Blay J.-Y.,University of Lyon |
Shen L.,Peking University |
Kang Y.-K.,University of Ulsan |
Rutkowski P.,Center of Oncology of Poland |
And 12 more authors.
The Lancet Oncology | Year: 2015
Background: Nilotinib inhibits the tyrosine kinase activity of ABL1/BCR-ABL1 and KIT, platelet-derived growth factor receptors (PDGFRs), and the discoidin domain receptor. Gain-of-function mutations in KIT or PDGFRα are key drivers in most gastrointestinal stromal tumours (GISTs). This trial was designed to test the efficacy and safety of nilotinib versus imatinib as first-line therapy for patients with advanced GISTs. Methods: In this randomised, open-label, multicentre, phase 3 trial (ENESTg1), participants from academic centres were aged 18 years or older and had previously untreated, histologically confirmed, metastatic or unresectable GISTs. Patients were stratified by previous adjuvant therapy and randomly assigned (1:1) via a randomisation list to receive oral imatinib 400 mg once daily or oral nilotinib 400 mg twice daily. The primary endpoint was centrally reviewed progression-free survival. Efficacy endpoints were assessed by intention-to-treat. This trial is registered with ClinicalTrials.gov, number NCT00785785. Findings: Because the futility boundary was crossed at a preplanned interim analysis, trial accrual terminated in April, 2011. Between March 16, 2009, and April 21, 2011, 647 patients were enrolled; of whom 324 were allocated nilotinib and 320 were allocated imatinib. At final analysis of the core study (data cutoff, October, 2012), 2-year progression-free survival was higher in the imatinib group (59·2% [95% CI 50·9-66·5]) than in the nilotinib group (51·6% [43·0-59·5]; hazard ratio 1·47 [95% CI 1·10-1·95]). In the imatinib group, the most common grade 3-4 adverse events were hypophosphataemia (19 [6%]), anaemia (17 [5%]), abdominal pain (13; 4%), and elevated lipase level (15; 5%), and in the nilotinib group were anaemia (18; 6%), elevated lipase level (15; 5%), elevated alanine aminotransferase concentration (12; 4%), and abdominal pain (11; 3%). The most common serious adverse event in both groups was abdominal pain (11 [4%] in the imatinib group, 14 [4%] in the nilotinib group). Interpretation: Nilotinib cannot be recommended for broad use to treat first-line GIST. However, future studies might identify patient subsets for whom first-line nilotinib could be of clinical benefit. Funding: Novartis Pharmaceuticals. © 2015 Elsevier Ltd.
Chawla S.,Sarcoma Oncology Center |
Henshaw R.,Georgetown University |
Seeger L.,University of California at Los Angeles |
Choy E.,Massachusetts General Hospital |
And 12 more authors.
The Lancet Oncology | Year: 2013
Background: Giant cell tumour of bone (GCTB) is a very rare, aggressive, and progressive osteolytic tumour for which no standard medicinal treatment or chemotherapy exists. We report interim safety and efficacy results from a phase 2 study of denosumab in patients with GCTB. Methods: We did an international, open-label, parallel-group, phase 2 trial of patients with histologically confirmed GCTB and radiographically measurable active disease. Eligible patients were adults or skeletally mature adolescents with radiographic evidence of at least one mature long bone who were at least 12 years old and weighed at least 45 kg. We divided patients into three cohorts-those with surgically unsalvageable GCTB (cohort 1), those with salvageable GCTB whose surgery was associated with severe morbidity (cohort 2), and those who transferred from a previous study of denosumab for GCTB (cohort 3). Patients in cohorts 1 and 2 received 120 mg of subcutaneous denosumab every 4 weeks with loading doses on days 8 and 15 of the first cycle; those in cohort 3 continued the regimen from the previous study. Investigator-determined disease status and clinical benefit were assessed every 4 weeks. Our primary endpoint was the safety profile of denosumab in terms of adverse events and laboratory abnormalities. Prespecified secondary endpoints were time to disease progression in cohort 1 and the proportion of patients without any surgery at 6 months in cohort 2. Safety analyses included all patients who received at least one dose of denosumab. Efficacy analyses included all eligible patients who received at least one dose of denosumab. This study is registered with ClinicalTrials.gov, identifier NCT00680992. Findings: 282 patients, including ten adolescents, were included between Sept 9, 2008, and March 25, 2011. Of the 281 patients analysable for safety, three (1%) had osteonecrosis of the jaw and 15 (5%) hypocalcaemia. The most common grade 3-4 adverse events were hypophosphataemia, which occurred in nine (3%) patients, and anaemia, back pain, and pain in extremities, each of which occurred in three patients (1%). Serious adverse events were reported in 25 (9%) patients. No treatment-related deaths were reported. On the basis of investigators' assessment of disease status, 163 of 169 (96%) analysable patients in cohort 1 had no disease progression after median follow-up of 13 months (IQR 5·8-21·0). In cohort 2, 74 of 100 (74%) analysable patients had no surgery and 16 of 26 (62%) patients who had surgery underwent a less morbid procedure than planned. Median follow-up in cohort 2 was 9·2 months (IQR 4·2-12·9). Interpretation: Adverse events were consistent with the known safety profile of denosumab. Denosumab was associated with tumour responses and reduced the need for morbid surgery in patients with GCTB. Denosumab represents a new treatment option for patients with GCTB. Funding: Amgen. © 2013 Elsevier Ltd.
