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Bradley J Monk, Domenica Lorusso, Antoine Italiano, Stan B Kaye, Miguel Aracil, Adnan Tanović, Maurizio D'Incalci
Trabectedin is a marine-derived product that was originally isolated from the Caribbean sea squirt Ecteinascidia turbinata and the first anticancer marine drug to be approved by the European Union. It is currently used as a single agent for the treatment of patients with soft tissue sarcoma after failure of anthracyclines and ifosfamide, or for those patients who are unsuited to receive these agents, and in patients with relapsed, platinum-sensitive ovarian cancer in combination with pegylated liposomal doxorubicin...
September 15, 2016: Cancer Treatment Reviews
Jorge Hernando-Cubero, Pilar Sanz-Moncasi, Alba Hernández-García, Isabel Pajares-Bernard, Javier Martínez-Trufero
The Ewing's sarcoma family of tumors (ESFT) comprises a number of rare malignant tumors. Standard first-line treatment for patients with these tumors includes chemotherapy with a five-drug regimen of vincristine, doxorubicin (Adriamycin(®)) and cyclophosphamide, alternating with ifosfamide and etoposide (VAC/IE). In cases of inadequate response, there are a number of second-line regimens available. However, further treatment options are required for those patients with disease unresponsive to standard treatment...
October 2016: Oncology Letters
Matt L Harlow, Nichole Maloney, Joseph Roland, María José Guillén-Navarro, Matthew K Easton, Susan M Kitchen-Goosen, Elissa A Boguslawski, Zachary B Madaj, Ben K Johnson, Megan J Bowman, Maurizio D'Incalci, Mary E Winn, Lisa Turner, Galen Hostetter, Carlos M Galmarini, Pablo M Aviles, Patrick J Grohar
There is a great need to develop novel approaches to target oncogenic transcription factors with small molecules. Ewing sarcoma is emblematic of this need, as it depends on the continued activity of the EWS-FLI1 transcription factor to maintain the malignant phenotype. We have previously shown that the small molecule trabectedin interferes with EWS-FLI1. Here we report important mechanistic advances and a second-generation inhibitor to provide insight into the therapeutic targeting of EWS-FLI1. We discovered that trabectedin functionally inactivated EWS-FLI1 by redistributing the protein within the nucleus to the nucleolus...
October 3, 2016: Cancer Research
G Galletti, F Caligaris-Cappio, M T S Bertilaccio
The development and progression of chronic B-cell tumors depend on a complex microenvironmental network of cells that include monocyte-derived macrophages. In chronic lymphocytic leukemia (CLL) the survival of malignant cells is supported in vitro by nurse-like cells, which differentiate from CD14(+) monocytes and have been identified as tumor-associated macrophages (TAMs). The role of the monocyte/macrophage lineage in CLL has been extensively studied in vitro, but only recently has been investigated in in vivo models...
October 14, 2016: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
Inder Pal Singh, Purvi Shah
INTRODUCTION: 1,2,3,4-Tetrahydroisoquinoline (THIQ) is one of the "privileged scaffolds", commonly found in nature. Initially, this class of compounds was known for its neurotoxicity. Later on, 1-methyl-1,2,3,4-tetrahydroisoquinoline was proved as an endogeneous Parkinsonism-preventing agent in mammals. The fused THIQs have been studied for their role as anticancer antibiotics. The US FDA approval of the trabectedin for the treatment of soft tissue sarcomas, is a milestone in the anticancer drug discovery...
September 13, 2016: Expert Opinion on Therapeutic Patents
Ritika Zijoo, Margaret von Mehren
INTRODUCTION: Trabectedin (ET-743) is a synthetic marine derived alkylating agent, extracted originally from a Caribbean Sea sponge. It is approved for the treatment of Soft Tissue sarcomas (STS) in Europe and recently by the FDA for liposarcomas and leiomyosarcomas. AREAS COVERED: Trabectedin has multiple mechanisms of action, including one targeting the FUS-CHOP oncogene in Myxoid/Round cell Liposarcomas. Numerous Phase I, II and III clinical trials have been conducted with Trabectedin...
October 2016: Expert Opinion on Pharmacotherapy
Ingrid M E Desar, Anastasia Constantinidou, Suzanne E J Kaal, Robin L Jones, Winette T A van der Graaf
Soft-tissue sarcomas (STS) are a heterogeneous group of rare solid tumors of mesenchymal origin. This paper reviews the current status of systemic treatment in advanced and metastatic soft tissue sarcomas, with an emphasis on trabectedin. Trabectedin is a unique type of chemotherapeutic agent with multiple potential mechanisms of action. We discuss the putative mechanisms, as well as the toxicity and administration schedules of trabectedin, followed by its efficacy in first-line systemic therapy and beyond first-line systemic therapy...
