To develop a mathematical model to adjust the timing of computed tomography (CT) scans with the hazard of cancer recurrence in time to facilitate early detection of cancer recurrence.
The clinical ...data were extracted from the randomized Scandinavian Sarcoma Group (SSG) XVIII/Arbeitsgemeinschaft Internistische Onkologie (AIO) trial database. The SSG XVIII/AIO trial was registered (trial no. NCT00116935) and approved by the national or institutional review boards. In the trial, 1- and 3-year durations of adjuvant imatinib mesylate in the treatment of patients with gastrointestinal stromal tumor (GIST) were compared. A nonhomogeneous Poisson model with a piecewise log-constant hazard in time that accounts for the nonlinear pattern of GIST recurrence was applied to tumor site, mitotic count, and recurrence data. The optimal times to obtain follow-up CT scans were computed by modifying the frequency of CT scans with the hazard of tumor recurrence in time. The hazard-adjusted follow-up schedules were compared with the National Comprehensive Cancer Network (NCCN) guidelines of the United States, which suggest imaging with CT at intervals of 3-6 months for 3-5 years and then annually.
Optimized timing of CT scans on the basis of hazard of recurrence resulted in follow-up schedule options where CT is performed more sparsely than in the NCCN guidelines during adjuvant imatinib administration and more frequently, at approximately 3-month intervals, during the first 2 years that follow imatinib discontinuation when the risk of recurrence was the greatest. The number of CT scans could be reduced by a median of 31% (from 13 to nine) compared with the standard schedules within the first 6 years of follow-up without increasing the delay in recurrence detection.
Detection of GIST recurrence may be enhanced by adjusting the timing of the CT scans with the hazard of recurrence. The method may be applicable to other human tumor types. Online supplemental material is available for this article.
Regulatory T-cells (Tregs) are central for immune homeostasis and divided in thymus-derived natural Tregs and peripherally induced iTreg. However, while phenotype and function of iTregs are well ...known, a remarkable lack exists in knowledge about signaling mechanisms leading to their generation from naïve precursors in peripheral tissues. Using antigen specific naïve T-cells from mice, we investigated CD4+ CD25+ FoxP3- iTreg induction during antigen-specific T-cell receptor (TCR) stimulation with weak antigen presenting cells (APC). We show that early signaling pathways such as ADAM-17-activation appeared similar in developing iTreg and effector cells (Teff) and both initially shedded CD62-L. But iTreg started reexpressing CD62-L after 24 h while Teff permanently downmodulated it. Furthermore, between 24 and 72 hours iTreg presented with significantly lower phosphorylation levels of Akt-S473 suggesting lower activity of the PI3K/Akt-axis. This was associated with a higher expression of the Akt hydrophobic motif-specific phosphatase PHLPP1 in iTreg. Importantly, the lack of costimulatory signals via CD28 from weak APC was central for the development of regulatory function in iTreg but not for the reappearance of CD62-L. Thus, T-cells display a window of sensitivity after onset of TCR triggering within which the intensity of the PI3K/Akt signal controls entry into either effector or regulatory pathways.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The integrin LFA-1 (CD11a/CD18) plays a critical role in the interaction of T cells with antigen presenting cells (APCs) to promote lymphocyte differentiation and proliferation. This integrin can be ...present either in a closed or in an open active conformation and its activation upon T-cell receptor (TCR) stimulation is a critical step to allow interaction with APCs. In this study we demonstrate that the serine/threonine kinase Ndr2 is critically involved in the initiation of TCR-mediated LFA-1 activation (open conformation) in T cells. Ndr2 itself becomes activated upon TCR stimulation and phosphorylates the intracellular integrin binding partner Filamin A (FLNa) at serine 2152. This phosphorylation promotes the dissociation of FLNa from LFA-1, allowing for a subsequent association of Talin and Kindlin-3 which both stabilize the open conformation of LFA-1. Our data suggest that Ndr2 activation is a crucial step to initiate TCR-mediated LFA-1 activation in T cells.
