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Abstract Background Leiomysarcoma of intravascular origin is an exceedingly rare entity of malignant soft tissue tumors. They are most frequently encountered in the retroperitoneum arising from the inferior vena cava and are scarcely found to arise from vessels of the extremities. These tumors were analysed with particular reference to treatment outcome and prognosis. The aim of this article is to broaden the knowledge of the clinical course of this rare malignancy. Method During 2000 and 2009 twelve patients were identified with an intravascular origin of a leiomyosarcoma. Details regarding the clinical course, follow-up and outcome were assessed with focus on patient survival, tumor relapse and metastases and treatment outcome. 3 year survival probability was calculated using Kaplan-Meier method. Results Vascular leiomyosarcomas accounted for 0.7% of all malignant soft tissue tumors treated at our soft tissue sarcoma reference center. The mean follow up period was 38 months. Tumor relapse was encountered in six patients. 6 patients developed metastatic disease. The three year survival was 57%. Conclusion Vascular leiomysarcoma is a rare but aggressive tumor entity with a high rate of local recurrence and metastasis.

Abstract Background Cancer cells display widespread changes in DNA methylation that may lead to genetic instability by global hypomethylation and aberrant silencing of tumor suppressor genes by focal hypermethylation. In turn, altered DNA methylation patterns have been used to identify putative tumor suppressor genes. Methods In a methylation screening approach, we identified ECRG4 as a differentially methylated gene. We analyzed different cancer cells for ECRG4 promoter methylation by COBRA and bisulfite sequencing. Gene expression analysis was carried out by semi-quantitative RT-PCR. The ECRG4 coding region was cloned and transfected into colorectal carcinoma cells. Cell growth was assessed by MTT and BrdU assays. ECRG4 localization was analyzed by fluorescence microscopy and Western blotting after transfection of an ECRG4-eGFP fusion gene. Results We found a high frequency of ECRG4 promoter methylation in various cancer cell lines. Remarkably, aberrant methylation of ECRG4 was also found in primary human tumor tissues, including samples from colorectal carcinoma and from malignant gliomas. ECRG4 hypermethylation associated strongly with transcriptional silencing and its expression could be re-activated in vitro by demethylating treatment with 5-aza-2'-deoxycytidine. Overexpression of ECRG4 in colorectal carcinoma cells led to a significant decrease in cell growth. In transfected cells, ECRG4 protein was detectable within the Golgi secretion machinery as well as in the culture medium. Conclusions ECRG4 is silenced via promoter hypermethylation in different types of human cancer cells. Its gene product may act as inhibitor of cell proliferation in colorectal carcinoma cells and may play a role as extracellular signaling molecule.

Abstract Introduction Merkel cell carcinoma and dermatofibrosarcoma protuberans are two very rare neoplasms. The simultaneous occurrence of two different tumour entities at the same anatomical site, collision tumours, is a rare phenomenon. Case presentation We present a rare case of a 74-year-old woman with a previous history of a recurrent dermatofibrosarcoma protuberans presenting with a metastatic Merkel cell carcinoma. Further investigation revealed a collision tumour of a metastatic lesion of the Merkel cell carcinoma within a tumour relapse of a dermatofibrosarcoma protuberans. Conclusion Synchronous occurrence of two different tumour entities is extremely rare and has not been described for Merkel cell carcinoma and dermatofibrosarcoma. Merkel cell carcinoma, a tumour of the elderly or immunocompromised patients, leads to early metastasis and can be expected to be the limiting factor for prognoses.

Abstract Background Intravascular leiomyosarcoma is a rare tumour entity originating from venous vessel structures and most frequently affecting the inferior vena cava. Case presentation A 69-year old patient presented with a biopsy proven leiomyosarcoma of the right supraclavicular region. Tumour resection and histological assessment verified the intravascular tumour origin arising from the internal jugular vein and extending into the surrounding soft tissue. Conclusion In the presence of a biopsy proven diagnosis of leiomyosarcoma the rare condition of an intravascular tumour origin has to be considered even without signs of venous stases. This may result in an altered surgical strategy. Microthrombembolism and pulmonary metastases may complicate the course of the disease.

Abstract Background Alveolar sarcoma of the soft parts (ASPS) represents a very rare entity of soft tissue sarcoma with special features such as young peak age incidence and frequent metastasis to the brain. The aim of this study was a clinicopathological analysis with special reference to treatment and outcome. Methods From the database of the BG-University Hospital Bergmannsheil, 1597 soft tissue sarcoma (STS) cases were reviewed and 11 consecutive patients with ASPS were isolated. Data was acquired from patients' charts and contact to patients, their relatives or general practitioners, with special reference to treatment and clinical course. The average follow up time from the time of the definite operation for the primary tumor was 6.5 years. Kaplan-Meier method was used to calculate survival. Results Patients with localized disease who received complete resection and adjuvant radiation and who did not develop recurrence or metastatic disease within 2 years after surgery had a positive outcome. The size of the tumor, its localization, and the time of untreated growth before treatment did not influence the long-term results. All patients who developed recurrent disease also suffered from distant metastasis, reflecting the aggressive biology of the tumor. All patients with distant metastasis had the lungs and the brain affected. Conclusion Due to the limited number of patients with ASPS, prospective studies would have to span decades to gather a significant collective of patients; therefore, it is not possible to comment meaningfully on a possible benefit of neoadjuvant or adjuvant therapy. We recommend wide surgical excision and, in the absence of data telling otherwise, adjuvant radiation. In cases with recurrent disease or metastasis, the prognosis is bad and further treatment will be restricted to palliation in most cases.

