Reconstruction of Soft-Tissue Defects at the Foot and Ankle after Oncological Resection

Introduction: Solid malignancies at the foot and ankle region are rare and include mainly soft tissue sarcomas, bone sarcomas and skin malignancies. Complete surgical resection with clear margins still remains the mainstay of therapy in these malignancies. However, attainment of negative surgical margins in patients with locally advanced tumors of the foot and ankle region may require extensive surgery and could result in loss of extremity function. In these circumstances, plastic surgical techniques can frequently reduce functional impairment and cover soft tissue defects, particularly in cases of large tumor size or localization adjacent to critical anatomic structures, thereby improving the quality of life for these patients. The aim of this article is to illustrate the various treatment options of plastic surgery in the multimodal therapy of patients with malignant tumors of the foot and ankle region.Material und methods: This article is based on the review of the current literature and the evaluation of the author’s own patient database.Results: The local treatment of malignant extremity tumors has undergone major changes over the last few decades. Primary amputations have been increasingly replaced by limb-sparing techniques, preserving extremity function as much as possible. Although defect coverage at the foot and ankle region is demanding due to complex anatomical features and functional requirements, several plastic surgical treatment options can be implemented in the curative treatment of patients with malignant solid tumors in this area. Soft tissue defects after tumor resection can be covered by a variety of local flaps. If local flaps are not applicable, free flap transfers, such as the anterolateral thigh (ALT) flap, parascapular flap or latissimus dorsi flap, can be utilized to cover nearly all kinds of defects in the foot and ankle region. Conclusion: Soft tissue reconstruction in the foot and ankle region is a vital component of limb-sparing surgery. It enables complete resection of locally advanced tumors and subsequent adjuvant radiotherapy. Modern plastic surgical techniques should, therefore, be integrated in the multimodal treatment concept of malignancies in the foot and ankle region

Merkel cell carcinoma metastasis and dermatofibrosarcoma protuberans presenting as a collision tumour: a case report and review of the literature

<p>Abstract</p> <p>Introduction</p> <p>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.</p> <p>Case presentation</p> <p>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.</p> <p>Conclusion</p> <p>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.</p

Intravascular leiomyosarcoma of the brachiocephalic region – report of an unusual tumour localisation: case report and review of the literature

<p>Abstract</p> <p>Background</p> <p>Intravascular leiomyosarcoma is a rare tumour entity originating from venous vessel structures and most frequently affecting the inferior vena cava.</p> <p>Case presentation</p> <p>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.</p> <p>Conclusion</p> <p>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.</p

Inhibition of early steps in the lentiviral replication cycle by cathelicidin host defense peptides

BACKGROUND: The antibacterial activity of host defense peptides (HDP) is largely mediated by permeabilization of bacterial membranes. The lipid membrane of enveloped viruses might also be a target of antimicrobial peptides. Therefore, we screened a panel of naturally occurring HDPs representing different classes for inhibition of early, Env-independent steps in the HIV replication cycle. A lentiviral vector-based screening assay was used to determine the inhibitory effect of HDPs on early steps in the replication cycle and on cell metabolism. RESULTS: Human LL37 and porcine Protegrin-1 specifically reduced lentiviral vector infectivity, whereas the reduction of luciferase activities observed at high concentrations of the other HDPs is primarily due to modulation of cellular activity and/ or cytotoxicity rather than antiviral activity. A retroviral vector was inhibited by LL37 and Protegrin-1 to similar extent, while no specific inhibition of adenoviral vector mediated gene transfer was observed. Specific inhibitory effects of Protegrin-1 were confirmed for wild type HIV-1. CONCLUSION: Although Protegrin-1 apparently inhibits an early step in the HIV-replication cycle, cytotoxic effects might limit its use as an antiviral agent unless the specificity for the virus can be improved

Nucleofection: A New Method for Cutaneous Gene Transfer?

Background. Transfection efficacy after nonviral gene transfer in primary epithelial cells is limited. The aim of this study was to compare transfection efficacy of the recently available method of nucleofection with the established transfection reagent FuGENE6. Methods. Primary human keratinocytes (HKC), primary human fibroblasts (HFB), and a human keratinocyte cell line (HaCaT) were transfected with reporter gene construct by FuGENE6 or Amaxa Nucleofector device. At corresponding time points, β-galactosidase expression, cell proliferation (MTT-Test), transduction efficiency (X-gal staining), cell morphology, and cytotoxicity (CASY) were determined. Results. Transgene expression after nucleofection was significantly higher in HKC and HFB and detected earlier (3 h vs. 24 h) than in FuGENE6. After lipofection 80%–90% of the cells remained proliferative without any influence on cell morphology. In contrast, nucleofection led to a decrease in keratinocyte cell size, with only 20%–42% proliferative cells. Conclusion. Related to the method-dependent increase of cytotoxicity, transgene expression after nucleofection was earlier and higher than after lipofection

