[Show abstract][Hide abstract] ABSTRACT: Angiosarcomas (AS) are rare vascular malignancies. They are subdivided into primary (PAS) and secondary angiosarcomas (SAS). The objective was to compare the characteristics of AS subtypes.
Eighteen PAS and ten SAS patients treated at our institution between 2004 and 2012 were included in this study.
Median age of PAS and SAS patients was 52.9 and 64.2 years, respectively (p = 0.1448). The percentage of women was 27.8% for PAS, but 80.0% for SAS (p = 0.0163). While PAS occurred throughout the body, the majority of SAS arose from the breast (p = 0.0012). All SAS were radiation-induced with a median latency of 7.7 years. The majority of patients with PAS and SAS underwent surgery as primary or recurrence treatment (p > 0.95). Local recurrence was developed by 27.8% of PAS and 50.0% of SAS (p = 0.4119). 61.1% of PAS metastasized, but only 40.0% of SAS (p = 0.4328). Median overall survival for PAS and SAS was 19 and 57 months, respectively (p = 0.2306).
Radical surgery remains the mainstay of both primary and recurrence treatment. SAS show a high local recurrence rate, while PAS tend towards developing early metastases. Overall, prognosis is poor for both groups.
[Show abstract][Hide abstract] ABSTRACT: Purpose:
In 2004, we started an intergroup randomized trial of adjuvant imatinib versus no further therapy after R0-R1 surgery patients with localized, high- or intermediate-risk GI stromal tumor (GIST).
Patients and methods:
Patients were randomly assigned to 2 years of imatinib 400 mg daily or no further therapy after surgery. The primary end point was overall survival; relapse-free survival (RFS), relapse-free interval, and toxicity were secondary end points. In 2009, given the concurrent improvement in prognosis of patients with advanced GIST, we changed the primary end point to imatinib failure-free survival (IFFS), with agreement of the independent data monitoring committee. We report on a planned interim analysis.
A total of 908 patients were randomly assigned between December 2004 and October 2008: 454 to imatinib and 454 to observation. Of these, 835 patients were eligible. With a median follow-up of 4.7 years, 5-year IFFS was 87% in the imatinib arm versus 84% in the control arm (hazard ratio, 0.79; 98.5% CI, 0.50 to 1.25; P = .21); RFS was 84% versus 66% at 3 years and 69% versus 63% at 5 years (log-rank P < .001); and 5-year overall survival was 100% versus 99%, respectively. Among 528 patients with high-risk GIST by local pathologist, 5-year IFFS was 79% versus 73%; among 336 centrally reviewed high-risk patients, it was 77% versus 73%, respectively.
This study confirms that adjuvant imatinib has an overt impact on RFS. No significant difference in IFFS was observed, although in the high-risk subgroup there was a trend in favor of the adjuvant arm. IFFS was conceived as a potential end point in the adjuvant setting because it is sensitive to secondary resistance, which is the main adverse prognostic factor in patients with advanced GIST.
Journal of Clinical Oncology 11/2015; DOI:10.1200/JCO.2015.62.4304 · 18.43 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Purpose:
Three years of adjuvant imatinib therapy are recommended for patients with GI stromal tumor (GIST) with high-risk features, according to survival findings in the Scandinavian Sarcoma Group XVIII/AIO (Arbeitsgemeinschaft Internistische Onkologie) trial. To investigate whether the survival benefits have persisted, we performed the second planned analysis of the trial.
Patients and methods:
Eligible patients had macroscopically completely excised, KIT-positive GIST with a high risk of recurrence, as determined by using the modified National Institutes of Health criteria. After surgery, the patients were randomly assigned to receive imatinib for either 1 or 3 years. The primary objective was recurrence-free survival (RFS), and the secondary objectives included survival.