Abstract Background Elastofibromas are benign soft tissue tumours mostly of the infrascapular region between the thoracic wall, the serratus anterior and the latissimus dorsi muscle with a prevalence of up to 24% in the elderly. The pathogenesis of the lesion is still unclear, but repetitive microtrauma by friction between the scapula and the thoracic wall may cause the reactive hyperproliferation of fibroelastic tissue. Methods We present a series of seven cases with elastofibroma dorsi with reference to clinical findings, further clinical course and functional results after resection, as well as recurrence. Data were obtained retrospectively by clinical examination, phone calls to the patients' general practitioners and charts review. Follow-up time ranged from four months to nine years and averaged 53 months. Results The patients presented with swelling of the infrascapular region or snapping scapula. In three cases, the lesion was painful. The ratio men/women was 2/5 with a mean age of 64 years. The tumor sizes ranged from 3 to 13 cm. The typical macroscopic aspect was characterized as poorly defined fibroelastic soft tissue lesion with a white and yellow cut surface caused by intermingled remnants of fatty tissue. Microscopically, the lesions consisted of broad collagenous strands and densely packed enlarged and fragmented elastic fibres with mostly round shapes. In all patients but one, postoperative seroma (which had to be punctuated) occurred after resection; however, at follow-up time, no patient reported any decrease of function or sensation at the shoulder or the arm of the operated side. None of the patients experienced a relapse. Conclusion In differential diagnosis of soft tissue tumors located at this specific site, elastofibroma should be considered as likely diagnosis. Due to its benign behaviour, the tumor should be resected only in symptomatic patients.

Abstract Background Solitary fibrous tumors (SFT) represent a rare entity of soft tissue tumors. Previously considered being of serosal origin and solely limited to the pleural cavity the tumor has been described in other locations, most particularly the head and neck. Extrathoracic SFT in the soft tissues of the trunk and the extremities are very rare. Nine cases of this rare tumor entity are described in the course of this article with respect to clinicopathological data, follow-up and treatment results. Methods Data were obtained from patients' records, phone calls to the patients' general practitioners, and clinical follow-up examination, including chest X-ray, abdominal ultrasound, and MRI or computed tomography. Results There were 6 females and 3 males, whose age at time of diagnosis ranged from 32 to 92 years (mean: 62.2 years). The documented tumors' size was 4.5 to 10 cm (mean: 7 cm). All tumors were located in deep soft tissues, 3 of them epifascial, 2 subfascial, 4 intramuscular. Four tumors were found at the extremities, one each at the flank, in the neck, at the shoulder, in the gluteal region, and in the deep groin. Two out of 9 cases were diagnosed as atypical or malignant variant of ESFT. Complete resection was performed in all cases. Follow-up time ranged from 1 to 71 months. One of the above.mentioned patients with atypical ESFT suffered from local relapse and metastatic disease; the remaining 8 patients were free of disease. Conclusion ESFT usually behave as benign soft tissue tumors, although malignant variants with more aggressive local behaviour (local relapse) and metastasis may occur. The risk of local recurrence and metastasis correlates to tumor size and histological status of surgical resection margins and may reach up to 10% even in so-called "benign" tumors. Tumor specimens should be evaluated by experienced soft tissue pathologists. The treatment of choice is complete resection followed by extended follow-up surveillance.

Abstract Background Because of the high resistance rate of fibrosarcomas against cytotoxic agents clinical chemotherapy of these tumors is not established. A better understanding of the diverse modes of tumor cell death following cytotoxic therapies will provide a molecular basis for new chemotherapeutic strategies. In this study we elucidated the response of a fibrosarcoma cell line to clinically used cytostatic agents on the level of gene expression. Methods HT1080 fibrosarcoma cells were exposed to the chemotherapeutic agents doxorubicin, actinomycin D or vincristine. Total RNA was isolated and the gene expression patterns were analyzed by microarray analysis. Expression levels for 46 selected candidate genes were validated by quantitative real-time PCR. Results The analysis of the microarray data resulted in 3.309 (actinomycin D), 1.019 (doxorubicin) and 134 (vincristine) probesets that showed significant expression changes. For the RNA synthesis blocker actinomycin D, 99.4% of all differentially expressed probesets were under-represented. In comparison, probesets down-regulated by doxorubicin comprised only 37.4% of all genes effected by this agent. Closer analysis of the differentially regulated genes revealed that doxorubicin induced cell death of HT1080 fibrosarcoma cells mainly by regulating the abundance of factors mediating the mitochondrial (intrinsic) apoptosis pathway. Furthermore doxorubicin influences other pathways and crosstalk to other pathways (including to the death receptor pathway) at multiple levels. We found increased levels of cytochrome c, APAF-1 and members of the STAT-family (STAT1, STAT3), while Bcl-2 expression was decreased. Caspase-1, -3, -6, -8, and -9 were increased indicating that these proteases are key factors in the execution of doxorubicin mediated apoptosis. Conclusion This study demonstrates that chemotherapy regulates the expression of apoptosis-related factors in fibrosarcoma cells. The number and the specific pattern of the genes depend on the used cytotoxic drug. The response rates on the gene expression level, i.e. the number of genes regulated by the drugs actinomycin D, doxorubicin and vincristine, correlate to the clinical effectiveness of the drugs. Doxorubicin seems to exert its cytotoxic mechanism by regulating genes, which are involved in several different apoptosis regulating pathways. The exact knowledge of the genes affected by the drugs will help to understand the diverse modes of soft tissue sarcoma cell death in response to cytotoxic therapies.

