Publications by authors named "Patrick Adam"

63 Publications

Mapping the HLA Ligandome of Colorectal Cancer Reveals an Imprint of Malignant Cell Transformation.

Cancer Res 2018 08 22;78(16):4627-4641. Epub 2018 May 22.

University of Tübingen, Interfaculty Institute for Cell Biology, Department of Immunology, Tübingen, Germany.

Immune cell infiltrates have proven highly relevant for colorectal carcinoma prognosis, making colorectal cancer a promising candidate for immunotherapy. Because tumors interact with the immune system via HLA-presented peptide ligands, exact knowledge of the peptidome constitution is fundamental for understanding this relationship. Here, we comprehensively describe the naturally presented HLA ligandome of colorectal carcinoma and corresponding nonmalignant colon (NMC) tissue. Mass spectrometry identified 35,367 and 28,132 HLA class I ligands on colorectal carcinoma and NMC, attributable to 7,684 and 6,312 distinct source proteins, respectively. Cancer-exclusive peptides were assessed on source protein level using the Kyoto Encyclopedia of Genes and Genomes (KEGG) and protein analysis through evolutionary relationships (PANTHER), revealing pathognomonic colorectal carcinoma-associated pathways, including Wnt, TGFβ, PI3K, p53, and RTK-RAS. Relative quantitation of peptide presentation on paired colorectal carcinoma and NMC tissue further identified source proteins from cancer- and infection-associated pathways to be overrepresented merely within the colorectal carcinoma ligandome. From the pool of tumor-exclusive peptides, a selected HLA-ligand subset was assessed for immunogenicity, with the majority exhibiting an existing T-cell repertoire. Overall, these data show that the HLA ligandome reflects cancer-associated pathways implicated in colorectal carcinoma oncogenesis, suggesting that alterations in tumor cell metabolism could result in cancer-specific, albeit not mutation-derived, tumor antigens. Hence, a defined pool of unique tumor peptides, attributable to complex cellular alterations that are exclusive to malignant cells, might comprise promising candidates for immunotherapeutic applications. Cancer-associated pathways are reflected in the antigenic landscape of colorectal cancer, suggesting that tumor-specific antigens do not necessarily have to be mutation-derived but may also originate from other alterations in cancer cells. .
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/0008-5472.CAN-17-1745DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6235106PMC
August 2018

The t(14;18) translocation is absent from endothelial and follicular dendritic cells of follicular lymphoma (FL) and shows heterogeneous presence in preserved FL mantle zones.

Diagn Pathol 2018 May 2;13(1):25. Epub 2018 May 2.

Institute of Pathology and Neuropathology and Comprehensive Cancer Center (CCC), Eberhard-Karls-University Tübingen, Liebermeisterstr. 8, 72076, Tübingen, Germany.

Background: The translocation t(14;18)(q32;q21) is the genetic hallmark of follicular lymphoma (FL) and can be observed in 85-90% of cases. Whether the translocation is restricted to cells with germinal center B-cell phenotype or can be observed in other cell types of the microenvironment remains debated. Of interest, cases of associated histiocytic and dendritic cell sarcomas arising in the background of FL have been shown to be clonally related and carry the t(14;18), suggesting a "transdifferentiation" of the malignant FL clone into a neoplasm of a different hematopoietic lineage.

Methods: We analyzed the presence of the t(14;18)(q32;q21) as a surrogate marker of the malignant clone in cells of the FL microenvironment using combined fluorescence immunophenotyping and interphase cytogenetics targeting the BCL2 gene locus. In addition to non-lymphoid cells in FL, we analysed FL with preserved IgD+ mantle zones and cases of in situ follicular neoplasia (ISFN) to investigate whether cells of non-germinal center B-cell phenotype are part of the malignant clone.

Results: Six (40%) of 15 manifest FL cases with preserved IgD+ mantle zones did not harbour the t(14;18)(q32;q21) translocation. In all t(14;18) + FL cases, follicular dendritic cells and endothelial cells lacked the t(14;18) translocation. 2/9 FL revealed t(14;18)- IgD+ mantle zone B-cells. In the seven ISFN cases, the t(14;18) translocation was strictly confined to germinal center cells.

Conclusions: The t(14;18) translocation in follicular lymphoma is limited to B-cells. The origin of IgD+ mantle cells is heterogeneous, in the majority of cases belonging to the neoplastic clone, whereas a minority of cases of manifest FL show nonneoplastic mantle zones, similar to ISFN.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13000-018-0703-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5930855PMC
May 2018

Next generation sequencing of the clonal IGH rearrangement detects ongoing mutations and interfollicular trafficking in in situ follicular neoplasia.

PLoS One 2017 22;12(6):e0178503. Epub 2017 Jun 22.

Institute of Pathology and Neuropathology, Eberhard Karls University of Tübingen and Comprehensive Cancer Center, University Hospital Tübingen, Tübingen, Germany.

Follicular lymphoma (FL) is characterized genetically by a significant intraclonal diversity of rearranged immunoglobulin heavy chain (IGH) genes and a substantial cell migration activity (follicular trafficking). Recently, in situ follicular neoplasia (ISFN), characterized by accumulations of immunohistochemically strongly BCL2-positive, t(14;18)+ clonal B cells confined to germinal centers in reactive lymph nodes, has been identified as a precursor lesion of FL with low risk of progression to manifest FL. The extent of ongoing somatic hypermutation of rearranged IGH genes and interfollicular trafficking in ISFN is not known. In this study we performed an in depth analysis of clonal evolution and cell migration patterns in a case of pure ISFN involving multiple lymph nodes. Using laser microdissection and next generation sequencing (NGS) we documented significant intraclonal diversity of the rearranged IGH gene and extensive interfollicular migration between germinal centers of the same lymph node as well as between different lymph nodes. Furthermore, we identified N-glycosylation motifs characteristic for FL in the CDR3 region.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0178503PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5480878PMC
September 2017

Expression of SOX11, PAX5, TTF-1 and ISL-1 in medulloblastoma.

