Staging by imaging in gynecologic cancer and the role of ultrasound: an update of European joint consensus statements.

In recent years the role of diagnostic imaging by pelvic ultrasound in the diagnosis and staging of gynecological cancers has been growing exponentially. Evidence from recent prospective multicenter studies has demonstrated high accuracy for pre-operative locoregional ultrasound staging in gynecological cancers. Therefore, in many leading gynecologic oncology units, ultrasound is implemented next to pelvic MRI as the first-line imaging modality for gynecological cancer.

The chemokine system and its contribution to leukemogenesis and treatment responsiveness in patients with acute myeloid leukemia.

The chemokine family consists of approximately 50 small (8-14 kDa), basic proteins that are expressed and released by a wide range of normal and malignant cells. Most chemokines act through heptahelical transmembrane G protein- coupled receptors. Based on their molecular structure these cytokines are divided into the two major subgroups CCL and CXCL chemokines that bind to CCR or CXCR receptors respectively.

Circulating T cells derived from acute leukemia patients with severe therapy-induced cytopenia express a wide range of chemokine receptors.

Normal T cells can mediate antileukemic reactivity after allogeneic stem cell transplantation and T cell targeting immunotherapy is now considered for patients receiving conventional chemotherapy. This antileukemic reactivity is most effective in patients with a low leukemia cell burden, and this burden is expected to be lowest early after transplantation/chemotherapy when patients are cytopenic. Local T cell recruitment will then be essential for the efficiency of the antileukemic response.

Subclassification of patients with acute myelogenous leukemia based on chemokine responsiveness and constitutive chemokine release by their leukemic cells.

Background And Objectives: Chemokines are soluble mediators involved in angiogenesis, cellular growth control and immunomodulation. In the present study we investigated the effects of various chemokines on proliferation of acute myelogenous leukemia (AML) cells and constitutive chemokine release by primary AML cells.

Design And Methods: Native human AML cells derived from 68 consecutive patients were cultured in vitro.

Stress-induced in vitro apoptosis of native human acute myelogenous leukemia (AML) cells shows a wide variation between patients and is associated with low BCL-2:Bax ratio and low levels of heat shock protein 70 and 90.

Spontaneous in vitro apoptosis reflects a true biological heterogeneity between patients which has to be considered when in vitro models are used to study regulation of apoptosis in native human AML cells. Even though the balance between pro- and anti-apoptotic signaling seems to have a prognostic impact in AML, the possible clinical relevance of spontaneous apoptosis remains to be clarified. High apoptosis/low viability was associated with low levels of heat shock proteins 70 and 90 as well as low Bcl-2:Bax ratio for patients heterogeneous with regard to morphology, membrane molecule expression, genetic abnormalities and response to therapy.

T lymphocyte chemotactic chemokines in acute myelogenous leukemia (AML): local release by native human AML blasts and systemic levels of CXCL10 (IP-10), CCL5 (RANTES) and CCL17 (TARC).

T cell targeting immunotherapy is now considered in acute myelogenous leukemia (AML), and local recruitment of antileukemic T cells to the AML microcompartment will then be essential. This process is probably influenced by both intravascular as well as extravascular levels of T cell chemotactic chemokines. We observed that native human AML cells usually showed constitutive secretion of the chemotactic chemokines CXCL10 and CCL5, whereas CCL17 was only released for a subset of patients and at relatively low levels.

Antiangiogenic therapy in acute myelogenous leukemia: targeting of vascular endothelial growth factor and interleukin 8 as possible antileukemic strategies.

Acute myelogenous leukemia (AML) is an aggressive disorder with an overall disease-free survival of 40-50% even for the younger patients under 60 years of age who can receive the most intensive treatment. The median age at the time of diagnosis is 60-65 years, and the large majority of elderly patients usually receive less intensive chemotherapy or only supportive therapy due to the high treatment-related mortality when using intensive therapy for elderly individuals. Thus, there is a need for new therapeutic approaches to improve the treatment in younger patients and to make AML-directed therapy with acceptable toxicity possible in elderly individuals.

Lipoteichoic acid derived from Enterococcus faecalis modulates the functional characteristics of both normal peripheral blood leukocytes and native human acute myelogenous leukemia blasts.