Klein-Weigel P.F.,HELIOS Klinikum Berlin Buch |
Richter J.G.,Heinrich Heine University Düsseldorf
VASA. Zeitschrift für Gefässkrankheiten | Year: 2014
Thromboangiitis obliterans (TAO, Buerger's disease) is an inflammatory vascular disease affecting small and medium sized arteries and veins. It is characterized by segmental thrombotic occlusions by highly mononuclear cellular thrombi. Its occurrence and re-occurrence is closely related to tobacco use. Immunohistological examinations and the detections of various autoantibodies led to the new paradigm of an immunopathogenesis of TAO. Clinically it is characterized by distal ischemia syndromes in young people and high amputation rates. This article summarizes the disease characteristics, clinical features, and diagnostic and therapeutic approaches and focuses on new therapeutic options, i.e. stem cell derived therapies, immunoadsorption, and the endothelin-receptor-blocking agent bosentan.
Reichardt P.,HELIOS Klinkum Bad Saarow |
Reichardt A.,HELIOS Klinikum Berlin Buch
Zentralblatt fur Chirurgie - Zeitschrift fur Allgemeine, Viszeral- und Gefasschirurgie | Year: 2011
Gastrointestinal stromal tumours (GIST) are the most frequent mesenchymal tumours of the gastrointestinal tract. The gold standard therapy is their complete surgical removal with safety margins of 12cm. Intraoperative damage to the tumour must be avoided because tumour rupture carries a very high risk of peritoneal spread. Since metastases to lymph nodes in general does not occur in GIST a lymph node dissection is not indicated. Depending on the size of the tumour, the number of mitoses and the localisation of the primary tumour, the risk of recurrence after potentially curative resection is considerable in many cases. Patients with intermediate and high risk according to Miettinens classification should receive adjuvant treatment with imatinib. Exceptions are those patients whose tumours exhibit a mutation in exon18, D842V of PDGFRA. According to current data the therapy is continued for 3years. This leads not only to a significant improvement of the progression-free survival in comparison to therapy for 1year but also, especially, to an improvement of overall survivial. In the case of local advanced tumours that can only be resected by a mutilation operation, a primary systemic therapy with imatinib should be initiated on account of its extremely high efficacy. Standard therapy for local advanced or metastasizing GIST is imatinib at a dose of 400mg/day. Patients with mutations in KIT exon9 should be treated with 800mg imatinib/day, since they profit from a significantly longer progression-free survival. Therapy with imatinib should always be continued up to progression or intolerance. In the case of progression under 400mg imatinib the ESMO guidelines recommend a dose increase to 800mg/day as about a third of the patients respond to this higher dose. In the case of further progression a switch to second-line therapy with sunitinib is recommended. After exploitation of all registered therapy options the patients should be offerred an experimental therapy within the framework of a clinical trial. © Georg Thieme Verlag KG Stuttgart. New York.
Bauer R.,Umweltbundesamt Federal Environmental Agency |
Dizer H.,Helios Klinikum Berlin Buch |
Graeber I.,Umweltbundesamt Federal Environmental Agency |
Rosenwinkel K.-H.,Leibniz University of Hanover |
Lopez-Pila J.M.,Umweltbundesamt Federal Environmental Agency
Water Research | Year: 2011
The aim of the present study was to estimate the performance of slow sand filtration (SSF) facilities, including the time needed for reaching stabilization (maturation), operated with surface water bearing high fecal contamination, representing realistic conditions of rivers in many emerging countries. Surface water spiked with wastewater was infiltrated at different pore water velocities (PWV) and samples were collected at different migration distances. The samples were analyzed for phages and to a lesser extent for fecal bacteria and enteric adenoviruses. At the PWV of 50 cm/d, at which somatic phages showed highest removal, their mean log10 removal after 90 cm migration was 3.2. No substantial differences of removal rates were observed at PWVs between 100 and 900 cm/d (2.3 log10 mean removal). The log10 mean removal of somatic phages was less than the observed for fecal bacteria and tended more towards that of enteric adenoviruses This makes somatic phages a potentially better process indicator than Escherichia coli for the removal of viruses in SSF. We conclude that SSF, and by inference in larger scale river bank filtration (RBF), is an excellent option as a component in multi-barrier systems for drinking water treatment also in areas where the sources of raw water are considerably fecally polluted, as often found in many emerging countries. © 2010 Elsevier Ltd.