Pathol Res Pract 2016 Nov 11;212(11):965-971. Epub 2016 Aug 11.

Department of Pathomorphology, Medical University of Gdansk, Poland.

The aim of our study was to evaluate the immunohistochemical expression of SOX11, PAX5, TTF-1 and ISL-1 in medulloblastoma (MB) to investigate their diagnostic usefulness.

Methods: Immunohistochemical expression of PAX5 (two antibodies: Dako, DAK-Pax5; and BD, clone 24), TTF-1 (Dako, 8G7G3/1), SOX11 (CL0142; Abcam) and ISL-1 (1 H9, Abcam) was analyzed using the h-score and Remmele score in 25 cases of MB.

Results: There were 18 MBs of classic and 7 of desmoplastic type. SOX11 was strongly expressed in all tumors. The expression of PAX5 was higher and more frequent in a case of DAK-Pax5 clone (25/25) than clone 24 (6/25). ISL-1 was positive in 11 (44%) and TTF-1 in 3 (12%) cases. ISL-1 expression correlated positively (p<0.001), while TTF-1 correlated negatively with the age of patients (p=0.039). PAX5 expression correlated with ISL-1 (p=0.039) and showed a trend toward higher expression in the desmoplastic subtype (p=0.069).

Conclusions: SOX11 is strongly and robustly expressed in MBs. PAX5 expression pattern differs substantially among two antibody clones. TTF-1 and ISL-1 is associated with the age of patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.prp.2016.08.006DOI Listing
November 2016

Hemangiopericytoma/solitary fibrous tumor of the greater omentum: A case report and review of the literature.

Int J Surg Case Rep 2016 21;23:160-2. Epub 2016 Apr 21.

Department of General, Visceral and Transplant Surgery, Eberhard-Karls-University Hospital Tuebingen, Germany.

Introduction: Hemangiopericytoma (HPC) has been first described in 1942 by Stout as a tumor originating from the capillary surrounding pericytes. It is known to occur in any anatomical site, especially the extremities and retroperitoneum.

Presentation Of Case: We describe a case of a 24year old patient presenting with lower abdominal pain due to a tumor of the greater omentum, the patient was treated by conventional laparotomy with tumor resection and the histological evaluation confirmed the diagnosis Hemangiopericytoma/Solitary fibrous tumor (HPC/SFT). The patient has regularly followed-up with periodic imaging for the last 4 years, with no recurrences.

Discussion And Conclusion: According to our knowledge, HPC rarely develops in the greater omentum, only 20 cases were described in the literature. Primary surgical resection is the treatment of choice. There is no benefit of radiation or systemic chemotherapy. Angiogenic inhibitors represent promising systemic therapeutic concepts.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ijscr.2016.04.028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4855784PMC
June 2016

Occupancy of red-naped sapsuckers in a coniferous forest: using LiDAR to understand effects of vegetation structure and disturbance.

Ecol Evol 2015 Nov 2;5(22):5383-5393. Epub 2015 Nov 2.

School of Mechanical and Materials Engineering Washington State University PO Box 642920 Pullman Washington 99164-2920.

Red-naped sapsuckers () are functionally important because they create sapwells and cavities that other species use for food and nesting. Red-naped sapsucker ecology within aspen () has been well studied, but relatively little is known about red-naped sapsuckers in conifer forests. We used light detection and ranging (LiDAR) data to examine occupancy patterns of red-naped sapsuckers in a conifer-dominated system. We surveyed for sapsuckers at 162 sites in northern Idaho, USA, during 2009 and 2010. We used occupancy models and an information-theoretic approach to model sapsucker occupancy as a function of four LiDAR-based metrics that characterized vegetation structure and tree harvest, and one non-LiDAR metric that characterized distance to major roads. We evaluated model support across a range of territory sizes using Akaike's information criterion. Top model support was highest at the 4-ha extent, which suggested that 4 ha was the most relevant scale describing sapsucker occupancy. Sapsuckers were positively associated with variation of canopy height and harvested area, and negatively associated with shrub and large tree density. These results suggest that harvest regimes and structural diversity of vegetation at moderate extents (e.g., 4 ha) largely influence occurrence of red-naped sapsuckers in conifer forests. Given the current and projected declines of aspen populations, it will be increasingly important to assess habitat relationships, as well as demographic characteristics, of aspen-associated species such as red-naped sapsuckers within conifer-dominated systems to meet future management and conservation goals.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ece3.1768DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6102520PMC
November 2015

Impact of tumour volume on prediction of progression-free survival in sinonasal cancer.

Radiol Oncol 2015 Sep 21;49(3):286-90. Epub 2015 Aug 21.

Department of Diagnostic and Interventional Neuroradiology, University Hospital Tübingen, Germany.

Background: The present study aimed to analyse potential prognostic factors, with emphasis on tumour volume, in determining progression free survival (PFS) for malignancies of the nasal cavity and the paranasal sinuses.

Patients And Methods: Retrospective analysis of 106 patients with primary sinonasal malignancies treated and followed-up between March 2006 and October 2012. Possible predictive parameters for PFS were entered into univariate and multivariate Cox regression analysis. Kaplan-Meier curve analysis included age, sex, baseline tumour volume (based on MR imaging), histology type, TNM stage and prognostic groups according to the American Joint Committee on Cancer (AJCC) classification. Receiver operating characteristic (ROC) curve analysis concerning the predictive value of tumour volume for recurrence was also conducted.

