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Thomas Decker

Publications and source records attributed to Thomas Decker.

At least 19 recordsLinked to original sources
PubMed2026

Margin Adequacy in Phyllodes Tumors Revisited: Reappraisal of the Evidence Base and Knowledge Gaps.

The optimal surgical margin for minimizing local recurrence (LR) and distant metastasis in phyllodes tumors (PTs) remains controversial. Despite multiple observational cohorts, variation among studies limits the interpretation of margin-outcome associations. We therefore performed a structured critical interpretative synthesis (CIS) to evaluate whether the current evidence supports specific margin thresholds. The CIS incorporated a systematic review, random-effects meta-analysis, an appraisal of existing meta-analyses and guidelines, and an expert interpretative analysis of 40 single-cohort studies from 2015 to 2025 evaluating surgical margin width and outcomes in PTs. Authors' recommendations regarding margin adequacy were extracted as interpretative "author conclusions." In parallel, LR and distant metastasis outcomes were pooled by tumor grade using random-effects models with prediction intervals. Final margin recommendations were derived by integrating CIS findings and multidisciplinary expert judgment. Current management guidelines do not recommend re-excision for positive or close margins in benign PTs. Contemporary guidelines are also concordant in advising negative margins for borderline and malignant PTs, although the specified margin width ranges from 1 to 10 mm. Within this range, no association has been established between increasing margin width and the risk of LR or malignant transformation upon LR. The estimated LR rates are 12.5% for borderline and 16.5% for malignant PTs. Malignant transformation on recurrence occurred in only 1% and 3% of all benign and borderline PTs, respectively. Approximately 14% of malignant PT metastasize, often without LR. Current heterogeneous evidence does not show lower recurrence with margins wider than a negative (≥1 mm) margin in PTs. For borderline and malignant PTs, a mandatory 10-mm threshold is insufficiently supported, as narrower negative margins may be adequate in selected cases. However, an optimal margin threshold cannot be defined from current data. These conclusions are practice-supporting rather than guideline-defining and reinforce the need for high-quality evidence to establish harmonized, grade-specific margin recommendations.

Humans↗
PubMed2006

Negative and positive regulation of gene expression by mouse histone deacetylase 1.

Histone deacetylases (HDACs) catalyze the removal of acetyl groups from core histones. Because of their capacity to induce local condensation of chromatin, HDACs are generally considered repressors of transcription. In this report, we analyzed the role of the class I histone deacetylase HDAC1 as a transcriptional regulator by comparing the expression profiles of wild-type and HDAC1-deficient embryonic stem cells. A specific subset of mouse genes (7%) was deregulated in the absence of HDAC1. We identified several putative tumor suppressors (JunB, Prss11, and Plagl1) and imprinted genes (Igf2, H19, and p57) as novel HDAC1 targets. The majority of HDAC1 target genes showed reduced expression accompanied by recruitment of HDAC1 and local reduction in histone acetylation at regulatory regions. At some target genes, the related deacetylase HDAC2 partially masks the loss of HDAC1. A second group of genes was found to be downregulated in HDAC1-deficient cells, predominantly by additional recruitment of HDAC2 in the absence of HDAC1. Finally, a small set of genes (Gja1, Irf1, and Gbp2) was found to require HDAC activity and recruitment of HDAC1 for their transcriptional activation. Our study reveals a regulatory cross talk between HDAC1 and HDAC2 and a novel function for HDAC1 as a transcriptional coactivator.

Animals↗
PubMed2006

Cytoplasmic Listeria monocytogenes stimulates IFN-beta synthesis without requiring the adapter protein MAVS.

The mitochondria-associated adapter protein MAVS (also called IPS-1, VISA or CARDIF, designated MAVS for reasons of simplicity in our manuscript) relays signals from cytoplasmic sensors of viral RNA to the IRF3 kinase complex and the interferon-beta (IFN-beta) gene. Using siRNA-mediated knock-down in macrophages we show that IFN-beta synthesis in response to transfected, intracellular double-stranded RNA (dsRNA), a pathogen-associated molecular pattern of viruses, is decreased in absence of MAVS. By contrast, the Gram-positive bacterium Listeria monocytogenes targets the IFN-beta gene without detectable MAVS requirement. The data show that MAVS is not a central adapter protein for all cytoplasmic pathogen sensors that stimulate IFN-beta synthesis.

Adaptor Proteins, Signal Transducing↗
PubMed2006

Cyclin E but not bcl-2, bax or mcl-1 is differentially expressed in ZAP 70-positive and ZAP 70-negative B-CLL cells.