Over the past decade, the development of new targeted therapeutics directed against specific molecular pathways involved in tumor cell proliferation and survival has allowed an essential improvement ...in carcinoma treatment. Unfortunately, the scenario is different for sarcomas, a group of malignant neoplasms originating from mesenchymal cells, for which the main therapeutic approach still consists in the combination of surgery, chemotherapy, and radiation therapy. The lack of innovative approaches in sarcoma treatment stems from the high degree of heterogeneity of this tumor type, with more that 70 different histopathological subtypes, and the limited knowledge of the molecular drivers of tumor development and progression. Currently, molecular therapies are available mainly for the treatment of gastrointestinal stromal tumor, a soft-tissue malignancy characterized by an activating mutation of the tyrosine kinase KIT. Since the first application of this approach, a strong effort has been made to understand sarcoma molecular alterations that can be potential targets for therapy. The low incidence combined with the high level of histopathological heterogeneity makes the development of clinical trials for sarcomas very challenging. For this reason, preclinical studies are needed to better understand tumor biology with the aim to develop new targeted therapeutics. Currently, these studies are mainly based on
testing, since cell lines, and in particular patient-derived models, represent a reliable and easy to handle tool for investigation. In the present review, we summarize the most important models currently available in the field, focusing in particular on the three-dimensional spheroid/organoid model. This innovative approach for studying tumor biology better represents tissue architecture and cell-cell as well as cell-microenvironment crosstalk, which are fundamental steps for tumor cell proliferation and survival.
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.
After the revelation of kinase targeting with orally available small molecules, the use of imatinib in chronic myelogenous leukemia and in gastrointestinal stromal tumor (GIST) has now become ...commonplace and just two of many examples of the use of kinase inhibitors in cancer. In this article, we discuss important practice points that may impact upon questions of therapy of primary and metastatic GIST, with the hope that the questions addressed in this rare solid tumor can serve as examples of what can be achieved with kinase‐directed therapies in other cancers. We present cases that highlight some of the key issues in GIST management and afterward discuss both points of consensus and controversial issues in what is now recognized as one of the most common forms of sarcoma.
Implications for Practice:
The treatment of gastrointestinal stromal tumor (GIST) has become sophisticated with the availability of three approved agents in many countries and 15 years of experience with primary and metastatic disease. Important lessons from tyrosine‐kinase inhibitors in GIST can be gleaned from this experience and will impact implementation of similar agents for other cancers.
This article highlights important practice points that impact upon questions of therapy of primary and metastatic gastrointestinal stromal tumor (GIST) to provide examples of what potentially can be achieved with kinase‐directed therapies in other cancers. This article also presents cases that highlight some of these key issues in GIST management and addresses both points of consensus and controversial issues in what is now recognized as one of the most common forms of sarcoma.
Implantation of the fertilized egg into the maternal uterus depends on the fine balance between inflammatory and anti-inflammatory processes. Whilst regulatory T cells (Tregs) are reportedly involved ...in protection of allogeneic fetuses against rejection by the maternal immune system, their role for pregnancy to establish, e.g., blastocyst implantation, is not clear. By using 2-photon imaging we show that Foxp3(+) cells accumulated in the mouse uterus during the receptive phase of the estrus cycle. Seminal fluid further fostered Treg expansion. Depletion of Tregs in two Foxp3.DTR-based models prior to pairing drastically impaired implantation and resulted in infiltration of activated T effector cells as well as in uterine inflammation and fibrosis in both allogeneic and syngeneic mating combinations. Genetic deletion of the homing receptor CCR7 interfered with accumulation of Tregs in the uterus and implantation indicating that homing of Tregs to the uterus was mediated by CCR7. Our results demonstrate that Tregs play a critical role in embryo implantation by preventing the development of a hostile uterine microenvironment.
From February 2001 to February 2002, 946 patients with advanced GI stromal tumors (GISTs) treated with imatinib were included in a controlled EORTC/ISG/AGITG (European Organisation for Research and ...Treatment of Cancer/Italian Sarcoma Group/Australasian Gastro-Intestinal Trials Group) trial. This analysis investigates whether the response classification assessed by RECIST (Response Evaluation Criteria in Solid Tumors), predicts for time to progression (TTP) and overall survival (OS).
