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Biomedical subjects

Klaus Bumm

Publications and source records attributed to Klaus Bumm.

13 recordsLinked to original sources
PubMed2006

Tumor-associated antigenic pattern in squamous cell carcinomas of the head and neck--analysed by SEREX.

Most immuno-therapeutic approaches are based on tumor-associated antigens and many newly identified proteins have led to trials exploiting their possible therapeutic applicability. So far only limited information on the antigenic profile of head and neck squamous cell carcinomas (HNSCC) exists. Serological analysis of tumor antigens by recombinant cDNA expression cloning (SEREX) was used to identify the immunogenic patterns in our HNSCC patient collective. A cDNA expression library derived from a pharynx HNSCC case was screened with autologous and heterologous sera. Thirty-seven positive clones coding for 17 immunoreactive gene products, which elicited an in vivo tumor response, were found. Results were confirmed and extended by expression analysis using RT-PCR and in situ-hybridisation. The protein-sequence of five clones exists so far only hypothetically. Of all identified proteins only KIAA0530 has previously been associated with a HNSCC related immune response. All other proteins have not yet been described in a context with HNSCC antigenic patterns. Antibodies against a heat shock transcription factor 2 (HSF2) were found in 2 out of 10 sera from HNSCC patients. In summary, using the SEREX technique, we isolated 17 immunogenic antigens in HNSCC's and confirmed the clinical relevance of KIAA0530. Further analysis concerning their feasibility as target structures for an immunotherapy approach is currently conducted.

Antibodies, Neoplasm↗
PubMed2005

Sperm protein 17 expression defines 2 subsets of primary esthesioneuroblastoma.

Esthesioneuroblastomas (ENBs) are rare malignant tumors of the nasal vault, the origin, diagnosis, and management of which are still subjects of discussion. That there is no related prognostic factor or generally recognized therapeutic regimen highlights the need for further analyses of its underlying biologic features and investigations of new marker proteins that allow more reliable clinical testing. We here show that sperm protein 17 (Sp17) is expressed in the ciliated cells of the normal olfactory epithelium and in a proportion of primary ENB lesions. We found an association between Sp17 expression and metastases at relapse (P = .035), chromogranin expression (P = .014), and a female sex prevalence. A statistically nonsignificant relation was found between Sp17 and S-100, synaptophysin, and neurofilament expression. No correlation was also found between Sp17 expression and the proliferative capacity of the lesion that was evaluated by Ki-67 immunohistochemistry. The results of this study show the usefulness of Sp17 as a means of discriminating 2 subsets of primary ENB lesions and seem to suggest the existence of 2 distinct cell pathways in their origin and development.

Adolescent↗
PubMed2005

New endoscopic instruments for paranasal sinus surgery.

BACKGROUND: Minimally invasive endoscopic and microscopic procedures represent state of the art paranasal sinus surgery techniques in both diagnostic and surgical fields. To combine favorable aspects of both techniques, we evaluated the clinical applicability and effectiveness of multifunctional microendoscopes, providing multiple features to ensure highest accuracy and surveillance when performing crucial steps in paranasal sinus surgery. METHODS: The study included both anatomic experiments on cadaveric heads and clinical tests on patients undergoing routine paranasal surgery. The systems applicability was evaluated in procedures approaching the frontal and sphenoid sinus. Three different endoscopes, 2 straight and the other 1 with a 90 degrees angle, were tested. They integrate canals for flushing and suction and a working canal for either drilling or obtaining biopsies with a miniaturized forceps. For stereotactic feedback, the applicability in combination with a computer-navigation system was evaluated. RESULTS: Anatomic tests were performed to optimize illumination and to test drilling features and forceps biopsies. In all cases, the frontal sinus ostium and the sphenoid sinus anterior wall was easily identified and enlarged by drilling under visual and stereotactic control. Continuous suction and irrigation ensured a constant visual surveillance by removing drilling debris and blood. Best suited for multifunctional endoscopic surgery were drill heads with a cylinder shape, for placing bore holes along the Z axis, and spherical drill heads, for furbishing and enlarging drill holes. CONCLUSION: These new instruments have proven their applicability in paranasal sinus surgery. Multifunctional endoscopic procedures were deemed best suited for maneuvers requiring highest precision, such as the surgery of the frontal and sphenoid sinus.

Endoscopes↗
PubMed2005

Sialoscopy in cases of unclear swelling of the major salivary glands.

OBJECTIVE: Sialoscopy has developed into an important diagnostic and therapeutic tool for diseases of the major salivary glands. STUDY DESIGN AND SETTING: We evaluated 103 patients with chronic swelling of the major salivary glands. Routine diagnostic measures revealed no clear diagnosis. The findings of 109 sialoscopies are described. A semi-rigid endoscope (with a diameter of 1.1 mm and 2 integrated working channels) was used for sialoscopy, 51.5% of the cases in Warthon's duct and 48.5% in Stensen's duct. RESULTS: Pathologic findings resulted in 83.0% of the submandibular and in 96% of the parotid ducts. Obstruction neither due to sialolithiasis nor stenosis was observed in 56.3%, whereas sialolithiasis was observed in 20.3% of the patients. In 36 (35%) patients, an interventional sialoscopy was performed. CONCLUSIONS: In cases of invisible salivary duct obstruction, especially in those with low mineralized calculi, strictures, stenoses, or postinflammatory changes, sialoscopy gives immediate and direct information about causal pathologies. Moreover, further therapy can be planned within the same procedure.