The clinical course of chronic lymphocytic leukemia is variable. While some patients have indolent disease, others require aggressive treatment within a short time after diagnosis. Differences in the expression of proteins regulating cell cycle and apoptosis may be responsible for the heterogeneous course of the disease. Recently, protein ZAP 70 [zeta-chain (T-cell receptor) associated protein kinase 70 kDa] has been found to be differentially expressed within two biologic subgroups, characterized by the presence or absence of somatic mutations in specific immunoglobulin heavy-chain variable region genes. In the present work, we analyzed highly purified B-CLL cells from 60 patients for ZAP 70 expression and the expression of cyclin E, bcl-2, bax, and mcl-1 as well as the ratios of bcl-2/bax and mcl-1/bax. The results indicate that cyclin E is expressed significantly higher in ZAP 70-positive as in ZAP 70-negative samples. We did not observe significant differences within the expression of Bcl-2 family member proteins. We conclude that higher cyclin E expression in samples of ZAP 70-positive patients may reflect a larger proliferating compartment in vivo compared to ZAP 70-negative patients and that cyclin E may add prognostic information in this context for patients with B-CLL.

Adult↗
PubMed2006

Targeting the proteasome in mantle cell lymphoma: a promising therapeutic approach.

Mantle cell lymphoma (MCL) is a distinctive non-Hodgkin's lymphoma sub-type, characterized by over-expression of cyclin D1 as a consequence of chromosomal translocation t(11;14)(q13;q32). MCL remains an incurable disease, combining the unfavorable clinical features of aggressive and indolent lymphomas. The blastic variant of MCL, which is often associated with additional cytogenetic alterations, has an even worse prognosis and new treatment options are clearly needed. The 26S proteasome is a large multi-catalytic multi-protein complex, present in all eukaryotic cells. It is responsible for the degradation of a variety of short-lived proteins and exhibits a key position in cellular processes including apoptosis and cell cycle progression. Targeting the ubiquitin - proteasome pathway has only recently been identified as a promising new therapeutic option for cancer patients. Interestingly, an increased activity of the proteasome pathway has been described in MCL cells and the inhibition of the proteasome seems to be a promising therapeutic approach for this incurable disease.

Boronic Acids↗
PubMed2006

Mammalian target of rapamycin inhibition induces cell cycle arrest in diffuse large B cell lymphoma (DLBCL) cells and sensitises DLBCL cells to rituximab.

Diffuse large B-cell lymphoma (DLBCL) is a common lymphoma entity. Although a significant amount of DLBCL patients can be cured with modern chemotherapeutic regimens, a substantial proportion of patients die because of progressive disease. Therefore, new therapeutic strategies are clearly needed. Inhibitors of mTOR [mammalian target of rapamycin (Rap)] represent a new class of antiproliferative drugs with applications as immunosuppressive and anticancer agents. Extensive safety data exist on the mTOR inhibitor RAD001, which is already approved as an immunosuppressant in organ transplant recipients. Rap and RAD001 inhibited cell cycle progression in DLBCL cells by inducing a G1 arrest without inducing apoptosis. Phosphorylation of the main targets of mTOR, p70 s6 kinase and 4-EBP-1 was reduced in cells cultured in the presence of RAD001. Cell cycle arrest was accompanied by reduced phosphorylation of the retinoblastoma protein (RB) as well as reduced expression of cyclin D3 and A in all cell lines. Although the effect of the chemotherapeutic agent vincristine (vin) was not enhanced by RAD001, rituximab-induced cytotoxicity was augmented in the rituximab-sensitive cell lines. mTOR inhibition is a promising therapeutic strategy in DLBCL by inducing a G1 arrest and augments rituximab-induced cytotoxicity. Therefore, combination of these drugs might be an interesting new therapeutic approach in DLBCL patients.

Adaptor Proteins, Signal Transducing↗
PubMed2006

Cell cycle inhibition in malignant lymphoma: disease control by attacking the cellular proliferation machinery.

Disruption of a proper regulation of cell proliferation can ultimately cause cancer. Most human B cell malignancies are driven by chromosomal translocations or other genetic alterations which directly affect the function of critical cell cycle proteins, such as cyclins and cyclin-dependent kinases. In addition, the transformation of indolent lymphomas into aggressive malignancies is often accompanied by a loss of tumor suppressors controlling important cell cycle checkpoints. A better understanding of cell cycle deregulations in human tumors has promoted the introduction of a new class of antiproliferative drugs into cancer therapies. These drugs exert their function by specifically blocking important cell cycle proteins. In the present review we discuss how alterations in the cell cycle control contribute to the malignant transformation of B cells. Furthermore, we provide an overview of novel direct and indirect cell cycle inhibitors and their impact on the treatment of patients with B cell lymphomas.