A total of 400 patients were entered onto this open-label study between February 4, 2004, and September 29, 2008. During a median follow-up of 90 months, 171 recurrences and 69 deaths were detected. Patients assigned to the 3-year group had longer RFS than those assigned to the 1- year group; 5-year RFS was 71.1% versus 52.3%, respectively (hazard ratio [HR], 0.60; 95% CI 0.44 to 0.81; P < .001), and survival was 91.9% versus 85.3% (HR, 0.60; 95% CI, 0.37 to 0.97; P = .036). Patients in the 3-year group survived longer in the subset with centrally confirmed GIST and without macroscopic metastases at study entry (93.4% v 86.8%; HR, 0.53; 95% CI, 0.30 to 0.93; P = .024). Similar numbers of cardiac events and second cancers were recorded in the groups.
Three years of adjuvant imatinib therapy results in longer survival than 1 year of imatinib. High 5-year survival rates are achievable in patient populations with high-risk GIST.
Journal of Clinical Oncology 11/2015; DOI:10.1200/JCO.2015.62.9170 · 18.43 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Antiangiogenic substances and radiation therapy (RT) may have synergistic effects and improve irradiation efficacy. We present a cohort study evaluating the toxicity of combined sunitinib and RT as neoadjuvant treatment of extremity and retroperitoneal soft tissue sarcoma (STS).
Sixteen patients with locally advanced extremity (6/16) or retroperitoneal (10/16) STS were treated with continuous-dosing sunitinib (15/16: 37.5 mg daily; 1/16: 25 mg daily) and standard RT (45-50.4 Gy) preoperatively. Surgery was scheduled 5-9 weeks following neoadjuvant treatment. The primary goal of the study was to determine combined treatment toxicity according to the Common Terminology Criteria for Adverse Events. Secondary goals were the evaluation of postoperative morbidity and treatment response.
Eight of 16 patients developed grade 3, and one patient developed grade 4, hematological toxicity. One patient experienced grade 3 hand-foot syndrome. The most frequent treatment toxicities of any grade were hematological (15/16) or dermatological (9/16). Three patients had partial response, 11 had stable disease, and 2 had progressive disease according to Response Evaluation Criteria in Solid Tumors (RECIST). Fourteen of 16 patients underwent surgery; tumors were not removed in two patients because of patient refusal or intercurrent metastatic disease. The proportion of tumor necrosis exceeded 90 % in 5 of 14 patients, and 4 patients had postoperative complications requiring reintervention.
Preoperative treatment with concurrent sunitinib and RT was tolerable, and postoperative morbidity did not increase. Combined treatment with RT and sunitinib was also feasible in patients with retroperitoneal STS, and warrants further investigation.
[Show abstract][Hide abstract] ABSTRACT: Hintergrund Gastrointestinale Stromatumoren (GIST) sind die häufigste mesenchymale Neoplasie des Gastrointestinaltraktes. Sie unterscheiden sich hinsichtlich Tumorbiologie, Behandlungsstrategie und insbesondere Indikationsstellung zum chirurgischen Vorgehen in wesentlichen Aspekten von gastrointestinalen Karzinomen. Jeder an der Behandlung von GIST beteiligte Chirurg sollte mit diesen Aspekten vertraut sein. Ziel der Arbeit In dieser Arbeit wird der Stellenwert der Positronenemissionstomographie (PET) in der chirurgischen Behandlung von Patienten mit GIST diskutiert und ein Ausblick auf die Entwicklung von auf GIST maßgeschneiderten molekularen Tracern gegeben. Ergebnisse In verschiedenen klinischen Szenarien ist die PET eine wertvolle Hilfe für die Therapieplanung und insbesondere chirurgische Indikationsstellung in der multimodalen Behandlung von GIST. Hervorzuheben sind das Primärstaging, das Monitoring unter neoadjuvanter Therapie sowie das Staging und die Verlaufskontrolle in der metastasierten Situation. Der routinemäßig eingesetzte Tracer ist 18F-FDG, der zuverlässig den Metabolismus von GIST-Läsionen abbildet. Verglichen mit Computertomographie/Magnetresonanztomographie erlaubt das 18F-FDG-PET häufig eine frühere und genauere Responsebeurteilung. GIST-spezifische molekulare Tracer, die eine direkte Prognose zum Therapieansprechen und frühzeitige Informationen zur Resistenzentwicklung liefern könnten, befinden sich in der präklinischen Entwicklung. Hier sind aber noch pharmakokinetische und immunologische Hürden zu überwinden. Fernziel ist die Entwicklung von „theranostics“, also Substanzen, die zugleich diagnostische und therapeutische Zwecke erfüllen. Diskussion In der multimodalen Therapie von GIST und der Indikationsstellung zum chirurgischen Vorgehen hat die PET einen festen Stellenwert.