Results: The main histological subgroup consisted of epithelial tumours (77%). The majority of the patients (68%) showed advanced tumour burden (AJCC stage III-IV). Lymph node involvement was present in 18 cases. The mean tumour volume was 26.6 ± 21.2 cm(3). The median PFS for all patients was 24.9 months (range: 2.5-84.5 months). The ROC curve analysis for the tumour volume showed 58.1% sensitivity and 75.4% specificity for predicting recurrence. Tumour volume, AJCC staging, T- and N- stage were significant predictors in the univariate analysis. Positive lymph node status and tumour volume remained significant and independent predictors in the multivariate analysis.

Conclusions: Radiological tumour volume proofed to be a statistically reliable predictor of PFS. In the multivariate analysis, T-, N- and overall AJCC staging did not show significant prognostic value.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1515/raon-2015-0028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4577226PMC
September 2015

[Diagnosis and differential diagnosis of Cushing's syndrome].

Dtsch Med Wochenschr 2015 Aug 25;140(17):1294-5. Epub 2015 Aug 25.

Klinik für Endokrinologie und Diabetologie, Universitätsklinikum Düsseldorf.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1055/s-0041-103503DOI Listing
August 2015

A retrospective international study on primary extranodal marginal zone lymphoma of the lung (BALT lymphoma) on behalf of International Extranodal Lymphoma Study Group (IELSG).

Hematol Oncol 2016 Dec 7;34(4):177-183. Epub 2015 Jul 7.

Haematoncology Division, European Institute of Oncology, Milan, Italy.

Primary lymphoma of the lung is a rare entity. Clinical features, optimal treatment, role of surgery and outcomes are not well defined, and the follow-up is variable in published data. Clinical data of 205 patients who were confirmed to have bronchus mucosa-associated lymphoid tissue lymphoma from December 1986 to December 2011 in 17 different centres worldwide were evaluated. Fifty-five per cent of the patients were female. The median age at diagnosis was 62 (range 28-88) years. Only 9% had a history of exposure to toxic substances, while about 45% of the patients had a history of smoking. Ten per cent of the patients had autoimmune disease at presentation, and 19% patients had a reported preexisting lung disease. Treatment modalities included surgery alone in 63 patients (30%), radiotherapy in 3 (2%), antibiotics in 1 (1%) and systemic treatment in 128 (62%). Patients receiving a local approach, mainly surgical resection, experienced significantly improved progression-free survival (p = 0.003) versus those receiving a systemic treatment. There were no other significant differences among treatment modalities. The survival data confirm the indolent nature of the disease. Local therapy (surgery or radiotherapy) results in long-term disease-free survival for patients with localized disease. Systemic treatment, including alkylating-containing regimens, can be reserved to patients in relapse after incomplete surgical excision or for patients with advanced disease. Copyright © 2015 John Wiley & Sons, Ltd.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/hon.2243DOI Listing
December 2016

Analysis of incomplete excisions of basal-cell carcinomas after breadloaf microscopy compared with 3D-microscopy: a prospective randomized and blinded study.

J Cutan Pathol 2015 Aug 17;42(8):542-53. Epub 2015 Jun 17.

Department of Dermatology, Eberhard-Karls-University, Tuebingen, Germany.

Basal-cell carcinomas may show irregular, asymmetric subclinical growth. This study analyzed the efficacy of 'breadloaf' microscopy (serial sectioning) and three-dimensional (3D) microscopy in detecting positive tumor margins. Two hundred eighty-three (283) tumors (51.2%) were put into the breadloaf microscopy group; 270 tumors (48.8%) into the 3D microscopy group. The position of any detected tumor outgrowths was identified in clock face fashion. The time required for cutting and embedding the specimens and the examination of the microscopic slides was measured. Patient/tumor characteristics and surgical margins did not differ significantly. Tumor outgrowths at the excision margin were found in 62 of 283 cases (21.9%) in the breadloaf microscopy group and in 115 of 270 cases (42.6%) in the 3D microscopy group, constituting a highly significant difference (p < 0.001). This difference held true with incomplete excision of fibrosing (infiltrative/sclerosing/morpheaform) tumors [32.9% in the breadloaf microscopy group and 57.5% in the 3D microscopy group (p = 0.003)] and also with solid (nodular) tumors [16.1 and 34.2%, respectively (p < 0.001)]. The mean overall examination time required showed no important difference. In summary, for detection of tumor outgrowths, 3D microscopy has almost twice the sensitivity of breadloaf microscopy, particularly in the situation of aggressive/infiltrative carcinomas.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/cup.12535DOI Listing
August 2015

TLR signaling-induced CD103-expressing cells protect against intestinal inflammation.

Inflamm Bowel Dis 2015 Mar;21(3):507-19

*Interfacultary Institute for Microbiology and Infection Medicine, Department for Medical Microbiology and Hygiene, University of Tübingen, Tübingen, Germany; †Institute of Food Research, Norwich Research Park, Norwich, United Kingdom; ‡NIZO Food Research, Ede, the Netherlands; §TI Food and Nutrition, Wageningen, the Netherlands; ‖Host Microbe Interactomics Group, Wageningen University, Wageningen, the Netherlands; and ¶Institute of Pathology, University of Tübingen, Tübingen, Germany.

Background: Toll-like receptor (TLR) expression in patients with inflammatory bowel disease is increased when compared with healthy controls. However, the impact of TLR signaling during inflammatory bowel disease is not fully understood.

Methods: In this study, we used a murine model of acute phase inflammation in bone marrow chimeric mice to investigate in which cell type TLR2/4 signal induction is important in preventing intestinal inflammation and how intestinal dendritic cells are influenced. Mice were either fed with wild-type bacteria, able to initiate the TLR2/4 signaling cascade, or with mutant strains with impaired signal induction capacity.