Abstract Background Soft tissue sarcomas comprise less than 1% of all solid malignancies. The presentation and behavior of these tumors differs depending on location and histological characteristics. Standard therapy consists of complete surgical resection in combination with adjuvant radiotherapy. The role of chemotherapy is not clearly defined and is largely restricted to clinical trials. Only a limited number of agents have proved to be effective in soft tissue sarcomas. The use of doxorubicin, epirubicin and ifosfamide allowed response rates of more than 20%. In addition, recent chemotherapy trials did not demonstrate any significant differences in efficacy for various histological subtypes. Methods The objective of this study was to gain additional information about the chemosensitivity of soft tissue sarcomas to seven 7 different chemotherapy agents as single drugs and 4 combinations. Therefore we used an established ATP based in-vitro testing system and examined 50 soft tissue sarcomas. Chemosensitivity was assessed using a luciferin-luciferase-based luminescence assay providing individual chemosensitivity indices for each agent tested. Results The sensitivity varied widely according to the histological subtypes. The tumors state of cellular dedifferentiation played a crucial role for the efficiency of the chemotherapeutic agents. The sensitivity also depended on the presentation of the sarcoma as a primary or recurrent tumor. The highest sensitivity was demonstrated for actinomycin D as a single agent, with 74% of the tumor samples exhibiting a high-grade sensitivity (20% low sensitivity, no resistance). The combination of actinomycin D and ifosfamide yielded a high sensitivity in 76% (2% resistance). Doxorubicin as a mono-therapy or in combination with ifosfamide achieved high sensitivity in 70% and 72%, respectively, and resistance in 6% of the samples. Conclusion Chemosensitivity testing is feasible in soft tissue sarcomas. It can be used to create sensitivity and resistance profiles of established and new cytotoxic agents and their combinations in soft tissue sarcomas. Our data demonstrate measurable discrepancies of the drug efficiency in soft tissue sarcomas, sarcoma subtypes and tumor recurrencies. However, current therapeutic regime does not take this in consideration, yet.

Different modes of sodium-D-glucose cotransporter-mediated D-glucose uptake regulation in Caco-2 cells. Am J Physiol Cell Physiol 287: C1041-C1047, 2004. First published June 16, 2004; 10.1152/ ajpcell.00197.2004.--We recently reported that a considerable amount of the sodium-D-glucose cotransporter SGLT1 present in Caco-2 cells, a model for human enterocytes, is located in intracellular compartments attached to microtubules (Kipp H, Khoursandi S, Scharlau D, and Kinne RKH. Am J Physiol Cell Physiol 285: C737-C749, 2003). A similar distribution pattern was also observed in enterocytes in thin sections from human jejunum, highlighting the validity of the Caco-2 cell model. Fluorescent surface labeling of five Caco-2 cells revealed that the intracellular compartments containing SGLT1 were accessible by endocytosis. To elucidate the role of endosomal SGLT1 in the regulation of sodium-dependent D-glucose uptake into enterocytes, we compared SGLT1-mediated D-glucose uptake into Caco-2 cells with the subcellular distribution of SGLT1 after challenging the cells with different stimuli. Incubation (90 min) of Caco-2 cells with mastoparan (50 [micro]M), a drug that enhances apical endocytosis, shifted a large amount of SGLT1 from the apical membrane to intracellular sites and significantly reduced sodium-dependent [alpha]-[[sup.14]C]methyl-D-glucose uptake (-60%). We also investigated the effect of altered extracellular D-glucose levels. Cells preincubated (1 h) with D-glucose-free medium exhibited significantly higher sodium-dependent [alpha]-[[sup.14]C]methyl-D-glucose uptake (+45%) than did cells preincubated with high D-glucose medium (100 mM, 1 h). Interestingly, regulation of SGLT1-mediated D-glucose uptake into Caco-2 cells by extracellular D-glucose levels occurred without redistribution of cellular SGLT1. These data suggest that, pharmacologically, D-glucose uptake can be regulated by a shift of SGLT1 between the plasma membrane and the endosomal pool; however, regulation by the physiological substrate D-glucose can be explained only by an alternative mechanism. endosomes; enterocytes