[Show abstract][Hide abstract] ABSTRACT: Introduction
In neoadjuvant therapy, irradiation has a deleterious effect on neoangiogenesis. The aim of this study was to examine the post-implantation effects of neoadjuvant irradiation on the survival and proliferation of autologous cells seeded onto an acellular human dermis (hAD; Epiflex). Additionally, we examined the influence of dermal hair follicle pores on viability and proliferation. We used dorsal skinfold chambers implanted in rats and in-situ microscopy to quantify cell numbers over 9 days.
24 rats received a skinfold chamber and were divided into 2 main groups; irradiated and unirradiated. In the irradiated groups 20Gy were applied epicutaneously at the dorsum. Epiflex pieces were cut to size 5x5mm such that each piece had either one or more visible hair follicle pores, or no such visible pores. Fibroblasts were transduced lentiviral with a fluorescent protein for cell tracking. Ma
PLoS ONE 05/2015; 10(5-5):e0125689. DOI:10.1371/journal.pone.0125689 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Objective
The capacity of thymomas to generate mature CD4+ effector T cells from immature precursors inside the tumor and export them to the blood is associated with thymoma-associated myasthenia gravis (TAMG). Why TAMG(+) thymomas generate and export more mature CD4+ T cells than MG(−) thymomas is unknown.Methods
Unfixed thymoma tissue, thymocytes derived thereof, peripheral blood mononuclear cells (PBMCs), T-cell subsets and B cells were analysed using qRT-PCR and western blotting. Survival of PBMCs was measured by MTT assay. FAS-mediated apoptosis in PBMCs was quantified by flow cytometry. NF-κB in PBMCs was inhibited by the NF-κB-Inhibitor, EF24 prior to FAS-Ligand (FASLG) treatment for apoptosis induction.ResultsExpression levels of the apoptosis inhibitor cellular FLICE-like inhibitory protein (c-FLIP) in blood T cells and intratumorous thymocytes were higher in TAMG(+) than in MG(−) thymomas and non-neoplastic thymic remnants. Thymocytes and PBMCs of TAMG patients showed nuclear NF-κB accumulation and apoptosis resistance to FASLG stimulation that was sensitive to NF-κB blockade. Thymoma removal reduced cFLIP expression in PBMCs.InterpretationWe conclude that thymomas induce cFLIP overexpression in thymocytes and their progeny, blood T cells. We suggest that the stronger cFLIP overexpression in TAMG(+) compared to MG(−) thymomas allows for the more efficient generation of mature CD4+ T cells in TAMG(+) thymomas. cFLIP overexpression in thymocytes and exported CD4+ T cells of patients with TAMG might contribute to the pathogenesis of TAMG by impairing central and peripheral T-cell tolerance.
[Show abstract][Hide abstract] ABSTRACT: The purpose of this investigation was to compare different dynamic cell seeding methods regarding their seeding efficiency, homogeneity, infiltration depth and proliferation within a human acellular dermis. In addition, the growth behaviour was observed during a 12-day static in vitro culture. The dynamic methods included orbital-shaker seeding and the use of a plate centrifuge with different rotational speeds, combinations of low-pressure for matrix degassing and centrifugal seeding. Scaffolds were incubated for up to 12 days statically. Cell distribution and infiltration depth were analysed histologically at days 0, 4, 8 and 12. Seeding efficiency and cell proliferation were quantified with the MTT-assay at the same time points. Centrifugal seeding with 300g for 5 × 1 min combined with matrix degassing significantly increased the seeding efficiency and homogeneity compared to the other methods. However, following static culture, no cells were detectable after 4 days in the inner matrix zones. Furthermore, none of the degassing+centrifugation groups reached a significantly higher proliferation at day 8 compared to the reference. The use of a single dynamic method resulted in an inefficient cell seeding. We archived the highest seeding efficiency, homogeneity and infiltration depth using a combination of degassing+centrifugation at 300g for 5 × 1 min.