Results: The induction of the TLR2/4 signal cascade in epithelial cells resulted in inflammation in bone marrow chimeric mice, whereas induction in hematopoietic cells had an opposed function. Furthermore, feeding of wild-type bacteria prevented disease; however, differing signal induction of bacteria had no effect on lamina propria dendritic cell activation. In contrast, functional TLR2/4 signals resulted in increased frequencies of CD103-expressing lamina propria and mesenteric lymph node dendritic cells, which were able to ameliorate disease.

Conclusions: The TLR-mediated amelioration of disease, the increase in CD103-expressing cells, and the beneficial function of TLR signal induction in hematopoietic cells indicate that the increased expression of TLRs in patients with inflammatory bowel disease might result in counterregulation of the host and serve in preventing disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/MIB.0000000000000292DOI Listing
March 2015

Three dimensional (3D) histology in daily routine: practical implementation and its evaluation.

J Dtsch Dermatol Ges 2014 Nov 29;12(11):1028-35. Epub 2014 Oct 29.

Department of Dermatology, Eberhard Karls Universität Tübingen, Germany.

Background: The continuous evaluation of the edges of a tumor by means of three-dimensional (3D) histology often appears complicated and require the surgeon and dermatopathologist to work together closely. We present clear rules that allow communication between all parties involved and then verify their application in daily routine.

Methods: Tissue processing, interpretation of results, as well as communication between the surgeon and the dermatopathologist are based on an algorithm with the aid of exact times and embedding cassettes, which allow precise topographic orientation. We evaluated the use of this method in daily clinic practice, taking into account 947 operated basal cell carcinomas in regard to the development of recurrent tumors.

Results: At a median follow-up of 47 months, 10 of the 947 operated basal cell carcinomas (1.1 %) recurred. Sclerodermiform basal cell carcinomas and basal cell carcinomas which could not be curatively resected (R0 resection) during the initial surgery showed a significantly higher recurrence rate (p < 0.05 and p < 0.001).

Conclusions: Standardized rules for dealing with excised tissue allow an effective application of 3D histology in daily clinical practice. 3D histology results in low recurrence rates. Sclerodermiform basal cell carcinomas which could not be curatively resected (R0 resection) were identified as a risk group for the development of recurrent tumors.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/ddg.12466DOI Listing
November 2014

Thymoma with loss of keratin expression (and giant cells): a potential diagnostic pitfall.

Virchows Arch 2014 Sep 13;465(3):313-20. Epub 2014 Jun 13.

Institute of Pathology, Ingolstadt, Germany.

Due to its profound therapeutic consequences, the distinction between thymoma and T-lymphoblastic lymphoma in needle biopsies is one of the most challenging in mediastinal pathology. One essential diagnostic criterion favouring thymoma is the demonstration of increased numbers of keratin-positive epithelial cells by immunohistochemistry. Loss of keratin expression in neoplastic epithelial cells could lead to detrimental misdiagnoses. We here describe a series of 14 thymic epithelial tumours (11 type B2 and B3 thymomas, 3 thymic carcinomas) with loss of expression of one or more keratins. Cases were analysed for expression of various keratins and desmosomal proteins by immunohistochemistry and immunofluorescence and compared with 45 unselected type B thymomas and 24 thymic carcinomas arranged in a multitissue histological array. All 14 cases showed highly reduced expression of at least one keratin, three cases were completely negative for all keratins studied. Of the 14 cases, 13 showed strong nuclear expression of p63. Expression of desmosomal proteins was preserved, suggesting intact cell contact structures. Loss of expression of broad-spectrum-keratins and K19 was observed in 3 and 5 % of unselected thymomas and in 30 and 60 % of thymic carcinomas. A proportion of keratin-depleted thymomas contained giant cells, reminiscent of thymic nurse cells. Loss of keratin expression in type B2 and B3 thymomas is an important diagnostic pitfall in the differential diagnosis with T-lymphoblastic lymphoma and can be expected in 5 % of cases. A panel of epithelial markers including p63 is warranted to ensure correct diagnosis of keratin-negative mediastinal tumours.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00428-014-1606-6DOI Listing
September 2014

Successful Hemospray treatment for recurrent diclofenac-induced severe diffuse lower gastrointestinal bleeding avoiding the need for colectomy.

Endoscopy 2014 22;46 Suppl 1 UCTN:E173-4. Epub 2014 Apr 22.

Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital Tübingen, Germany.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1055/s-0034-1365100DOI Listing
November 2014

ALK-positive cancer: still a growing entity.

Future Oncol 2014 Feb;10(2):305-21

Department of Pathomorphology, Medical University of Gdańsk, Mariana Smoluchowskiego 17, 80-214, Gdańsk, Poland.

 Since the discovery of ALK-positive anaplastic large-cell lymphoma in 1994 many other types of tumors showing ALK expression were disclosed. They form a heterogeneous group, including lung, renal and soft tissue tumors. The biological function of ALK, its role in carcinogenesis and impact exerted on the clinical outcome have been studied by many research groups. New drugs specifically dedicated for ALK inhibition, for example, crizotinib, have been synthesized and have become a viable treatment option for ALK-positive lung adenocarcinoma, and potentially for other ALK-positive cancers. This review summarizes the current state of knowledge concerning ALK-positive neoplasms, focusing on the clinical aspects of the subject.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2217/fon.13.184DOI Listing
February 2014

A recurrent 11q aberration pattern characterizes a subset of MYC-negative high-grade B-cell lymphomas resembling Burkitt lymphoma.

Blood 2014 Feb 7;123(8):1187-98. Epub 2014 Jan 7.

