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1004 Publications visible to you, out of a total of 1004
Prognostic factors for hematotoxicity of chemotherapy in aggressive non-Hodgkin's lymphoma.
GLA - German Lymphoma Alliance

Abstract (Expand)

BACKGROUND: Little is known on the heterogeneity of hematotoxicity in patients receiving multicycle chemotherapy. PATIENTS AND METHODS: We analyzed data of 1399 patients with aggressive lymphoma from … trials using CHOP (combination chemotherapy with cyclophosphamide, doxorubicin, vincristine and prednisone)-like therapies. Multivariate modeling was carried out for leukocytopenia, thrombocytopenia and anemia and the models were validated by two large independent datasets from trials with/without usage of the CD20-antibody rituximab. RESULTS: On the basis of these models, we are able to predict the remarkable heterogeneity of hematotoxicity and propose to use risk groups. Regarding leukocytopenia, the low toxicity risk group experienced World Health Organization grade 4 in <10% of the cycles while the high toxicity risk group in almost all cycles. For thrombocytopenia, groups were detectable with almost no grade 3 or 4 toxicity and others where two out of three cycles were affected. In a separate set of models, the first cycle toxicity was the strongest predictor for later hematotoxicity. The risk for leukocytopenia was associated with infections, antibiotic use, hospitalization and treatment-related mortality, indicating the clinical usefulness of the models. For the first time, a Web-based tool is made available to easily predict the hematotoxicity in clinical practice (www.toxcalculator.com). CONCLUSION: This analysis has implications for patient management and prophylaxis.

Authors: M. Ziepert, R. Schmits, L. Trumper, M. Pfreundschuh, M. Loeffler

Date Published: 1st Dec 2007

Publication Type: Not specified

Human Diseases: non-Hodgkin lymphoma

RAD51 135G–C modifies breast cancer risk among BRCA2 mutation carriers: results from a combined analysis of 19 studies
GC-HBOC - German Consortium for Hereditary Breast and Ovarian Cancer

Abstract (Expand)

RAD51 is an important component of double-stranded DNA-repair mechanisms that interacts with both BRCA1 and BRCA2. A single-nucleotide polymorphism (SNP) in the 5’ untranslated region (UTR) of RAD51, … 135G–\textgreaterC, has been suggested as a possible modifier of breast cancer risk in BRCA1 and BRCA2 mutation carriers. We pooled genotype data for 8,512 female mutation carriers from 19 studies for the RAD51 135G–\textgreaterC SNP. We found evidence of an increased breast cancer risk in CC homozygotes (hazard ratio [HR] 1.92 [95% confidence interval CI 1.25-2.94) but not in heterozygotes (HR 0.95 [95% CI 0.83-1.07]; P=.002, by heterogeneity test with 2 degrees of freedom [df]). When BRCA1 and BRCA2 mutation carriers were analyzed separately, the increased risk was statistically significant only among BRCA2 mutation carriers, in whom we observed HRs of 1.17 (95% CI 0.91-1.51) among heterozygotes and 3.18 (95% CI 1.39-7.27) among rare homozygotes (P=.0007, by heterogeneity test with 2 df). In addition, we determined that the 135G–\textgreaterC variant affects RAD51 splicing within the 5’ UTR. Thus, 135G–\textgreaterC may modify the risk of breast cancer in BRCA2 mutation carriers by altering the expression of RAD51. RAD51 is the first gene to be reliably identified as a modifier of risk among BRCA1/2 mutation carriers.

Authors: Antonis C. Antoniou, Olga M. Sinilnikova, Jacques Simard, Mélanie Léoné, Martine Dumont, Susan L. Neuhausen, Jeffery P. Struewing, Dominique Stoppa-Lyonnet, Laure Barjhoux, David J. Hughes, Isabelle Coupier, Muriel Belotti, Christine Lasset, Valérie Bonadona, Yves-Jean Bignon, Timothy R. Rebbeck, Theresa Wagner, Henry T. Lynch, Susan M. Domchek, Katherine L. Nathanson, Judy E. Garber, Jeffrey Weitzel, Steven A. Narod, Gail Tomlinson, Olufunmilayo I. Olopade, Andrew Godwin, Claudine Isaacs, Anna Jakubowska, Jan Lubinski, Jacek Gronwald, Bohdan Górski, Tomasz Byrski, Tomasz Huzarski, Susan Peock, Margaret Cook, Caroline Baynes, Alexandra Murray, Mark Rogers, Peter A. Daly, Huw Dorkins, Rita K. Schmutzler, Beatrix Versmold, Christoph Engel, Alfons Meindl, Norbert Arnold, Dieter Niederacher, Helmut Deissler, Amanda B. Spurdle, Xiaoqing Chen, Nicola Waddell, Nicole Cloonan, Tomas Kirchhoff, Kenneth Offit, Eitan Friedman, Bella Kaufmann, Yael Laitman, Gilli Galore, Gad Rennert, Flavio Lejbkowicz, Leon Raskin, Irene L. Andrulis, Eduard Ilyushik, Hilmi Ozcelik, Peter Devilee, Maaike P. G. Vreeswijk, Mark H. Greene, Sheila A. Prindiville, Ana Osorio, Javier Benitez, Michal Zikan, Csilla I. Szabo, Outi Kilpivaara, Heli Nevanlinna, Ute Hamann, Francine Durocher, Adalgeir Arason, Fergus J. Couch, Douglas F. Easton, Georgia Chenevix-Trench