Heterogeneous in vitro effects of doxorubicin on gene expression in primary human liposarcoma cultures

<p>Abstract</p> <p>Background</p> <p>Doxorubicin is considered one of the most potent established chemotherapeutics in the treatment of liposarcoma; however, the response rates usually below 30%, are still disappointing. This study was performed to identify gene expression changes in liposarcoma after doxorubicin treatment.</p> <p>Methods</p> <p>Cells of 19 primary human liposarcoma were harvested intraoperatively and brought into cell culture. Cells were incubated with doxorubicin for 24 h, RNA was isolated and differential gene expression was analysed by the microarray technique.</p> <p>Results</p> <p>A variety of genes involved in apoptosis were up and down regulated in different samples revealing a heterogeneous expression pattern of the 19 primary tumor cell cultures in response to doxorubicin treatment. However, more than 50% of the samples showed up-regulation of pro-apoptotic genes such as <it>TRAIL Receptor2</it>, <it>CDKN1A</it>, <it>GADD45A</it>, <it>FAS</it>, <it>CD40</it>, <it>PAWR</it>, <it>NFKBIA</it>, <it>IER3</it>, <it>PSEN1</it>, <it>RIPK2</it>, and <it>CD44</it>. The anti-apoptotic genes <it>TNFAIP3</it>, <it>PEA15</it>, <it>Bcl2A1</it>, <it>NGFB</it>, and <it>BIRC3 </it>were also up-regulated. The pro-apoptotic <it>CD14</it>, <it>TIA1</it>, and <it>ITGB2 </it>were down-regulated in more than 50% of the tumor cultures after treatment with doxorubicin, as was the antiapoptotic <it>YWHAH</it>.</p> <p>Conclusion</p> <p>Despite a correlation of the number of differentially regulated genes to the tumor grading and to a lesser extent histological subtype, the expression patterns varied strongly; however, especially among high grade tumors the responses of selected apoptosis genes were similar. The predescribed low clinical response rates of low grade liposarcoma to doxorubicin correspond to our results with only little changes on gene expression level and also divergent findings concerning the up- and down-regulation of single genes in the different sarcoma samples.</p

Feasibility of chemosensitivity testing in soft tissue sarcomas

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

TRAIL and Taurolidine induce apoptosis and decrease proliferation in human fibrosarcoma

<p>Abstract</p> <p>Background</p> <p>Disseminated soft tissue sarcoma still represents a therapeutic dilemma because effective cytostatics are missing. Therefore we tested TRAIL and Tarolidine (TRD), two substances with apoptogenic properties on human fibrosarcoma (HT1080).</p> <p>Methods</p> <p>Viability, apoptosis and necrosis were visualized by TUNEL-Assay and quantitated by FACS analysis (Propidiumiodide/AnnexinV staining). Gene expression was analysed by RNA-Microarray and the results validated for selected genes by rtPCR. Protein level changes were documented by Western Blot analysis. NFKB activity was analysed by ELISA and proliferation assays (BrdU) were performed.</p> <p>Results and discussion</p> <p>The single substances TRAIL and TRD induced apoptotic cell death and decreased proliferation in HT1080 cells significantly. Gene expression of several genes related to apoptotic pathways (TRAIL: <it>ARHGDIA</it>, <it>NFKBIA</it>, <it>TNFAIP3</it>; TRD: <it>HSPA1A/B</it>, <it>NFKBIA</it>, <it>GADD45A</it>, <it>SGK</it>, <it>JUN</it>, <it>MAP3K14</it>) was changed. The combination of TRD and TRAIL significantly increased apoptotic cell death compared to the single substances and lead to expression changes in a variety of genes (<it>HSPA1A/B</it>, <it>NFKBIA</it>, <it>PPP1R15A</it>, <it>GADD45A</it>, <it>AXL</it>, <it>SGK</it>, <it>DUSP1</it>, <it>JUN</it>, <it>IRF1</it>, <it>MYC</it>, <it>BAG5</it>, <it>BIRC3</it>). NFKB activity assay revealed an antipodal regulation of the several subunits of NFKB by TRD and TRD+TRAIL compared to TRAIL alone.</p> <p>Conclusion</p> <p>TRD and TRAIL are effective to induce apoptosis and decrease proliferation in human fibrosarcoma. A variety of genes seems to be involved, pointing to the NFKB pathway as key regulator in TRD/TRAIL-mediated apoptosis.</p

Alveolar soft part sarcoma: clinicopathological findings in a series of 11 cases

<p>Abstract</p> <p>Background</p> <p>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.</p> <p>Methods</p> <p>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.</p> <p>Results</p> <p>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.</p> <p>Conclusion</p> <p>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.</p> <p>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.</p