Institute of Human Genetics, University Hospital Schleswig-Holstein, Campus Kiel/Christian-Albrechts University, Kiel, Germany;

The genetic hallmark of Burkitt lymphoma (BL) is the t(8;14)(q24;q32) and its variants leading to activation of the MYC oncogene. It is a matter of debate whether true BL without MYC translocation exists. Here, we identified 59 lymphomas concordantly called BL by 2 gene expression classifiers among 753 B-cell lymphomas. Only 2 (3%) of these 59 molecular BL lacked a MYC translocation, which both shared a peculiar pattern of chromosome 11q aberration characterized by interstitial gains including 11q23.2-q23.3 and telomeric losses of 11q24.1-qter. We extended our analysis to 17 MYC-negative high-grade B-cell lymphomas with a similar 11q aberration and showed this aberration to be recurrently associated with morphologic and clinical features of BL. The minimal region of gain was defined by high-level amplifications in 11q23.3 and associated with overexpression of genes including PAFAH1B2 on a transcriptional and protein level. The recurrent region of loss contained a focal homozygous deletion in 11q24.2-q24.3 including the ETS1 gene, which was shown to be mutated in 4 of 16 investigated cases. These findings indicate the existence of a molecularly distinct subset of B-cell lymphomas reminiscent of BL, which is characterized by deregulation of genes in 11q.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/blood-2013-06-507996DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3931189PMC
February 2014

Prevalence of Achromobacter xylosoxidans in pulmonary mucosa-associated lymphoid tissue lymphoma in different regions of Europe.

Br J Haematol 2014 Mar 23;164(6):804-10. Epub 2013 Dec 23.

Institute of Pathology, University of Tübingen, Tübingen, Germany.

Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) comprises 7-8% of B-cell lymphomas and commonly originates from a background of long-standing chronic inflammation. An association with distinct bacteria species has been confirmed for several anatomical sites of MALT lymphoma. For pulmonary MALT lymphoma, however, a clear link with an infectious agent or autoimmune disorder has not yet been reported. Using a 16S rRNA gene-based approach, we have recently identified Achromobacter (Alcaligenes) xylosoxidans in eight of nine cases of pulmonary MALT lymphoma. A. xylosoxidans is a gram-negative betaproteobacterium with low virulence, but high resistance to antibiotic treatment. To further examine a potential association with A. xylosoxidans, 124 cases of pulmonary MALT lymphoma and 82 control tissues from six European countries were analysed using a specific nested PCR. Although prevalence rates for A. xylosoxidans varied significantly from country to country, they were consistently higher for MALT lymphoma as compared to controls. Overall, 57/124 (46%) pulmonary MALT lymphomas and 15/82 (18%) control tissues were positive for A. xylosoxidans (P = 0·004). Whether the significant association of A. xylosoxidans with pulmonary MALT lymphoma demonstrated in our study points to a potential causal role in the pathogenesis of this lymphoma will require further studies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/bjh.12703DOI Listing
March 2014

Using satellite and airborne LiDAR to model woodpecker habitat occupancy at the landscape scale.

PLoS One 2013 6;8(12):e80988. Epub 2013 Dec 6.

Department of Forest, Rangeland, and Fire Sciences, McCall Outdoor Science School, University of Idaho, Moscow, Idaho, United States of America.

Incorporating vertical vegetation structure into models of animal distributions can improve understanding of the patterns and processes governing habitat selection. LiDAR can provide such structural information, but these data are typically collected via aircraft and thus are limited in spatial extent. Our objective was to explore the utility of satellite-based LiDAR data from the Geoscience Laser Altimeter System (GLAS) relative to airborne-based LiDAR to model the north Idaho breeding distribution of a forest-dependent ecosystem engineer, the Red-naped sapsucker (Sphyrapicus nuchalis). GLAS data occurred within ca. 64 m diameter ellipses spaced a minimum of 172 m apart, and all occupancy analyses were confined to this grain scale. Using a hierarchical approach, we modeled Red-naped sapsucker occupancy as a function of LiDAR metrics derived from both platforms. Occupancy models based on satellite data were weak, possibly because the data within the GLAS ellipse did not fully represent habitat characteristics important for this species. The most important structural variables influencing Red-naped Sapsucker breeding site selection based on airborne LiDAR data included foliage height diversity, the distance between major strata in the canopy vertical profile, and the vegetation density near the ground. These characteristics are consistent with the diversity of foraging activities exhibited by this species. To our knowledge, this study represents the first to examine the utility of satellite-based LiDAR to model animal distributions. The large area of each GLAS ellipse and the non-contiguous nature of GLAS data may pose significant challenges for wildlife distribution modeling; nevertheless these data can provide useful information on ecosystem vertical structure, particularly in areas of gentle terrain. Additional work is thus warranted to utilize LiDAR datasets collected from both airborne and past and future satellite platforms (e.g. GLAS, and the planned IceSAT2 mission) with the goal of improving wildlife modeling for more locations across the globe.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0080988PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3855685PMC
September 2014

Endotoxicity of lipopolysaccharide as a determinant of T-cell-mediated colitis induction in mice.

Gastroenterology 2014 Mar 21;146(3):765-75. Epub 2013 Nov 21.

Institute of Medical Microbiology and Hygiene, University of Tübingen, Tübingen, Germany; German Centre for Infection Research (DZIF), Germany. Electronic address:

Background & Aims: The intestinal microbiota is an important determinant of the mucosal response. In patients with inflammatory bowel diseases, the mucosal immune system has inappropriate interactions with the intestinal microbiota. We investigated how the composition of the intestinal microbiota affects its endotoxicity and development of colitis in mice.

Methods: Germ-free C57BL/6J-Rag(1tm1Mom) (Rag1(-/-)) mice were colonized with 2 different types of complex intestinal microbiota. Colitis was induced in Rag1(-/-) mice by transfer of CD4(+)CD62L(+) T cells from C57BL/6J mice. Colonic tissues were collected and used for histologic analysis and cell isolation. Activation of lamina propria dendritic cells and T cells was analyzed by flow cytometry.