Date Published: 1st Dec 2007

Publication Type: Journal article

Human Diseases: hereditary breast ovarian cancer syndrome

3-D analysis of the invasion front in squamous cell carcinoma of the uterine cervix: histopathologic evidence for collective invasion per continuitatem.
ProstataCA

Abstract (Expand)

OBJECTIVE: To investigate spatial tumor invasion using ex vivo specimens and pursue a new morphometric approach for a quantitative assessment of the invasion front. STUDY DESIGN: Based on histologic … serial sections with up to 500 slices stained with hematoxylin-eosin, volumes of interest of the tumor invasion front were 3-D reconstructed for 13 specimens from patients with squamous cell carcinoma (SCC) of the uterine cervix. Starting from very sensitive automatic tumor segmentation, 404 presumptive loci of isolated tumor islets were detected within the reconstructed volume data sets. These loci were microscopically inspected on the slides utilizing the volume date set's coordinates. RESULTS: A single detached tumor cell cluster within the stroma could be verified and, additionally, 4 tumor emboli within lymph vessels. The main cause of all other suspect islets (false positive segmentations) was peritumoral inflammatory response. Spatial invasion front quantification was done using discrete compactness (3-D C(D)). A comparison with 2-D C(D) values from single slides yielded strong correlation (correlation coefficient: r = 0.94; p < 0.001). CONCLUSION: Collective migration in SCC of the cervix mainly occurs per continuitatem. 2-D C(D) appears adequate and applicable for the morphometry of tumor invasion front phenotypes.

Authors: J. Einenkel, U. D. Braumann, L. C. Horn, J. P. Kuska, M. Hockel

Date Published: 9th Nov 2007

Publication Type: Not specified

Human Diseases: cervical cancer

Large histological serial sections for computational tissue volume reconstruction.
ProstataCA

Abstract (Expand)

OBJECTIVES: A proof of principle study was conducted for microscopic tissue volume reconstructions using a new image processing chain operating on alternately stained large histological serial sections. … METHODS: Digital histological images were obtained from conventional brightfield transmitted light microscopy. A powerful nonparametric nonlinear optical flow-based registration approach was used. In order to apply a simple but computationally feasible sum-of-squared-differences similarity measure even in case of differing histological stainings, a new consistent tissue segmentation procedure was placed upstream. RESULTS: Two reconstructions from uterine cervix carcinoma specimen were accomplished, one alternately stained with p16(INK4a) (surrogate tumor marker) and H&E (routine reference), and another with three different alternate stainings, H&E, p16(INK4a), and CD3 (a T-lymphocyte marker). For both cases, due to our segmentation-based reference-free nonlinear registration procedure, resulting tissue reconstructions exhibit utmost smooth image-to-image transitions without impairing warpings. CONCLUSIONS: Our combination of modern nonparametric nonlinear registration and consistent tissue segmentation has turned out to provide a superior tissue reconstruction quality.

Authors: U. D. Braumann, N. Scherf, J. Einenkel, L. C. Horn, N. Wentzensen, M. Loeffler, J. P. Kuska

Date Published: 17th Oct 2007

Publication Type: Not specified

Human Diseases: cervical cancer

Acute renal failure in patients with severe sepsis and septic shock–a significant independent risk factor for mortality: results from the German Prevalence Study
SepNet - German Competence Network Sepsis

Abstract (Expand)

