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Distinct characteristics of e13a2 versus e14a2 BCR-ABL1 driven chronic myeloid leukemia under first-line therapy with imatinib.
Haematologica
PUBLISHED: 05-16-2014
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The vast majority of chronic myeloid leukemia patients express a BCR-ABL1 fusion gene mRNA encoding a 210 kDa tyrosine kinase which promotes leukemic transformation. A possible differential impact of the corresponding BCR-ABL1 transcript variants e13a2 ("b2a2") and e14a2 ("b3a2") on disease phenotype and outcome is still a subject of debate. A total of 1105 newly diagnosed imatinib-treated patients were analyzed according to transcript type at diagnosis (e13a2, n=451; e14a2, n=496; e13a2+e14a2, n=158). No differences regarding age, sex, or Euro risk score were observed. A significant difference was found between e13a2 and e14a2 when comparing white blood cells (88 vs. 65 × 10(9)/L, respectively; P<0.001) and platelets (296 vs. 430 × 10(9)/L, respectively; P<0.001) at diagnosis, indicating a distinct disease phenotype. No significant difference was observed regarding other hematologic features, including spleen size and hematologic adverse events, during imatinib-based therapies. Cumulative molecular response was inferior in e13a2 patients (P=0.002 for major molecular response; P<0.001 for MR4). No difference was observed with regard to cytogenetic response and overall survival. In conclusion, e13a2 and e14a2 chronic myeloid leukemia seem to represent distinct biological entities. However, clinical outcome under imatinib treatment was comparable and no risk prediction can be made according to e13a2 versus e14a2 BCR-ABL1 transcript type at diagnosis. (clinicaltrials.gov identifier:00055874).
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Imatinib mesylate.
Recent Results Cancer Res.
PUBLISHED: 04-24-2014
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Imatinib mesylate (Gleevec, Glivec [Novartis, Basel, Switzerland], formerly referred to as STI571 or CGP57148B) represents the paradigm of a new class of anticancer agents, so-called small molecules. They have a high selectivity against a specific molecular target known to be the cause for the establishment and maintenance of the malignant phenotype. Imatinib is a rationally designed oral signal transduction inhibitor that specifically targets several protein tyrosine kinases, Abl, Arg (Abl-related gene), the stem cell factor receptor (c-KIT), platelet-derived growth factor receptor (PDGF-R), and their oncogenic forms, most notably BCR-ABL. Imatinib has been shown to have remarkable clinical activity in patients with chronic myeloid leukemia (CML) and malignant gastrointestinal stroma tumors (GIST) leading to its approval for treatment of these diseases. Treatment with imatinib is generally well tolerated with a low incidence of severe side effects. The most common adverse events include mild to moderate edema, muscle cramps, diarrhea, nausea, skin rashes, and myelosuppression. Several mechanisms of resistance have been identified. Clonal evolution, amplification, or overexpression of BCR-ABL as well as mutations in the catalytic domain, P-loop, and other mutations have been demonstrated to play a role in primary and secondary resistance to imatinib, respectively. Understanding of the underlying mechanisms of resistance has led to the development of new second- and third-generation tyrosine kinase inhibitors (see chapters on dasatinib, nilotinib, bosutinib, and ponatinib).
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Neuroendocrine tumors of the bronchopulmonary system (typical and atypical carcinoid tumors): current strategies in diagnosis and treatment. Conclusions of an expert meeting February 2011 in Weimar, Germany.
Oncol Res Treat
PUBLISHED: 02-24-2014
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Neuroendocrine tumors (NETs; syn. carcinoid tumors) are highly or moderately differentiated neoplasms. They comprise a large variety of rare and heterogeneous tumors with an estimated incidence of 3-5/100,000/year. They can arise in virtually every internal organ, but mainly occur in the gastroenteropancreatic and bronchopulmonary systems. Around 25% of the NETs are localized in the bronchopulmonary system. Approximately 2% of all lung tumors are NETs. According to the World Health Organization (WHO) classification of lung tumors, bronchopulmonary NETs are subdivided into typical carcinoids (TCs) and atypical carcinoids (ACs). The parameter with the highest impact on NET behavior and prognosis is the histological classification and staging according to the tumor/node/metastasis (TNM) system. The diagnosis of NETs is established by histological examination and the immunohistochemical detection of general neuroendocrine markers, such as chromogranin A (CgA) and synaptophysin. Serum markers and the use of functional imaging techniques are important additive tools to establish the diagnosis of a NET. The only curative option for lung NETs is complete surgical resection. Beyond that, the currently available interdisciplinary therapeutic options are local ablation, biotherapy (somatostatin analogues), or chemotherapy. New therapeutic options such as peptide receptor radionuclide therapy (PRRT) and molecularly targeted therapies achieve promising results and are under further evaluation. This report is a consensus summary of the interdisciplinary symposium 'Neuroendocrine Tumors of the Lung and of the Gastroenteropancreatic System (GEP NET) - Expert Dialogue' held on February 25-26, 2011 in Weimar, Germany. At this conference, a panel of 23 German experts shared their knowledge and exchanged their thoughts about research, diagnosis, and clinical management of NETs, whereby special attention was paid to NETs of the respiratory tract.