Objectives: Several case reports have described complete hematological remissions for patients with otherwise untreated acute myelogenous leukemia (AML) who receive hematopoietic growth factor therapy during complicating bacterial infections. This may be caused by indirect cytokine effects, but direct effects of infecting agents on the malignant cells are also possible because bacterial molecules can bind to specific receptors expressed by normal and malignant leukocytes. Lipoteichoic acid (LTA) is a cell wall component of gram-positive bacteria, and it can activate normal immunocompetent cells through binding to specific cell membrane receptors.

Osteoblasts increase proliferation and release of pro-angiogenic interleukin 8 by native human acute myelogenous leukemia blasts.

Background And Objectives: Interactions between acute myelogenous leukemia (AML) blasts and non-leukemic cells in the bone marrow seem to be important for both disease development and susceptibility to chemotherapy. Recent studies have focused on the endothelial cells, but other non-leukemic cells may also be involved. In the present study we investigated how osteoblasts affect native human AML blasts.

The angioregulatory phenotype of native human acute myelogenous leukemia cells: influence of karyotype, Flt3 abnormalities and differentiation status.

Introduction: The cytogenetic abnormalities and the response to induction therapy have been regarded as the most important prognostic parameters in acute myelogenous leukemia (AML) patients. Recent studies have demonstrated that internal tandem duplications and specific D-835 point mutations of the Flt3 gene, as well as the angioregulatory phenotype represent additional adverse prognostic factors. The aim of the study was to investigate possible associations between genetic abnormalities, differentiation status and angioregulatory phenotype in native human AML blasts.

Interleukin-7 (IL-7) in patients receiving intensive chemotherapy for acute myelogenous leukemia: studies of systemic IL-7 Levels and IL-7 responsiveness of circulating T lymphocytes.

Early immune reconstitution after intensive chemotherapy for acute myelogenous leukemia (AML) occurs after 2-4 weeks of cytopenia, but T cell reconstitute is usually completed after several months. Interleukin-7 (IL-7) is a T cell growth factor involved in the late immune reconstitution, but its function during the early period of cytopenia has not been investigated. In the present study, we found that patients with untreated AML had decreased IL-7 serum levels, and induction chemotherapy had divergent effects on these levels.

Serum levels of angiogenin, basic fibroblast growth factor and endostatin in patients receiving intensive chemotherapy for acute myelogenous leukemia.

Angiogenesis seems to be important both in the pathogenesis of acute myelogenous leukemia (AML) and for the susceptibility of AML blasts to chemotherapy. Recent clinical studies even suggest that antiangiogenic therapy can induce disease control in patients with AML relapse. In this context we have investigated the profile of the systemic component of angiogenic regulation in AML by characterizing the serum levels of (i) the angiogenic regulators angiogenin, basic fibroblast growth factor (bFGF) and endostatin; (ii) the endothelial cell marker soluble (s) E-selectin.

Biological treatment in acute myelogenous leukaemia: how should T-cell targeting immunotherapy be combined with intensive chemotherapy?

T-cell targeting immunotherapy is now considered as a possible strategy in the treatment of acute myelogenous leukaemia (AML). Clinical importance of antileukaemic T-cell reactivity after allogeneic stem cell transplantation (SCT) is well established and the early experience from IL-2 therapy suggests that even autologous T-cells can mediate antileukaemic reactivity. The clinical experience also indicates that immunotherapy should begin when the leukaemia cell burden is minimal, and the detection of an operative cellular immune system, even in patients with chemotherapy-induced cytopenia, further suggests that it is possible to begin T-cell targeting therapy early after chemotherapy while patients are still cytopenic.

Effects of azoles on human acute myelogenous leukemia blasts and T lymphocytes derived from acute leukemia patients with chemotherapy-induced cytopenia.

The effects of azoles (fluconazole, ketoconazole, miconazole, itraconazole) on human acute myelogenous leukemia (AML) blasts and T lymphocytes were studied in vitro. All the azoles altered spontaneous proliferation, cytokine-dependent proliferation and constitutive cytokine secretion by native AML blasts for a subset of patients, and all the drugs then had divergent effects. All four drugs also affected the responsiveness (cytokine-dependent and mitogen-stimulated proliferation, cytokine release) of clonogenic CD4+ and CD8+ T cells derived from acute leukemia patients with chemotherapy-induced cytopenia.

Hematopoietic growth factors in patients receiving intensive chemotherapy for malignant disorders: studies of granulocyte-colony stimulating factor (G-CSF), granulocyte-macrophage colony stimulating factor (GM-CSF), interleukin-3 (IL-3) and Flt-3 ligand (Flt3L).