Animals↗
PubMed2005

A concept for the clinical implementation of sentinel lymph node biopsy in patients with breast carcinoma with special regard to quality assurance.

The development of standardized and reproducible clinical pathways is an important precondition for quality assurance in medicine, especially if a new method has not yet been ultimately validated. Sentinel lymph node biopsy (SLNB) is a widely accepted new surgical procedure in the treatment of early breast carcinoma. However, numerous steps of the method and details of the technique are not standardized and, thus, hamper quality assurance for SLNB. The German Society of Senology appointed an interdisciplinary consensus committee to work out guidelines for the standardized performance and quality-assured implementation of SLNB on a nationwide, homogeneous standard. The committee consisted of surgeons, gynecologists, radiooncologists, nuclear physicians, oncologists, and pathologists. Relevant questions related to patient selection, lymphatic mapping, surgery, histopathologic work-up, further local and systemic treatment decisions, patient information, training, and follow-up were evaluated with respect to clinical evidence, objectivity, and reproducibility. Clinical pathways were developed on the basis of this analysis. Requirements to the performing institutions and surgeons were defined.

Breast Neoplasms↗
PubMed2005

Improving the reproducibility of diagnosing micrometastases and isolated tumor cells.

BACKGROUND: The latest edition of the tumor-lymph node-metastasis (TNM) classification of malignant tumors distinguishes between isolated tumor cells (pN0) and micrometastases (pN1mi). The reproducibility of these categories has not been assessed previously. METHODS: Digital images from 50 cases with low-volume lymph node involvement from axillary sentinel lymph nodes were circulated twice for evaluation (Evaluation Rounds 1 and 2) among the members of the European Working Group for Breast Screening Pathology, and the members were asked to categorize lesions as micrometastasis, isolated tumor cells, or something else and to classify each case into a pathologic lymph node (pN) category of the pathologic TNM system. Methods for improving the low reproducibility of the categorizations were discussed between the two evaluation rounds. kappa Statistics were used for the assessment of interobserver variability. RESULTS: The kappa value for the consistency of categorizing low-volume lymph node load into micrometastasis, isolated tumor cells, or neither of those changed from 0.39 to 0.49 between Evaluation Rounds 1 and 2, but it was slightly lower for the pN categories (0.35 and 0.44, respectively). Interpretation of the definitions of isolated tumor cells (especially with respect to their localization within the lymph node), lack of guidance on how to measure them if they were multiple, and lack of any definitions for multiple simultaneous foci of lymph node involvement were listed among the causes of discordant diagnoses. CONCLUSIONS: The results of the current study indicated that the definitions available have minor contradictions and do not permit a reproducible distinction between micrometastases and isolated tumor cells. Refinement of these definitions, therefore, is required. One refinement that may improve reproducibility is suggested in this report.

Biopsy, Needle↗
PubMed2005

The yin and yang of type I interferon activity in bacterial infection.

Interferons (IFNs) are cytokines that are important for immune responses, particularly to intracellular pathogens. They are divided into two structurally and functionally distinct types that interact with different cell-surface receptors. Classically, type I IFNs are potent antiviral immunoregulators, whereas the type II IFN enhances antibacterial immunity. However, as outlined here, type I IFNs are also produced in response to infection with other pathogens, and an increasing body of work shows that type I IFNs have an important role in the host response to bacterial infection. Strikingly, their activity can be either favourable or detrimental, and can influence various immune effector mechanisms.

Animals↗
PubMed2005

A secreted low-molecular-weight protein from Helicobacter pylori induces cell-cycle arrest of T cells.

BACKGROUND & AIMS: Although Helicobacter pylori is recognized by the human immune system, the bacteria are not eliminated and lead to a chronic inflammation of the gastric mucosa. METHODS: We investigated the interaction of H. pylori with human lymphocytes. T and B lymphocytes were isolated from H. pylori-infected patients and stimulated with anti-CD3/CD28 or interleukin-6. RESULTS: Proliferation of lymphocytes was abolished on co-incubation with different H. pylori strains (1-5 bacteria/cell) or with protein extracts of culture supernatants. Inhibition of proliferation was independent of known virulence factors. The factor is a protein or protein complex with an apparent molecular weight between 30 and 60 kilodaltons, clearly distinct from VacA. Although antigen-specific activation of T cells (as shown by nuclear factor of activated T cells [NFAT]-activation, interferon-gamma production, and CD25 or CD69 up-regulation) remained intact, cell-cycle analysis showed that S-phase entry of T cells was inhibited completely by H. pylori. Consequently, stimulated T cells arrested in the G1 phase of the cell cycle. Western blot analysis showed markedly reduced phosphorylation of the retinoblastoma protein (pRb), suggesting inhibition of G1 cyclin-dependent kinase activity. In line with this, activities of cyclin D3 and cyclin E were down-regulated, and levels of the cyclin-dependent kinase inhibitor p27Kip1 were increased. Mouse embryonic fibroblasts deficient in p27 showed a decrease in H. pylori-induced inhibition of cell proliferation, suggesting a central role for p27 in mediating H. pylori-induced G1 arrest. CONCLUSIONS: Induction of cell-cycle arrest in lymphocytes may be of major significance for the chronic persistence of bacteria in the human stomach.