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Younger patients with chronic myeloid leukemia do well in spite of poor prognostic indicators: results from the randomized CML study IV.
Ann. Hematol.
PUBLISHED: 07-25-2013
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Since the advent of tyrosine kinase inhibitors, the impact of age on outcome of chronic myeloid leukemia (CML) patients has changed. We therefore analyzed patients from the randomized CML study IV to investigate disease manifestations and outcome in different age groups. One thousand five hundred twenty-four patients with BCR-ABL-positive chronic phase CML were divided into four age groups: (1) 16-29 years, n?=?120; (2) 30-44 years, n?=?383; (3) 45-59 years, n?=?495; and (4)??60 years, n?=?526. Group 1 (adolescents and young adults (AYAs)) presented with more aggressive disease features (larger spleen size, more frequent symptoms of organomegaly, higher white blood count, higher percentage of peripheral blasts and lower hemoglobin levels) than the other age groups. In addition, a higher rate of patients with BCR-ABL transcript levels >10 % on the international scale (IS) at 3 months was observed. After a median observation time of 67.5 months, no inferior survival and no differences in cytogenetic and molecular remissions or progression rates were observed. We conclude that AYAs show more aggressive features and poor prognostic indicators possibly indicating differences in disease biology. This, however, does not affect outcome.
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Changes in lung function after surgery for mesothelioma.
Asian Cardiovasc Thorac Ann
PUBLISHED: 02-23-2013
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The effect of pleurectomy/decortication or extrapleural pleuropneumonectomy on pulmonary function has not yet been evaluated. The aim of this study was to determine the parameters of pulmonary function before and after pleurectomy/decortication or extrapleural pleuropneumonectomy.
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Impact of additional cytogenetic aberrations at diagnosis on prognosis of CML: long-term observation of 1151 patients from the randomized CML Study IV.
Blood
PUBLISHED: 10-28-2011
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The prognostic relevance of additional cytogenetic findings at diagnosis of chronic myeloid leukemia (CML) is unclear. The impact of additional cytogenetic findings at diagnosis on time to complete cytogenetic (CCR) and major molecular remission (MMR) and progression-free (PFS) and overall survival (OS) was analyzed using data from 1151 Philadelphia chromosome-positive (Ph(+)) CML patients randomized to the German CML Study IV. At diagnosis, 1003 of 1151 patients (87%) had standard t(9;22)(q34;q11) only, 69 patients (6.0%) had variant t(v;22), and 79 (6.9%) additional cytogenetic aberrations (ACAs). Of these, 38 patients (3.3%) lacked the Y chromosome (-Y) and 41 patients (3.6%) had ACAs except -Y; 16 of these (1.4%) were major route (second Philadelphia [Ph] chromosome, trisomy 8, isochromosome 17q, or trisomy 19) and 25 minor route (all other) ACAs. After a median observation time of 5.3 years for patients with t(9;22), t(v;22), -Y, minor- and major-route ACAs, the 5-year PFS was 90%, 81%, 88%, 96%, and 50%, and the 5-year OS was 92%, 87%, 91%, 96%, and 53%, respectively. In patients with major-route ACAs, the times to CCR and MMR were longer and PFS and OS were shorter (P < .001) than in patients with standard t(9;22). We conclude that major-route ACAs at diagnosis are associated with a negative impact on survival and signify progression to the accelerated phase and blast crisis.