The levels of hematopoietic growth factors in patients receiving intensive chemotherapy for malignant disorders were investigated using a variety of approaches. Firstly, serum levels of granulocyte-macrophage colony-stimulating factor (GM-CSF), G-CSF and Flt3-ligand (Flt3L) were examined in acute leukemia patients with treatment-induced cytopenia and complicating bacterial infections. Increased serum levels of both G-CSF and Flt3-ligand (Flt3L) were detected when these patients developed therapy-induced leukopenia, whereas GM-CSF levels were low or undetectable.

New strategies in the treatment of acute myelogenous leukemia: mobilization and transplantation of autologous peripheral blood stem cells in adult patients.

During the last decade high-dose Ara-C (HIDAC; single doses of 3 g/m(2)) and autologous stem cell transplantation have been increasingly used as postremission therapy in adult acute myelogenous leukemia (AML). Controlled clinical trials have demonstrated a long-term disease-free survival of 40%-50% for patients treated with at least two courses of HIDAC. Other studies have demonstrated that postremission autologous bone marrow transplantation results in a disease-free survival equal to or better than conventional chemotherapy.

Autologous stem cell transplantation as post-remission therapy in adult acute myelogenous leukemia: does platelet contamination of peripheral blood mobilized stem cell grafts influence the risk of leukemia relapse?

Conventional chemotherapy of acute myelogenous leukemia (AML) results in an overall long-term disease-free survival of less than 50%, but for selected subsets of younger patients the prognosis can be improved by allogeneic stem cell transplantation. The use of autologous stem cell transplantation is now investigated as an alternative to allotransplantation due to its lower risk of serious complications. However, autotransplantation is associated with a relatively high risk of post-transplant AML relapse that can be derived from contaminating leukemia cells in the autograft.

Effects of imipenem and cilastatin on human T-lymphocytes derived from acute leukemia patients with chemotherapy-induced leucopenia: studies of T-lymphocyte responses in the presence of acute myelogenous leukemia (AML) blast accessory cells.

The effects of imipenem and cilastatin on human T-lymphocytes were studied in vitro. As responder T-cells were used T-lymphocyte clones derived from acute leukemia patients with chemotherapy-induced cytopenia, and the accessory cells were highly enriched acute myelogenous leukemia (AML) blasts. The effects of imipenem and cilastatin on phytohemagglutinin (PHA), anti-CD3 and anti-CD3+anti-CD28 stimulated activation were assayed, and in addition drug effects on cytokine-dependent proliferation of activated T-lymphocytes were investigated.

Acute myelogenous leukemia blasts as accessory cells during T lymphocyte activation: possible implications for future therapeutic strategies.

Both clinical and experimental evidence indicate that T lymphocytes can mediate antileukemic effects in acute myelogenous leukemia (AML). These antileukemic effects can be either nonspecific cytotoxicity (killer cell activity) or reactivity against leukemia-specific antigenic peptides presented by self-HLA molecules. The antigen-specific T cell activation requires recognition of specific peptides together with costimulatory signalling.

IL-4, IL-10 and IL-13 in acute myelogenous leukemia.

Cytokines are important regulators of acute myelogenous leukemia (AML) blast proliferation. For a subset of patients the AML blasts show constitutive cytokine secretion and can undergo autonomous proliferation in vitro, whereas for other patients the blasts are dependent on exogenous cytokines for proliferation. The capability of autocrine proliferation is an adverse prognostic factor in AML.

Interleukin 4 (IL4), IL10 and IL13 Inhibit in vitro Cytokine Secretion by Acute Myelogenous Leukemia Blasts in the Presence of Exogenous Hematopoietic Growth Factors.

The cytokines Interleukin 4 (IL4), IL10 and IL13 have divergent effects on acute myelogenous leukemia (AML) blast proliferation in vitro, and their final effect (enhancement/inhibition/no effect) depends on individual differences between patients and the presence of other exogenous cytokines. In contrast to these divergent effects on blast proliferation, all three cytokines inhibit constitutive (spontaneous) AML blast cytokine secretion independent of their effects on spontaneous blast proliferation. In the present study we investigated whether the inhibitory effects on AML blast cytokine secretion could be reversed by exogenous granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF) or IL3.