Antigens, CD19↗
PubMed2004

IFN regulatory factor 3-dependent induction of type I IFNs by intracellular bacteria is mediated by a TLR- and Nod2-independent mechanism.

Like viruses, intracellular bacteria stimulate their host cells to produce type I IFNs (IFN-alpha and IFN-beta). In our study, we investigated the signals and molecules relevant for the synthesis of and response to IFN by mouse macrophages infected with Listeria monocytogenes. We report that IFN-beta is the critical immediate-early IFN made during infection, because the synthesis of all other type I IFN, expression of a subset of infection-induced genes, and the biological response to type I IFN was lost upon IFN-beta deficiency. The induction of IFN-beta mRNA and the IFN-beta-dependent sensitization of macrophages to bacteria-induced death, in turn, was absolutely dependent upon the presence of the transcription factor IFN regulatory factor 3 (IRF3). IFN-beta synthesis and signal transduction occurred in macrophages deficient for TLR or their adaptors MyD88, TRIF, or TRAM. Expression of Nod2, a candidate receptor for intracellular bacteria, increased during infection, but the protein was not required for Listeria-induced signal transduction to the Ifn-beta gene. Based on our data, we propose that IRF3 is a convergence point for signals derived from structurally unrelated intracellular pathogens, and that L. monocytogenes stimulates a novel TLR- and Nod2-independent pathway to target IRF3 and the type I IFN genes.

Adaptor Proteins, Signal Transducing↗
PubMed2004

Stereotactic vacuum-assisted breast biopsies in 500 women with microcalcifications: radiological and pathological correlations.

AIM: We compared radiological assessment with pathological diagnoses in 500 consecutive vacuum-assisted breast biopsies performed for microcalcifications. METHODS: Lesions were biopsied using a 11-gauge mammotome device. Before biopsy, microcalcifications were classified according to the Breast Imaging Reporting and Data System (BI-RADS). Histopathological and radiological diagnosis were compared. RESULTS: Histopathology revealed 333 (67%) benign lesions. Benign lesions were classified as BI-RADS 3 in 19%, and as suspicious in 35%. 167 lesions (33%) were malignant. Malignant lesions were classified as suspicious or highly suggestive of malignancy in 63%. Frequency of malignancy in BI-RADS categories 4 and 5 was 35% and 100%, respectively. In BI-RADS 3 microcalcifications, the malignancy frequency was 19%. The mammographic features with the highest positive predictive value for malignancies were pleomorphic morphology (42%) and a linear or segmental distribution (51%). The microcalcification morphology was not reliably able to predict malignancy. CONCLUSION: In this study, BI-RADS 3 microcalcification lesions had a malignancy rate that is higher than previously reported. Vacuum-assisted biopsy is useful in any indeterminate and suspicious microcalcifications and provides maximum information before any operative intervention.

Adult↗
PubMed2004

Functional evaluation of the role of inhibitor of apoptosis proteins in chronic lymphocytic leukemia.

OBJECTIVE: The slow accumulation of malignant cells in chronic lymphocytic leukemia (CLL) suggests a defect in the induction of apoptosis in these cells. Previous studies have found sporadic alterations in the apoptotic apparatus in CLL cells, but a widespread defect has not been detected until now. A crucial checkpoint in the progression of apoptosis is the activity of inhibitor of apoptosis proteins (IAP) that control the activity of caspases upon the release of cytochrome c from mitochondria. The aim of this study was to evaluate the role of IAP in the regulation of apoptosis in CLL cells. MATERIALS AND METHODS: Lysates from CLL cells were prepared, and the regular function of components of the cytochrome c-dependent caspase-activating machinery (the apoptosome) was investigated. The effect of IAP in caspase-inhibition was tested using a peptide derived from the mitochondrial IAP antagonist Smac/DIABLO. Regulation of expression as well as inhibitory function of the X-linked IAP (XIAP) by cytokines was analyzed. RESULTS: The apoptosome was found to be structurally and functionally competent in CLL. XIAP expression was enhanced by culture in the presence of cytokines. Smac/DIABLO was easily detectable in CLL cells and was released into the cytosol during apoptosis. No inhibitory effect of IAP was detected in CLL, irrespective of XIAP levels and culture conditions. CONCLUSION: Although XIAP is present in CLL cells and is up-regulated in conditions where apoptosis is prevented, no caspase-inhibiting anti-apoptotic effect of IAP is detectable. This is likely due to the high expression of Smac/DIABLO in CLL cells that is sufficient to overcome the caspase-inhibiting effect of IAP.