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Long-term survival after treatment with gemcitabine and oxaliplatin with and without paclitaxel plus secondary surgery in patients with cisplatin-refractory and/or multiply relapsed germ cell tumors.
Eur. Urol.
PUBLISHED: 04-01-2011
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Chemotherapy including gemcitabine, oxaliplatin, and/or paclitaxel has shown efficacy in germ cell tumor patients after progression during cisplatin-based chemotherapy or relapse after high-dose chemotherapy including complete responses in 5-15%.
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The immunohistochemical staining pattern of Gab2 correlates with distinct stages of chronic myeloid leukemia.
Hum. Pathol.
PUBLISHED: 02-02-2011
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Grb2-associated binder 2 protein (Gab2) is a member of scaffold proteins, playing crucial roles in (receptor-) tyrosine kinase and cytokine signaling. Chronic myeloid leukemia cells with t(9;22)(q34;q11) express the Bcr/Abl fusion protein, which interacts with Grb2 and Gab2 signaling, thereby triggering hematopoietic cell proliferation. The aim of this study was to examine in detail the total and subcellular Gab2 protein expression in myeloid cells in bone marrow biopsies of patients with chronic myeloid leukemia in different disease stages. The study included 50 fixed bone marrow biopsies of controls (unaffected hematopoiesis, n = 11) and Bcr/Abl-positive chronic myeloid leukemia cases (n = 39) of different stages (chronic phase, n = 13; accelerated phase, n = 4; blast crisis, n = 11; complete remission, n = 11). Immunohistochemistry and quantitative evaluation of Gab2 staining in 600 myeloid cells/bone marrow biopsy were performed before statistical analyses. Immunohistochemistry revealed Gab2 expression in hematopoietic cells. Gab2-positive myeloid cells occurred significantly more frequent in chronic myeloid leukemia cases than in controls (P < .001) and appeared to markedly increase from chronic phase to accelerated phase to blast crisis. Importantly, within the distinct stages of chronic myeloid leukemia, a significant switch of Gab2-positive myeloid cells with cytoplasmic or nuclear/perinuclear Gab2 staining occurred: Nuclear/perinuclear Gab2-positive myeloid cells significantly increased from chronic phase to accelerated phase (P = .001) and from chronic phase to blast crisis (P < .001). Still, an overlap and, hence, a wider range of Gab2 staining patterns were seen between and within chronic myeloid leukemia stages, most likely reflecting a high plasticity of Grb2-associated binder 2 functions in the progression of chronic myeloid leukemia. In summary, the present study, for the first time, analyzed Grb2-associated binder 2 protein expression in bone marrow biopsies of patients with chronic myeloid leukemia in detail, demonstrating a novel and distinct Grb2-associated binder 2 staining pattern in normal and chronic myeloid leukemia bone marrow biopsies as well as in distinct chronic myeloid leukemia stages. Grb2-associated binder 2 immunohistochemistry may provide a valuable supplementary tool to routine histopathology and standard immunohistochemistry for classification and staging of (borderline) chronic myeloid leukemia bone marrow biopsies and hence improved therapeutic disease management.
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A phase III randomized equivalence study of biosimilar filgrastim versus Amgen filgrastim in patients receiving myelosuppressive chemotherapy for breast cancer.
Onkologie
PUBLISHED: 09-06-2010
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Filgrastim was developed to treat chemotherapy-induced neutropenia. This phase III study was designed to demonstrate bioequivalence of Amgen filgrastim and a biosimilar filgrastim developed by Hospira (Study GCF071; sponsored by Hospira).
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Long-term follow-up of patients with chronic myeloid leukemia having received autologous stem cell transplantation.
Ann. Hematol.