BACKGROUND Sound data about the prevalence of acute renal failure (ARF) among patients with severe sepsis and septic shock are lacking. Further, it is not known whether ARF is an independent risk factor …r for mortality in septic patients or merely an indicator of disease severity. METHODS A prospective cross-sectional one-day prevalence study was carried out in a representative sample of German ICUs, divided into five strata (\textless 200 beds; 201-400 beds; 401-600 beds; \textgreater 600 beds; university hospitals). 3877 patients were screened of whom 415 had severe sepsis and septic shock. RESULTS Fourteen patients (3.4%) had chronic dialysis-dependent RF and were excluded from analysis. Of the remaining 401 patients, 166 (41.4%) had ARF, as defined by a rise in creatinine above twice the upper limit of normal and/or a drop in urine output to \textless 0.5 ml/kg bodyweight. Median APACHE II score was 22 in patients with ARF and 16 in patients without ARF (p\textless 0.0001). Patients with severe sepsis/septic shock had an overall hospital mortality of 55.2%. Hospital mortality in patients with ARF was 67.3% and without ARF 42.8% (p\textless 0.0001). After adjustment for APACHE II score and age, ARF remained a significant independent risk factor for death [odds ratio (OR) 2.11, 95% confidence interval (CI) 1.27-3.52]. Mortality in septic patients was not associated with pre-existing, non-dialysis-dependent chronic kidney disease, whereas in dialysis-dependent patients with sepsis mortality increased to 86%. CONCLUSION In this representative survey in patients with severe sepsis/septic shock, prevalence of ARF is high with 41.4%. ARF represents a significant independent risk factor for mortality in these patients.

Authors: Michael Oppert, Christoph Engel, Frank-Martin Brunkhorst, Holger Bogatsch, Konrad Reinhart, Ulrich Frei, Kai-Uwe Eckardt, Markus Loeffler, Stefan John

Date Published: 15th Oct 2007

Publication Type: Journal article

Human Diseases: disease by infectious agent

Cytogenetic and molecular biological characterization of an adult medulloblastoma
Genetical Statistics and Systems Biology

Abstract (Expand)

Medulloblastoma is a malignant invasive embryonal tumor, occurring in children mainly. It is rare in adults (\textless1% of adult brain tumors), and so comprehensive cytogenetic and molecular biological … data on adult medulloblastomas are very limited. Conventional therapies provide disappointing long-term disease control, and new therapeutic options are being tested. We performed comprehensive cytogenetic analyses of an adult medulloblastoma, WHO grade IV, using trypsin-Giemsa staining (GTG-banding), multicolor fluorescence in situ hybridization (M-FISH), and locus-specific FISH, complemented by molecular karyotyping using high-density single nucleotide polymorphism (SNP) arrays. GTG-banding of 25 metaphases revealed 31 structural chromosomal aberrations, predominantly located on chromosomes 4q, 9q, 10q, 11p, and 20q, which were confirmed by M-FISH. Two novel, so far not described translocations were found: t(4;11)(q25;p15) and t(9;20)(p23;p12). GTG-banding, locus-specific FISH, and M-FISH detected numerical changes of chromosomes 8, 14, 18, 19, 20, 21, and 22. Molecular karyotyping by SNP array confirmed chromosomal changes -2p, -10q, -16q, and -Xq and revealed de novo partial uniparental disomy 1q and 9q. Applying an upcoming therapeutic approach, we found that primary medulloblastoma cells were resistant to TRAIL, a novel anticancer cytokine, but could be efficiently sensitized by cotreatment with the proteasome inhibitor bortezomib. Bortezomib-TRAIL cotreatment may serve as a powerful therapeutic option for medulloblastoma patients.

Authors: Heidrun Holland, Ronald Koschny, Wolfgang Krupp, Jürgen Meixensberger, Manfred Bauer, Ralf Schober, Holger Kirsten, Tom M. Ganten, Peter Ahnert

Date Published: 1st Oct 2007

Publication Type: Journal article

Association of the BRCA1 missense variant R1699W with a malignant phyllodes tumor of the breast
GC-HBOC - German Consortium for Hereditary Breast and Ovarian Cancer

Abstract (Expand)

Familial breast carcinomas that are attributable to BRCA1 or BRCA2 mutations have characteristic morphologic and immunhistochemical features. BRCA1-associated carcinomas are poorly differentiated … infiltrating ductal carcinomas frequently exhibiting morphologic features of typical or atypical medullary carcinomas such as prominent lymphocytic infiltrate and pushing margins. We report on a patient carrying the deleterious BRCA1 germline mutation R1699W, who presented with a malignant phyllodes tumor of the breast. The re-investigation of archival material by a reference pathologist of the German Consortium for Hereditary Breast and Ovarian Cancer (GCHBOC) revealed BRCA-associated pronounced pushing margins. In a total of 618 unrelated index patients who are registered in the GCHBOC database, no other phyllodes tumor has been described, while 10 carriers of the R1699W mutant have been identified. We conclude that the histopathologic appearance of the phyllodes tumor indicates an association with the BRCA1 mutation R1699W although it is a rare event in BRCA-positive families.

Authors: Kerstin Rhiem, Uta Flucke, Christoph Engel, Barbara Wappenschmidt, Axel Reinecke-Lüthge, Reinhard Büttner, Rita Katharina Schmutzler

Date Published: 1st Jul 2007

Publication Type: Journal article

Human Diseases: hereditary breast ovarian cancer syndrome

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