Aged↗
PubMed2004

Expression of cyclin E in resting and activated B-chronic lymphocytic leukaemia cells: cyclin E/cdk2 as a potential therapeutic target.

Disease progression in B-cell chronic lymphocytic leukaemia (B-CLL) is determined by the interplay between proliferation kinetics in the proliferating compartment and cell death in the accumulating compartment. Improving our knowledge of cell cycle regulation in B-CLL cells might therefore be important for identifying therapeutic targets. Cyclin E was detected by Western blotting in purified B-CLL cells from peripheral blood samples of all 12 patient tested but not in normal peripheral blood B cells. While cyclin-dependent kinase 2 (cdk2) expression was similar in different samples, p27 and cyclin E expression was highly variable. We further investigated the regulation of p27, cyclin E and cdk2 in an in vitro model of cycling B-CLL cells. Cyclin E and cdk2 expression was increased in B-CLL cells stimulated with a CpG-oligodeoxynucleotide and interleukin-2, while p27 expression rapidly declined. This was accompanied by the increased formation of cyclin E-cdk2 complexes, which were able to phosphorylate Histone H1 in vitro. Pharmacological inhibition of cdk2 activity with Roscovitine-inhibited thymidine incorporation and Histone H1 phosphorylation. We conclude that further evaluation of cyclin E and p27 in peripheral blood cells might help to identify prognostic subgroups. In addition, inhibition of Cyclin E-cdk2 activity by Roscovitine might be a new therapeutic strategy in B-CLL.

Aged↗
PubMed2004

Sepsis: avoiding its deadly toll.

Systemic bacterial infection may culminate in a frequently fatal septic shock syndrome. The underlying pathology is the result of an uncontrolled inflammatory response, stimulated by the pathogen and its products. Toll-like receptors (TLRs) are critically involved in sensing bacteria and, in the case of sepsis, stimulate a pathogenic response by the innate immune system. A new study reports a successful attempt to inhibit systemic inflammation in mice by disrupting the formation of complexes between Gram-positive bacteria and their cognate receptor, TLR2.

Animals↗
PubMed2003

Induction of caspase-dependent programmed cell death in B-cell chronic lymphocytic leukemia by anti-CD22 immunotoxins.

B cells of chronic lymphocytic leukemia (CLL) are long-lived in vivo, possibly because of defects in apoptosis. We investigated BL22, an immunotoxin composed of the Fv portion of an anti-CD22 antibody fused to a 38-kDa Pseudomonas exotoxin-A fragment. B cells from 22 patients with CLL were immunomagnetically enriched (96% purity) and were cultured with BL22 or an immunotoxin that does not recognize hematopoietic cells. The antileukemic activity of BL22 was correlated with CD22 expression, as determined by flow cytometry. BL22 induced caspase-9 and caspase-3 activation, poly(adenosine diphosphate [ADP]-ribose)polymerase (PARP) cleavage, DNA fragmentation, and membrane flipping. Cell death was associated with the loss of mitochondrial membrane potential and the down-regulation of Mcl-1 and X-chromosomal inhibitor of apoptosis protein (XIAP). Furthermore, BL22 induced a proapoptotic 18-kDa Bax protein and conformational changes of Bax. Z-VAD.fmk abrogated apoptosis, confirming that cell death was executed by caspases. Conversely, interleukin-4, a survival factor, inhibited spontaneous death in culture but failed to prevent immunotoxin-induced apoptosis. BL22 cytotoxicity was markedly enhanced when combined with anticancer drugs including vincristine. We also investigated HA22, a newly engineered immunotoxin, in which BL22 residues are mutated to improve target binding. HA22 was more active than BL22. In conclusion, these immunotoxins induce caspase-mediated apoptosis involving mitochondrial damage. Combination with chemotherapy is expected to improve the efficacy of immunotoxin treatment.

Aged↗