2016: Cancer Management and Research
Gianmaria Miolo, Alessandra Viel, Vincenzo Canzonieri, Tania Baresic, Angela Buonadonna, Davide Adriano Santeufemia, Della Puppa Lara, Giuseppe Corona
We report an interesting clinical case of a patient carrying a specific BRCA2 germline variant affected by bone and hepatic metastases from a high grade uterine stromal sarcoma who obtained a complete metabolic response after only 3 cycles of trabectedin treatment (1.5 mg/m(2) given intravenously over 24 hours every 21 days). Molecular investigations linked this outstanding positive pharmacological response with the loss of heterozygosity (LOH) of the mutated BRCA2 gene. These data support the hypothesis that the response to trabectedin may be positively conditioned by the different DNA repair defects present in the neoplasm and that BRCAness tumor genotype is important in determining the efficacy of trabectedin-based chemotherapy...
October 2, 2016: Cancer Biology & Therapy
Jennifer Y Sheng, Sujana Movva
Soft tissue sarcomas are rare tumors that present with distant metastasis in up to 10% of patients. Survival has improved significantly because of advancements in histologic classification and improved management approaches. Older agents such as doxorubicin, ifosfamide, gemcitabine, and paclitaxel continue to demonstrate objective response rates from 18% to 25%. Newer agents such as trabectedin, eribulin, aldoxorubicin, and olaratumab have demonstrated improvements in progression-free survival, overall survival, or toxicity profiles...
October 2016: Surgical Clinics of North America
Johanne Daupin, Pascal Paubel, Julie Fillon, Isabelle Debrix, Daniele G Soares, Jean-Pierre Lotz
INTRODUCTION: The active clinical research programme of trabectedin continues to improve knowledge on the therapeutic activity and toxicity of the drug in the treatment of soft tissue sarcomas (STS). In contrast, limited number of data is available on its use outside of clinical trials. PATIENTS AND METHODS: We retrospectively analysed efficacy and safety of trabectedin when given in daily practice to patients with advanced/recurrent STS. Outcomes were compared with previously published works including clinical and retrospective studies...
August 18, 2016: Journal of Chemotherapy
Ann Colosia, Shahnaz Khan, Michelle D Hackshaw, Alan Oglesby, James A Kaye, Jeffrey M Skolnik
This systematic literature review describes adverse events (AEs) among patients with soft tissue sarcoma (STS) who received second-line or later anticancer therapies. Searches were conducted in PubMed, EMBASE, and Cochrane Central Register of Controlled Trials for studies of adults with advanced or metastatic STS who received systemic anticancer therapy before enrollment in a randomized-controlled trial of pazopanib, another targeted cancer agent, or cytotoxic chemotherapy. Of 204 publications identified, seven articles representing six unique studies met inclusion criteria...
2016: Sarcoma
Mir A Hoda, Christine Pirker, Yawen Dong, Karin Schelch, Petra Heffeter, Kushtrim Kryeziu, Sushilla van Schoonhoven, Thomas Klikovits, Viktoria Laszlo, Anita Rozsas, Judit Ozsvar, Walter Klepetko, Balazs Döme, Michael Grusch, Balazs Hegedüs, Walter Berger
Malignant pleural mesothelioma (MPM) is characterized by widespread resistance to systemic therapy. Trabectedin is an antineoplastic agent targeting both the malignant cells and the tumor microenvironment that has been approved for the treatment of advanced soft tissue sarcoma and ovarian cancer. In this preclinical study, we evaluated the antineoplastic potential of trabectedin as a single agent and in drug combination approaches in human MPM. Therefore, we utilized an extended panel of MPM cell lines (n = 6) and primary cell cultures from surgical MPM specimens (n = 13), as well as nonmalignant pleural tissue samples (n = 2)...
October 2016: Molecular Cancer Therapeutics
Ravin Ratan, Shreyaskumar R Patel
Soft tissue sarcoma is a term used to describe a heterogeneous group of many rare tumors. Since the initial description of activity of doxorubicin, several additional agents have been brought to bear in the treatment of these diseases. Despite 2 recent drug approvals, doxorubicin and ifosfamide remain the most effective chemotherapy drugs available for the treatment of majority of these tumors. Optimal dosing and administration influence outcomes because of the steep dose-response curves associated with these agents...
October 2016: Cancer
Hideo Morioka, Shunji Takahashi, Nobuhito Araki, Hideshi Sugiura, Takafumi Ueda, Mitsuru Takahashi, Tsukasa Yonemoto, Hiroaki Hiraga, Toru Hiruma, Toshiyuki Kunisada, Akihiko Matsumine, Michiro Susa, Robert Nakayama, Kazumasa Nishimoto, Kazutaka Kikuta, Keisuke Horiuchi, Akira Kawai
BACKGROUND: Trabectedin is reported to be particularly effective against translocation-related sarcoma. Recently, a randomized phase 2 study in patients with translocation-related sarcomas unresponsive or intolerable to standard chemotherapy was conducted, which showed clinical benefit of trabectedin compared with best supportive care (BSC). Extraskeletal myxoid chondrosarcoma (EMCS) and Mesenchymal chondrosarcoma (MCS) are very rare malignant soft tissue sarcomas, and are associated with translocations resulting in fusion genes...
