate reducing bacteria.

A lysine rich C-terminal tail is directly involved in the toxicity of CSTX-1, a neurotoxic peptide from the venom of the spider Cupiennius salei.

CSTX-1 (74 amino acids, 8,352.62 Da) is a potent neurotoxin from the venom of Cupiennius salei. With the monoclonal antibody 9H3 against CSTX-1, we identified two similar peptides by Western blot analysis. These two peptides were purified by RP-HPLC: CSTX-2a (61 amino acids, 6865.75 Da) and CSTX-2b (60 amino acids, 6709.57 Da). Using ESI-MS analysis and sequencing we verified that CSTX-2a is a truncated version of CSTX-1. CSTX-2b differs from CSTX-2a by the absence of Arg61. Toxicity of CSTX-1, CSTX-2a, and CSTX-2b to Drosophila melanogaster showed that the absence of the last 13 amino acids of CSTX-1 results in a seven-fold activity loss. CSTX-2b, which lacks Arg61 is 190-fold less toxic. We conclude that the C-terminal part of CSTX-1, especially Arg61, is essential for the expression of toxicity. CSTX-1 is degraded to CSTX-2a and CSTX-2b by proteases that are released from venom gland cells by apocrine secretion.