Results: After transfer of CD4(+)CD62L(+) T cells, mice with intestinal Endo(lo) microbiota (a low proportion of Enterobacteriaceae, high proportion of Bacteroidetes, and low endotoxicity) maintained mucosal immune homeostasis, and mice with highly endotoxic Endo(hi) microbiota (a high proportion of Enterobacteriaceae and low proportion of Bacteroidetes) developed colitis. To determine whether the effects of Endo(hi) microbiota were related to the higher endotoxic activity of lipopolysaccharide (LPS), we compared LPS from Enterobacteriaceae with that of Bacteroidetes. Administration of Escherichia coli JM83 (wild-type LPS) to the mice exacerbated colitis, and Escherichia coli JM83 + htrBPG (mutated LPS, with lower endotoxicity, similar to that of Bacteroidetes) prevented development of colitis after transfer of the T cells to mice.

Conclusions: The endotoxicity of LPS produced by the intestinal microbiota is a determinant of whether mice develop colitis after transfer of CD4(+)CD62L(+) T cells. This finding might aid the design of novel biologics or probiotics to treat inflammatory bowel disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1053/j.gastro.2013.11.033DOI Listing
March 2014

Classical hodgkin lymphoma as de novo B-cell malignancy after treatment of multiple myeloma in the pre-lenalidomide era.

Clin Lymphoma Myeloma Leuk 2014 Feb 26;14(1):e7-e11. Epub 2013 Oct 26.

Department of Hematology, Oncology, Immunology, Rheumatology and Pulmonology, University Hospital of Tuebingen, Tuebingen, Germany. Electronic address:

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.clml.2013.07.101DOI Listing
February 2014

Identification of C/EBPβ target genes in ALK+ anaplastic large cell lymphoma (ALCL) by gene expression profiling and chromatin immunoprecipitation.

PLoS One 2013 31;8(5):e64544. Epub 2013 May 31.

Institute of Pathology and Neuropathology, University Hospital Tübingen and Comprehensive Cancer Center, Eberhard-Karls-University, Tübingen, Germany.

C/EBPβ (CCAAT enhancer binding protein) is a transcription factor that plays a crucial role in survival and transformation of ALK+ anaplastic large cell lymphoma (ALCL). The aim of this study was to identify the downstream targets of C/EBPβ responsible for ALK-mediated oncogenesis. C/EBPβ was knocked down in ALK+ ALCL cell lines with a C/EBPβ-shRNA, followed by gene expression profiling (GEP). GEP analysis revealed a reproducible signature of genes that were significantly regulated by C/EBPβ. Classification into biological categories revealed overrepresentation of genes involved in the immune response, apoptosis and cell proliferation. Transcriptional regulation by C/EBPβ was found in 6 of 11 (BCL2A1, G0S2, TRIB1, S100A9, DDX21 and DDIT4) genes investigated by chromatin immunoprecipitation. We demonstrated that BCL2A1, G0S2 and DDX21 play a crucial role in survival and proliferation of ALK+ ALCL cells. DDX21, a gene involved in rRNA biogenesis, was found differentially overexpressed in primary ALK+ ALCL cases. All three candidate genes were validated in primary ALCL cases by either immunohistochemistry or RT-qPCR. In conclusion, we identified and validated several key C/EBPβ-regulated genes with major impact on survival and cell growth in ALK+ ALCL, supporting the central role of C/EBPβ in ALK-mediated oncogenesis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0064544PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3669320PMC
February 2014

The BCL2 E17 and SP66 antibodies discriminate 2 immunophenotypically and genetically distinct subgroups of conventionally BCL2-"negative" grade 1/2 follicular lymphomas.

Hum Pathol 2013 Sep 2;44(9):1817-26. Epub 2013 May 2.

Institute of Pathology, Comprehensive Cancer Center, University of Tübingen, D-72076 Tübingen, Germany.

Follicular lymphoma (FL) is characterized by the translocation t(14;18)(q32;q21) resulting in constitutive overexpression of BCL2. However, in 10% to 15% of FL grade 1/2, immunohistochemical staining for BCL2 remains negative. To analyze the incidence of BCL2 negativity and the underlying molecular mechanisms in FL grade 1/2, BCL2 expression was investigated with 3 antibodies (clones 100D5, E17, SP66). The presence of a break in the BCL2 locus was determined by fluorescence in situ hybridization. The region of the BCL2 gene where the epitope of the standard BCL2 antibody resides was sequenced. Twenty-two (9.2%) of 240 identified cases of FL grade 1/2 were negative with the standard BCL2 antibody. Of these, 12 cases (55%) carried a break in the BCL2 gene locus, which, in all but one case, correlated with BCL2 expression using the alternative antibodies E17 and SP66 and with missense mutations of BCL2. Ten (45%) of the 22 cases had an intact BCL2 gene locus; 2 cases carried a BCL6/IGH translocation. All 10 cases were negative for the E17/SP66 antibodies and showed a wild-type sequence of BCL2. Six of these showed an aberrant phenotype, with CD10 negativity (30%) or CD23 expression (30%). In summary, the alternative E17/SP66 antibodies identify 2 immunohistochemically and genetically distinct subgroups of BCL2-"negative" FL grade 1/2.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.humpath.2013.02.004DOI Listing
September 2013

Circulating lysophosphatidylcholines are markers of a metabolically benign nonalcoholic fatty liver.

Diabetes Care 2013 Aug 20;36(8):2331-8. Epub 2013 Mar 20.

Division of Endocrinology, Department of Internal Medicine, University Hospital Tübingen, Tübingen, Germany.

Objective: Nonalcoholic fatty liver (NAFL) is thought to contribute to insulin resistance and its metabolic complications. However, some individuals with NAFL remain insulin sensitive. Mechanisms involved in the susceptibility to develop insulin resistance in humans with NAFL are largely unknown. We investigated circulating markers and mechanisms of a metabolically benign and malignant NAFL by applying a metabolomic approach.