PUBLISHED: 06-29-2010
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Prior to introduction of imatinib mesylate, the median survival of chronic myeloid leukemia (CML) patients was approximately 60 months and the standard treatment with interferon-alpha (IFN-?) resulted in major cytogenetic responses of 20-25%. As an alternative treatment approach besides allogeneic transplantation, intensive chemotherapy followed by autologous hematopoietic stem cell transplantation (autoHSCT) was investigated at that time with the rationale of debulking disease burden and mobilization and transplantation of Philadelphia chromosome-negative (Ph-) stem cells. In the era of tyrosine kinase inhibitors as state-of-the-art therapy for CML, the concept of autoHSCT has attracted only little interest and long-term follow-up and outcome data after autoHSCT in CML patients is scarce. In this long-term analysis, we report on 21 CML patients, mobilized in early chronic phase and transplanted with largely Ph- grafts, who received IFN? as maintenance therapy. Imatinib mesylate was administered upon cytogenetic relapse or disease progression while on IFN-?. The 10-year survival was 61% and 11 patients (52%) were alive at a median follow-up of 12.5 years (range 0.3-13.8) with eight patients in complete hematologic remission (CHR) and three of eight in major molecular remission (MMR). While all patients in MMR and two of five patients in CHR received imatinib, it is noteworthy that three patients remaining in CHR only received IFN-? maintenance after autoHSCT. With the limitations of a small patient population, this is the longest follow-up analysis demonstrating that autoHSCT in CML is very efficient to debulk the disease, restore Ph-negative hematopoiesis, and is able to induce major and sustained molecular responses in the majority of patients with substantial long-term survival rates.
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The efficacy and safety of BI 2536, a novel Plk-1 inhibitor, in patients with stage IIIB/IV non-small cell lung cancer who had relapsed after, or failed, chemotherapy: results from an open-label, randomized phase II clinical trial.
J Thorac Oncol
PUBLISHED: 06-08-2010
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To investigate the efficacy, safety, and pharmacokinetics of two dosing schedules of BI 2536, a novel polo-like kinase-1 inhibitor, in patients with relapsed stage IIIB/IV non-small cell lung cancer.
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Comparison of the pharmacodynamic profiles of a biosimilar filgrastim and Amgen filgrastim: results from a randomized, phase I trial.
Ann. Hematol.
PUBLISHED: 03-09-2010
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Further to the patent expiry of Neupogen (Amgen filgrastim), Hospira has developed a biosimilar filgrastim (Nivestim) that may offer a clinically effective alternative for multiple hematologic and oncologic indications. Here results are reported from a phase I trial, primarily designed to compare the pharmacodynamic profiles of Hospira filgrastim and Amgen filgrastim. A phase I, single-center, double-blind, randomized trial was undertaken to demonstrate equivalence of the pharmacodynamic characteristics of Hospira filgrastim and Amgen filgrastim. Fifty healthy volunteers were randomized to receive 5 or 10 microg/kg dosing, before further randomization to treatment sequence. All volunteers received five daily subcutaneous doses of Hospira filgrastim or Neupogen, with subsequent crossover to the alternative treatment. Bioequivalence was evaluated by analysis of variance; if the estimated 90% confidence intervals (CIs) for the ratio of test to reference treatment means were within the conventional equivalence limits of 0.80-1.25, then bioequivalence was concluded. Forty-eight volunteers completed the study. Geometric mean absolute neutrophil count area under the curve from time 0 to the last time point at day 5 (primary endpoint) was comparable in volunteers given Hospira filgrastim or Amgen filgrastim at 5 microg/kg (ratio of means, 0.98; 90% CI, 0.92-1.05) or 10 microg/kg (ratio, 0.97; 90% CI, 0.93-1.01); 90% CIs were within the predefined range necessary to demonstrate bioequivalence. Hospira filgrastim was well tolerated with no additional safety concerns over Amgen filgrastim. Hospira filgrastim is bioequivalent with Amgen filgrastim with regard to its pharmacodynamic characteristics.
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Pharmacokinetic profiles of a biosimilar filgrastim and Amgen filgrastim: results from a randomized, phase I trial.
Ann. Hematol.
PUBLISHED: 03-09-2010
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Recombinant human granulocyte colony-stimulating factor (filgrastim) has multiple hematologic and oncologic indications as Neupogen (Amgen filgrastim). Hospira has developed a biosimilar filgrastim (Nivestim). Here, results are reported from a phase I trial, primarily designed to compare the pharmacokinetic profiles of Hospira filgrastim and Amgen filgrastim. A phase I, single-center, open-label, randomized trial was undertaken to demonstrate equivalence of the pharmacokinetic characteristics of Hospira filgrastim and Amgen filgrastim. Forty-eight healthy volunteers were randomized to receive intravenous (i.v.) or subcutaneous (s.c.) dosing and then further randomized to order of treatment. Volunteers in each of the two dosing groups received a single 10microg/kg dose of Hospira filgrastim or Amgen filgrastim, with subsequent crossover. Bioequivalence was evaluated by analysis of variance; if the estimated 90% confidence intervals (CIs) for the ratio of test to reference treatment means were within the conventional equivalence limits of 0.80-1.25, then bioequivalence was concluded. Forty-six volunteers completed the study. Geometric mean area under the curve from time 0 to the last time point (primary endpoint) was similar in volunteers given Hospira filgrastim or Amgen filgrastim following i.v. (ratio of means: 0.96; 90% CI: 0.90-1.02) or s.c. (ratio of means: 1.02; 90% CI: 0.95-1.09) dosing; 90% CIs were within the predefined range necessary to demonstrate bioequivalence. Hospira filgrastim was well tolerated with no additional safety concerns over Amgen filgrastim. Hospira filgrastim is bioequivalent with Amgen filgrastim in terms of its pharmacokinetic properties and may provide a clinically effective alternative.