Per protocol, the first three disease assessments were done at 2, 4, and 6 months. For the purpose of the analysis (landmark method), disease response was subclassified in six categories: partial response (PR; > 30% size reduction), minor response (MR; 10% to 30% reduction), no change (NC) as either NC- (0% to 10% reduction) or NC+ (0% to 20% size increase), progressive disease (PD; > 20% increase/new lesions), and subjective PD (clinical progression).
A total of 906 patients had measurable disease at entry. At all measurement time points, complete response (CR), PR, and MR resulted in similar TTP and OS; this was also true for NC- and NC+, and for PD and subjective PD. Patients were subsequently classified as responders (CR/PR/MR), NC (NC+/NC-), or PD. This three-class response categorization was found to be highly predictive of further progression or survival for the first two measurement points. After 6 months of imatinib, responders (CR/PR/MR) had the same survival prognosis as patients classified as NC.
RECIST perfectly enables early discrimination between patients who benefited long term from imatinib and those who did not. After 6 months of imatinib, if the patient is not experiencing PD, the pattern of radiologic response by tumor size criteria has no prognostic value for further outcome. Imatinib needs to be continued as long as there is no progression according to RECIST.
Anthracyclines, as the most effective therapy, are the cornerstone of advanced stage sarcoma treatment. However, anthracyclines can also contribute to myocardial dysfunction and congestive heart ...failure, ultimately limiting the therapeutic potential of the drug. Coadministration of Dexrazoxane has been shown to effectively reduce cardiotoxicity, however primarily in patients suffering in diseases other than sarcoma.
The aim of this retrospective analysis was to evaluate safety and efficacy of chemotherapy with high cumulative doses of anthracyclines in combination with Dexrazoxane. The medical charts of 32 patients treated in four institutions were analyzed. Reasons for coadministration were rechallenge, reaching the cumulative anthracycline dose and preexisting heart failure.
The median age was 54 years 18-68 years. The median cumulative anthracycline dose before adding DRZ was 450 mg/m(2) and after administration of last anthracycline containing therapy 750 mg/m(2). Either during treatment or follow up, 2/27 patients (7 %) without preexisting major cardiac findings developed anthracycline-induced cardiotoxicity. The median overall survival (OS) from start of the first anthracycline containing chemotherapy was 46 months and 17 months from the initial coadministration of DRZ. At rechallenge, the median progression free survival (PFS) with DRZ was 7 months. In continuous therapy, the median PFS was 13 months from beginning of chemotherapy and 9 months from the addition of DRZ.
Chemotherapy with high cumulative doses of anthracyclines in addition with DRZ demonstrated a remarkable OS in these advanced disease patients. Cardiac side-effects due to high cumulative doses of anthracyclines requiring discontinuation of anthracycline treatment were rare. A PFS of 9 months from the beginning of the coadministration of DRZ indicates that continuing anthracycline therapy beyond established cumulative doses is a promising therapeutic option.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Physical interactions between T cells and antigen-presenting cells (APCs) form the basis of any specific immune response. Upon cognate contacts, a multimolecular assembly of receptors and adhesion ...molecules on both cells is created, termed the immunological synapse (IS). Very diverse structures of ISs have been described, yet the functional importance for T-cell differentiation is largely unclear. Here we discuss the principal structure and function of ISs. We then focus on two characteristic T-cell-APC pairs, namely T cells contacting dendritic cells (DCs) or naive B cells, for which extremely different patterns of the IS have been observed as well as fundamentally different effects on the function of the activated T cells. We provide a model on how differences in signaling and the involvement of adhesion molecules might lead to diverse interaction kinetics and, eventually, diverse T-cell differentiation. We hypothesize that the preferred activation of the adhesion molecule leukocyte function-associated antigen-1 (LFA-1) and of the negative regulator for T-cell activation, cytotoxic T-lymphocyte antigen-4 (CTLA-4), through contact with naive B cells, lead to prolonged cell-cell contacts and the generation of T cells with regulatory capacity. In contrast, DCs might have evolved mechanisms to avoid LFA-1 overactivation and CTLA-4 triggering, thereby promoting more dynamic contacts that lead to the preferential generation of effector cells.
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