Research Design And Methods: A total of 265 metabolites were analyzed before and after a 9-month lifestyle intervention in plasma from 20 insulin-sensitive and 20 insulin-resistant subjects with NAFL. The relevant plasma metabolites were then tested for relationships with insulin sensitivity in 17 subjects without NAFL and in plasma from 29 subjects with liver tissue samples.

Results: The best separation of the insulin-sensitive from the insulin-resistant NAFL group was achieved by a metabolite pattern including the branched-chain amino acids leucine and isoleucine, ornithine, the acylcarnitines C3:0-, C16:0-, and C18:0-carnitine, and lysophosphatidylcholine (lyso-PC) C16:0 (area under the ROC curve, 0.77 [P = 0.00023] at baseline and 0.80 [P = 0.000019] at follow-up). Among the individual metabolites, predominantly higher levels of lyso-PC C16:0, both at baseline (P = 0.0039) and at follow-up (P = 0.001), were found in the insulin-sensitive compared with the insulin-resistant subjects. In the non-NAFL groups, no differences in lyso-PC C16:0 levels were found between the insulin-sensitive and insulin-resistant subjects, and these relationships were replicated in plasma from subjects with liver tissue samples.

Conclusions: From a plasma metabolomic pattern, particularly lyso-PCs are able to separate metabolically benign from malignant NAFL in humans and may highlight important pathways in the pathogenesis of fatty liver-induced insulin resistance.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2337/dc12-1760DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3714475PMC
August 2013

Systemic IgG4-related sclerosing disease: spectrum of imaging findings and differential diagnosis.

AJR Am J Roentgenol 2012 Sep;199(3):W276-82

Department of Diagnostic Radiology, Eberhard-Karls-University, Tübingen, Germany.

Objective: The purposes of this article are to provide a practical review of the spectrum of imaging findings in patients with systemic IgG4-related sclerosing disease and to address the differential diagnoses.

Conclusion: IgG4-related sclerosing disease is a systemic disorder that can involve almost any organ. The imaging findings consist of diffuse and focal organ infiltration and encasement by inflammatory and fibrotic tissue. Awareness of the spectrum of imaging findings in IgG4-related disease should prompt further evaluation for systemic manifestations to avoid misdiagnosis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2214/AJR.11.8321DOI Listing
September 2012

Quorum sensing in the probiotic bacterium Escherichia coli Nissle 1917 (Mutaflor) - evidence that furanosyl borate diester (AI-2) is influencing the cytokine expression in the DSS colitis mouse model.

Gut Pathog 2012 Aug 3;4(1). Epub 2012 Aug 3.

Department of Internal Medicine I, University clinic Tübingen, Otfried Müllerstr, 10, 72076, Tübingen, Germany.

Background: "Quorum sensing" (QS) is the phenomenon which allows single bacterial cells to measure the concentration of bacterial signal molecules. Two principle different QS systems are known, the Autoinducer 1 system (AI-1) for the intraspecies communication using different Acyl-homoserine lactones (AHL) and AI-2 for the interspecies communication. Aim of this study was to investigate QS of Escherichia coli Nissle 1917 (Mutaflor).

Results: While E. coli Nissle is producing AI-2 in a density dependent manner, no AI-1 was produced. To study the effect of AI-2 in the DSS (dextran sulphate sodium) induced mouse model of acute colitis, we silenced the corresponding gene luxS by intron insertion. The mutant bacterium E. coli Nissle::luxS was equally effective in colonizing the colon and the mutation turned out to be 100% stable during the course of the experiment. Isolating RNA from the colon mucosa and performing semiquantitative RT PCR, we were able to show that the expression of the pro-inflammatory cytokine IFN-y was suppressed in mice being infected with the E. coli Nissle wild type. Mice infected with the E. coli Nissle::luxS mutant showed a suppressed expression of IL-10 compared to uninfected mice, while the expression of the pro-inflammatory cytokines IL-6 and TNF-α was higher in these mice. The expression of mBD-1 was suppressed in mice being infected with the mutant in comparison to the mice not infected or infected with the wild type. No differences were seen in the histological examination of the colon sections in the different groups of mice.

Conclusions: E. coli Nissle is producing AI-2 molecules, which are influencing the expression of cytokines in the mucosa of the colon in the DSS mice. However, if QS has a direct influence on the probiotic properties of E. coli Nissle remains to be elucidated.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/1757-4749-4-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3480846PMC
August 2012

Incidence of preclinical manifestations of mantle cell lymphoma and mantle cell lymphoma in situ in reactive lymphoid tissues.

Mod Pathol 2012 Dec 13;25(12):1629-36. Epub 2012 Jul 13.

Institute of Pathology and Comprehensive Cancer Center (CCC), University of Tübingen, Tübingen, Germany.

Recently, the occurrence of cyclin D1-positive B cells with mantle cell lymphoma phenotype in the inner mantle zones of morphologically inconspicuous lymph nodes has been described and termed mantle cell lymphoma 'in situ'. Prevalence and clinical significance of this lesion and related minimal mantle cell lymphoma infiltrates in reactive lymphoid tissues of healthy individuals, and of mantle cell lymphoma patients are unknown. All 1292 reactive lymph nodes from unselected consecutive surgical specimens of 131 patients without a history of lymphoma obtained over a 3-month period were stained for cyclin D1. In addition, all morphologically reactive lymph nodes and benign-appearing extranodal lymphoid infiltrates of patients diagnosed with mantle cell lymphoma in the years 2000-2011 were studied. Samples predating the lymphoma diagnosis for at least 2 months were available from 37/423 (9%) patients. A mantle cell lymphoma 'in situ' was not identified in any of the two groups. However, in four patients with subsequent mantle cell lymphoma diagnosis, an early manifestation of mantle cell lymphoma was detected retrospectively, antedating the lymphoma diagnosis for 2-86 months. In six mantle cell lymphoma patients, only small groups of cyclin D1-positive cells in morphologically reactive extranodal infiltrates were detected >2 months before the diagnosis of mantle cell lymphoma (range 3-59 months). Mantle cell lymphoma 'in situ' is an extremely rare phenomenon in morphologically reactive lymph nodes, in line with the low prevalence of t(11;14)-positive cells described in the peripheral blood of a healthy population. In mantle cell lymphoma patients, however, immunohistochemically detectable infiltrates of mantle cell lymphoma cells antedating the lymphoma diagnosis were found in a significant proportion of cases (10/37=27%). These consisted either of early mantle cell lymphoma with mantle zone growth pattern, or small extranodal accumulations of cyclin D1+ cells, whereas typical mantle cell lymphoma 'in situ' was not detected.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/modpathol.2012.117DOI Listing
December 2012