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Imatinib mesylate.
Recent Results Cancer Res.
PUBLISHED: 01-15-2010
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IMATINIB MESYLATE (Gleevec, Glivec [Novartis, Basel, Switzerland], formerly referred to as STI571 or CGP57148B) represents the paradigm of a new class of anticancer agents, the so-called small molecules. They have a high selectivity against a specific molecular target known to be the cause for the establishment and maintenance of the malignant phenotype. Imatinib is a rationally designed oral signal transduction inhibitor that specifically targets several protein tyrosine kinases, Abl, Arg (Abl-related gene), the stem-cell factor receptor (c-KIT), platelet-derived growth factor receptor (PDGF-R), and their oncogenic forms, most notably Bcr-Abl. Imatinib has been shown to have remarkable clinical activity in patients with chronic myeloid leukemia (CML) and malignant gastrointestinal stroma tumors (GIST) leading to its approval for treatment of these diseases.Treatment with imatinib is generally well tolerated with a low incidence of severe side effects. The most common adverse events (AE) include mild to moderate edema, muscle cramps, diarrhea, nausea, skin rashes, and myelosuppression.Several mechanisms of resistance have been identified. Clonal evolution, amplification, or overexpression of Bcr-Abl as well as mutations in the catalytic domain, P-loop, and other mutations have been demonstrated to play a role in primary and secondary resistance to imatinib, respectively. Improved understanding of the underlying mechanisms of resistance has led to the development of new second-generation tyrosine kinase inhibitors (see Chaps. 7-9).
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Severe Organizing Pneumonia after Two Cycles of Docetaxel as Fourth-Line Chemotherapy for Advanced Non-Small Cell Carcinoma of the Lung.
Case Rep Oncol
PUBLISHED: 02-16-2009
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Organizing pneumonia (formerly known as bronchiolitis obliterans organizing pneumonia, BOOP) is an inflammatory process of the bronchioles that can lead to the destruction of small airways and surrounding lung tissue. Although the majority of cases are idiopathic, certain chemicals and drugs can induce OP. Here, we report a 54-year-old male patient with advanced non-small cell lung cancer (NSCLC) who developed therapy-associated OP. He had undergone several other chemotherapies before being switched to docetaxel as monotherapy (75 mg/m(2)). Treatment was initially well tolerated, but after the second cycle the patient developed increasing shortness of breath. Computed tomography (CT) for staging after the second cycle showed bilateral predominantly interstitial infiltration highly suggestive of acute lung fibrosis. Bronchoscopy revealed signs of chronic bronchitis and watery discharge from both lungs. Bronchoalveolar lavage and transbronchial needle biopsy was performed. Based on histopathologic examination, diagnosis of OP was made. After cessation of docetaxel and initial high dose steroids, the infiltration ameliorated rapidly. This is the second case in the literature that associates docetaxel with rapid onset of bronchiolitis obliterans. Therefore, patients with lung cancer receiving docetaxel who develop respiratory symptoms should be suspected to develop OP.
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JoVE Visualize is a tool created to match the last 5 years of PubMed publications to methods in JoVE's video library.

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In developing our video relationships, we compare around 5 million PubMed articles to our library of over 4,500 methods videos. In some cases the language used in the PubMed abstracts makes matching that content to a JoVE video difficult. In other cases, there happens not to be any content in our video library that is relevant to the topic of a given abstract. In these cases, our algorithms are trying their best to display videos with relevant content, which can sometimes result in matched videos with only a slight relation.