Cell and Tissue Banking 03/2015; DOI:10.1007/s10561-015-9508-7 · 1.25 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Evaluation of the potential efficacy and safety of combination therapies for advanced soft tissue sarcomas (STS) has increased substantially after approval of trabectedin and pazopanib. Trabectedin's introduction in Europe in 2007 depended mainly on its activity in so-called L-sarcomas (liposarcoma and leiomyosarcoma); combination of trabectedin with other chemotherapies used in STS seems of particular interest.
We initiated within the German Interdisciplinary Sarcoma Group (GISG) a phase I dose escalating trial evaluating the combination of trabectedin and gemcitabine in patients with advanced and/or metastatic L-sarcomas (GISG-02; ClinicalTrials.gov NCT01426633). Patients were treated with increasing doses of trabectedin and gemcitabine. The primary endpoint was to determine the maximum tolerated dose.
Five patients were included in the study. Two patients were treated on dose level 1 comprising trabectedin 0.9 mg/m2 on day 1 and gemcitabine 700 mg/m2 on days 1 + 8, every 3 weeks. Due to dose-limiting toxicity (DLT) in both patients (elevated transaminases and thrombocytopenia), an additional three patients were treated on dose level -1 with trabectedin 0.7 mg/m2 plus gemcitabine 700 mg/m2. Of these three patients, two demonstrated another DLT; therefore, the trial was stopped and none of the dose levels could be recommended for phase II testing.
The GISG-02 phase I study was stopped with the conclusion that the combination of gemcitabine and trabectedin is generally not recommended for the treatment of patients with advanced and/or metastatic leiomyosarcoma or liposarcoma. Also, this phase I study strongly supports the necessity for careful evaluation of combination therapies.
[Show abstract][Hide abstract] ABSTRACT: Retroperitoneal soft tissue sarcomas (RPS) are rare tumors that include several well-defined histologic subtypes. Although surgery is the mainstay of curative therapy, no universally accepted recommendations concerning the best management have been developed to date. Optimization of the initial approach is critical for maximizing patient outcomes. An RPS Trans-Atlantic Working Group was established in 2013. The primary aim was to evaluate the current evidence critically and to develop a consensus document on the approach to this difficult disease. The outcome applies to primary RPS that is nonvisceral in origin. The evaluation included sarcomas of major veins (inferior vena cava, renal vein, ovarian/testicular vein), undifferentiated pleomorphic sarcoma of the psoas, and ureteric leiomyosarcoma (LMS). It excluded desmoid, lipoma and angiomyolipoma, gastrointestinal stromal tumors, visceral sarcomas such as those arising from the gut or its mesentery, uterine LMS, prostatic sarcoma, paratesticular/spermatic cord sarcoma, Ewing's sarcoma, alveolar/embryonal rhabdomyosarcoma, primitive peripheral neuro-ectodermal tumor, sarcoma arising from teratoma, carcinosarcoma, sarcomatoid carcinoma, clear cell sarcoma, radiation-induced sarcoma, paraganglioma, and malignant pheochromocytoma. Management of RPS was evaluated from diagnosis to follow-up, and a level of evidence was attributed to each statement. This rare and complex malignancy is best managed by an experienced multidisciplinary team in a specialized referral center. The best chance of cure is at the time of primary presentation, and an individualized management plan should be made based on the statements included in this article. International collaboration is critical for adding to the current knowledge. A prospective registry will be set up.