2016: BMC Cancer
André Cruz, Luís Bretes, Carlos Reis, Irene Furtado
Inferior vena cava leiomyosarcoma is a very rare tumor, accounting for only 0.5% of all soft tissue sarcomas. As the other leyomiosarcomas of vascular origin, they have a poor prognosis, and radical resection with surgical margins free of tumor is the only potentially curative treatment. We present a case of a 46 year-old woman with metastatic inferior vena cava leiomyosarcoma who progressed after anthracyclines and ifosfamide and achieved a complete and sustained response with trabectedin. Beyond progression, the patient started third line treatment with pazopanib...
April 2016: Acta Médica Portuguesa
Giacomo G Baldi, Samantha Di Donato, Rossana Fargnoli, Manjola Dona, Rossella Bertulli, Elisabetta Parisi, Lorenzo Fantini, Marta Sbaraglia, Mauro Panella
Evidence supporting rechallenge in patients responding to first exposure to trabectedin is limited. We report on a 39-year-old woman with advanced high-grade undifferentiated sarcoma (US) retreated twice with trabectedin after first response. The patient presented in June 2006 with an abdominal mass originating from the rear fascia of the rectus abdominis. Staging examinations did not indicate metastases and she underwent surgery; pathology showed a high-grade (FNCLCC G3) US. Subsequently, the patient received five cycles of adjuvant chemotherapy with epirubicin and ifosfamide...
October 2016: Anti-cancer Drugs
Rita De Sanctis, Andrea Marrari, Armando Santoro
INTRODUCTION: Trabectedin, a marine-derived DNA-binding antineoplastic agent, has been registered by the EMA and recently also by the FDA for the treatment of patients with advanced soft-tissue sarcoma (STS), a rare and heterogeneous disease. AREAS COVERED: The antitumor activity of trabectedin is related both to direct effects on cancer cells, such as growth inhibition, cell death and differentiation, and indirect effects related to its anti-inflammatory and anti-angiogenic properties...
August 2016: Expert Opinion on Pharmacotherapy
Ahmad Awada, Javier Cortés, Miguel Martín, Philippe Aftimos, Mafalda Oliveira, Sara López-Tarruella, Marc Espie, Pilar Lardelli, Sonia Extremera, Eva M Fernández-García, Suzette Delaloge
BACKGROUND: Preclinical and clinical data suggest that xeroderma pigmentosum G gene (XPG) status might predict trabectedin efficacy. This phase 2 study evaluated the efficacy of trabectedin at a dose of 1.3 mg/m(2) as a 3-hour intravenous infusion every 3 weeks in hormone receptor-positive, HER-2 (human epidermal growth factor receptor 2)-negative, advanced breast cancer patients according to the tumor level of XPG mRNA expression. PATIENTS AND METHODS: Patients were stratified into high-XPG (>3) or low-XPG (≤ 3) groups...
May 14, 2016: Clinical Breast Cancer
Erlinda M Gordon, K Kumar Sankhala, Neal Chawla, Sant P Chawla
UNLABELLED: Trabectedin (ET743, Yondelis(®), manufactured by Baxter Oncology GmbH, Halle/Westfalen, Germany, for Janssen Products, LP, Horsham, PA), derived from the marine ascidian, Ecteinascidia turbinata, is a natural alkaloid with multiple complex mechanisms of action. On 23 October 2015, 15 years after the results of the first Phase 1 clinical trial using trabectedin for chemotherapy-resistant solid malignancies was reported, and 8 years after its approval in Europe, the United States Food and Drug Administration (USFDA) finally approved trabectedin for the treatment of unresectable or metastatic liposarcoma or leiomyosarcoma that has failed a prior anthracycline-containing regimen...
July 2016: Advances in Therapy
Javier Martin-Broto, Antonio López Pousa, Ramón de Las Peñas, Xavier García Del Muro, Antonio Gutierrez, Javier Martinez-Trufero, Josefina Cruz, Rosa Alvarez, Ricardo Cubedo, Andrés Redondo, Joan Maurel, Juan A Carrasco, José A López-Martin, Ángeles Sala, José Andrés Meana, Rafael Ramos, Jordi Martinez-Serra, José A Lopez-Guerrero, Isabel Sevilla, Carmen Balaña, Ángeles Vaz, Ana De Juan, Regina Alemany, Andrés Poveda
PURPOSE: Doxorubicin and trabectedin are considered active drugs in soft tissue sarcoma (STS). The combination of both drugs was hypothesized to be advantageous and safe on the basis of preclinical evidence and a previous phase I trial, respectively. The aim of this study was to compare the clinical outcome of trabectedin plus doxorubicin with doxorubicin as first-line treatment of advanced STS patients. PATIENTS AND METHODS: In this open-label randomized phase II trial, the main end point was progression-free survival (PFS)...
July 1, 2016: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
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