Perfusion and flow extraction product as potential discriminators in untreated follicular and diffuse large B cell lymphomas using volume perfusion CT with attempt at histopathologic explanation.

AJR Am J Roentgenol 2012 Jun;198(6):1239-46

Department of Diagnostic and Interventional Radiology, Eberhard-Karls-University, Tübingen, Germany.

Objective: The purpose of this article is to measure perfusion parameters, including transit constant (K(trans)), in untreated follicular and diffuse large B cell lymphoma using volume perfusion CT, to establish their discriminating role and to search for a possible histopathologic background.

Subjects And Methods: Between January 2010 and June 2011, 46 consecutive patients with untreated histologically confirmed follicular lymphoma (n = 16) or diffuse large B cell lymphoma (n = 30) were enrolled. A 40-second volume perfusion CT of the tumor bulk using 6.9-cm z-axis coverage and a total of 26 volume measurements was performed. Blood flow (BF), blood volume (BV), and K(trans) were determined. Tumor size was recorded as the product of long- and short-axis diameters. In 13 of 46 patients, pathologic specimens of an appropriate size were available for assessment of microvessel density (MVD) and microvascular luminal diameter for comparison with volume perfusion CT measurements.

Results: Mean BF, BV, and K(trans) values were significantly higher in follicular lymphoma than in diffuse large B cell lymphoma, even after controlling for patient age and tumor size (p < 0.05, respectively). Although MVD was slightly, but not significantly, higher in follicular lymphoma versus diffuse large B cell lymphoma (p > 0.05), microvascular luminal diameter was significantly larger in follicular lymphoma than in diffuse large B cell lymphoma (p < 0.05). We defined cutoff values for BF, BV, and K(trans). If the cutoff points are met for all three parameters, the overall accuracy for correctly identifying diffuse large B cell lymphoma and follicular lymphoma was 90.5% and 87.5%, respectively.

Conclusion: Volume perfusion CT allows assessment of differences in vascularity of follicular and diffuse large B cell lymphomas, reflecting vascular luminal variability and histopathologic anatomy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2214/AJR.11.7858DOI Listing
June 2012

[Rare cause of insufficient metabolic control of diabetes mellitus - Case 10/2011].

Dtsch Med Wochenschr 2011 Oct 18;136(43):2196. Epub 2011 Oct 18.

Abteilung für Endokrinologie, Diabetes, Nephrologie, Angiologie und Klinische Chemie, Medizinische Universitätsklinik Tübingen.

History And Admission Findings: A 48-year-old patient presented with an insufficient control of his diabetes mellitus which was known since 3 years. The antidiabetic medication comprised metformin and exenatide.

Investigations: Physical examination revealed, beside elevated blood pressure, abdominal purple striae. Endocrine testing was consistent with ectopic Cushing's syndrome. Abdominal CT showed a 5 cm measuring, inhomogeneous, contrast-enhanced mass in the right suprarenal area which was positive on iodine-131 MIBG SPECT. Furthermore, urinary catecholamines were markedly increased.

Diagnosis, Treatment And Course: Diagnosis of an ACTH-producing pheochromocytoma was made and an open adrenalectomy was performed. Histology confirmed a pheochromocytoma with potential aggressive clinical behaviour according to the Pheocromocytoma of the Adrenal gland Scaled Score. 6 months after the intervention, glucose control was significantly improved with an HbA1c of 5.5%.

Conclusions: An ACTH-producing pheochromocytoma is a very rare cause of deterioration of glucose control. However, in presence of typical clinical findings an endocrine work-up is warranted.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1055/s-0031-1289124DOI Listing
October 2011

Dendritic cell tumor in a salivary gland lymph node: a rare differential diagnosis of salivary gland neoplasms.

Diagn Pathol 2011 Sep 30;6:94. Epub 2011 Sep 30.

Department of Otolaryngology, Head and Neck Surgery, University of Tübingen, Germany.

Dendritic cell tumors are extremely rare neoplasms arising from antigen-presenting cells of the immune system. We report a case of a 69-year-old man with an unremarkable medical history who presented with a 2-months history of a gradually enlarging painless, firm, mobile, 2 × 2-cm swelling at the caudal pole of the left parotid gland without systemic symptoms. Histologically, the tumor consisted of a spindle cell proliferation in an intraparotideal lymph node. Based on the histopathologic, immunohistochemical and electron microscopic findings, a dendritic cell tumor, not otherwise specified (NOS) in an intraparotideal lymph node was diagnosed.The patient underwent complete tumor resection, and is currently free of disease, 2 years after surgery. These extremely rare tumors must be distinguished from other more common tumors in the salivary glands. Awareness that dendritic cell tumors may occur in this localization, careful histologic evaluation and ancillary immunohistochemical and electron microscopical analyses should allow for recognition of this entity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/1746-1596-6-94DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3216896PMC
September 2011