Mayer J.P.,Helios Klinikum Berlin Buch |
Bettolli M.,Childrens Hospital of Eastern Ontario
World Journal of Gastroenterology | Year: 2014
Alimentary tract duplications are rare congenital lesions normally diagnosed in newborns and children that can occur anywhere from the mouth to the anus and have a reported incidence of approximately 1 in 4500 life births. Symptoms and clinical presentation vary greatly. The presentation varies according to age and location. The treatment finally is surgical; total resection when possible should be the aim of the intervention. In pediatric surgery minimally invasive surgical procedures became more and more important over the last decades. In consequence the operative procedure on alimentary tract duplications changed in this manner. We review on case reports and clinical reports on minimally invasive surgery in the treatment of alimentary tract duplications, determine the importance of minimally invasive techniques in the treatment of this rare entity and rule out that further studies in the field should be performed. © 2014 Baishideng Publishing Group Inc. All rights reserved.
Von Minckwitz G.,University Ts Frauenklinik Frankfurt |
Untch M.,Helios Klinikum Berlin Buch |
Loibl S.,University Ts Frauenklinik Frankfurt
Current Opinion in Obstetrics and Gynecology | Year: 2013
Purpose of Review: Neoadjuvant treatment is used by an increased number of patients with breast cancer. This study reviews the current literature on how new research findings have impacted patients and treatment selection. Recent Findings: The prognostic value of pathological complete response (pCR) is different in various breast cancer subtypes. pCR rate after neoadjuvant chemotherapy is associated with better outcome only for patients with human epidermal growth factor receptor 2 (HER2)-positive/hormone receptor negative or HER2-negative/hormone receptor negative (triple-negative) and some more aggressive HER2-negative/hormone receptor positive tumours. Knowledge on pCR in these subtypes can relieve patients from an initially unfavourable prognosis. For patients without a pCR, especially if a high proliferation can be detected in the residual tumour after neoadjuvant treatment, prognosis is still unfavourable and clinical trials exploring new targeted agents in this postneoadjuvant indication are currently under development. Neoadjuvant treatment allows treatment to be guided by monitoring response. Changing the regimen in case of no early response or intensification in case of early response has shown significant survival advantages especially in patients with hormone receptor positive tumours. Summary: The model of neoadjuvant chemotherapy has been improved over the last decade and is now successfully used to increase our knowledge not only on the pathophysiology of the disease but also on the activity of conventional and new treatment approaches. © 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins.
Reichardt P.,HELIOS Klinikum Berlin Buch
Future Oncology | Year: 2014
Soft tissue sarcomas (STS) are a heterogeneous group of rare malignancies frequently studied and treated as if they were one and the same disease. Evidence is emerging that distinct histopathological differences between the subtypes can significantly impact on optimal management of patients with STS. For the majority of patients with localized disease, surgery is the treatment of choice, sometimes combined with radiotherapy. For patients with advanced/refractory disease, there are a number of options. The first option is to consider cytotoxic chemotherapy with doxorubicin ± ifosfamide to reduce tumor size and make the tumor more amenable to surgery. If this is not possible, treatment should be aimed at reducing symptoms, improving patients' wellbeing and prolonging life. In this regard, understanding of the different biologies and sensitivities of the various histological subtypes of STS continues to expand, and an increasing number of targeted therapies are becoming available. Examples of more specific treatment options include taxanes in angiosarcoma, and trabectedin in leiomyosarcoma, liposarcoma and undifferentiated pleomorphic sarcoma. Although much remains to be learned about these rare malignancies, it is anticipated that small steps taken in recent years will lead to bigger leaps forward in future. © 2014 Future Medicine Ltd.
Strauss J.M.,Helios Klinikum Berlin Buch
Medizinische Klinik - Intensivmedizin und Notfallmedizin | Year: 2016
Dosing errors when administering medicine to children occur often and are due, e.g., to the commonly required dilution of the drugs, misjudgment of the patient's weight, confusion between drugs with similar names, and inadequate communication. Various aids (e.g., measuring tapes and dilution tables) have been designed to avoid mistakes to the greatest extent possible. In daily clinical practice, books and pocket cards are still used for rapid orientation. Use of smartphone-based apps continues to increase, whereby the user is ultimately responsible for their validity. In clinical practice, the simplest possible strategies should be used. A culture that encourages disclosure of errors is useful in order to optimize processes and avoid future errors. © 2015, The Author.
Reichardt P.,HELIOS Klinikum Berlin Buch
Expert Review of Anticancer Therapy | Year: 2013
Treatment of advanced soft tissue sarcoma remains a considerable therapeutic challenge. Doxorubicin-based combination therapy produces reasonable objective response rates but this comes at the cost of high associated toxicity in the absence of an overall survival benefit in the first-line setting. When selecting chemotherapeutic options for patients with advanced disease, it is important to define the goals and expectations of treatment. For the majority of patients with refractory soft tissue sarcoma, goals are long-term tumor stabilization with good quality of life. Trabectedin is an excellent choice in these patients. The fifth anniversary of the marketing authorization of Yondelis® (PharmaMar S.A., Madrid, Spain; trabectedin) in Europe provides an excellent opportunity to recap current knowledge and see what the future holds with this novel treatment. Trabectedin has made possible new models of care, such as long-term treatment and rechallenge. Its use has also fueled important and necessary debate about the criteria currently used to evaluate tumor response. © 2013 2013 Expert Reviews Ltd.