Adolescent↗
PubMed2004

Surgical application of a new robotic system for paranasal sinus surgery.

The applicability of a robotic system for fully automated surgical procedures approaching the sphenoid sinus is evaluated. An integrated robotic system, A73, for computer navigation-guided, fully automated, and telemanipulation robotic performance is described. Details of the system comprising newly designed surgical instruments for robotic operations and preoperative planning protocols are provided. Experiments with an operational accuracy of less than 1 mm were followed by surgical tests, in which the results of fully automated and telemanipulation performances on 5 cadaveric heads are seen. The A73 system has been successfully used for a reproducible and accurate resection of the anterior wall of the sphenoid sinus. Therefore, we conclude that this system is suited for further testing toward approaching fully automated and more complex procedures of paranasal surgery.

Cadaver↗
PubMed2004

Sperm protein 17 is expressed in human somatic ciliated epithelia.

It was once believed that sperm protein 17 (Sp17) was expressed exclusively in the testis and that its sole function was to bind to the oocyte during fertilization. However, immunohistochemistry of the human respiratory airways and reproductive systems show that it is abundant in ciliated cells but not in human cells with stereocilia and microvilli. The high degree of sequence conservation throughout its N-terminal half, and the presence of an A-kinase anchoring protein (AKAP)-binding motif within this region, suggest that Sp17 plays a regulatory role in a PKA-independent AKAP complex in both male germinal and ciliated somatic cells.

Antigens, Surface↗
PubMed2003

Testing recombinant adeno-associated virus-gene loading of dendritic cells for generating potent cytotoxic T lymphocytes against a prototype self-antigen, multiple myeloma HM1.24.

Recent studies demonstrate that recombinant adeno-associated virus (rAAV)-based antigen loading of dendritic cells (DCs) generates significant and rapid (one stimulation per week) cytotoxic T-lymphocyte (CTL) responses in vitro against viral antigens. As a more extensive analysis of the rAAV system, we have used a self-antigen, HM1.24, expressed in multiple myeloma (MM). Again, with one stimulation, significant major histocompatibility complex (MHC) class 1-restricted, anti-HM1.24-specific CTL killing was demonstrated against MM cells. Furthermore, higher expression of interferon-gamma (IFN-gamma) in T cells and higher expression levels of, in order of significance, CD80 (2.6- to 3.8-fold increase), CD86, and CD40 on DCs were also observed. The use of synthetic HM1.24-positive target cells further demonstrated the antigen specificity of these CTLs. There was also no evidence of natural killer cell involvement. These data extend our earlier studies and suggest that the rAAV-loading of DCs may be a particularly good protocol for generating CTLs against self-antigens, which may not otherwise be considered good targets because of their low immunogenicity. We also show that HM1.24 may be an effective antigen for targeting MM.

Antigens, Neoplasm↗
PubMed2003

Continuous absence of metaphase-defined cytogenetic abnormalities, especially of chromosome 13 and hypodiploidy, ensures long-term survival in multiple myeloma treated with Total Therapy I: interpretation in the context of global gene expression.

Metaphase cytogenetic abnormalities (CAs), especially of chromosome 13 (CA 13), confer a grave prognosis in multiple myeloma even with tandem autotransplantations as applied in Total Therapy I, which enrolled 231 patients between 1989 and 1994. With a median follow-up of almost 9 years, the prognostic implications of all individual CAs, detected prior to treatment and at relapse, were investigated. Among all CAs and standard prognostic factors examined prior to therapy, only hypodiploidy and CA 13 (hypo-13 CA), alone or in combination, were associated with shortest event-free survival and overall survival (OS). The shortest postrelapse OS was observed with hypo-13 CA, which was newly detected in 18 of all 28 patients presenting with this abnormality at relapse. Superior prognosis was associated with the absence of any CA at both diagnosis and relapse (10-year OS, 40%). The lack of independent prognostic implications of other CAs points to a uniquely aggressive behavior of hypo-13 CA (present in 16% of patients at diagnosis). With the use of microarray data in 146 patients enrolled in Total Therapy II, overexpression of cell cycle genes distinguished CA from no CA, especially in cases of del(13) detected by interphase fluorescence in situ hybridization (FISH). FISH 13, resulting in a haploinsufficiency of RB1 and other genes mapping to chromosome 13, as well as activation of IGF1R, appears to have an amplifying effect on cell cycle gene expression, thus providing a molecular explanation for the dire outcome of patients with CA 13 compared with those with other CAs.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2002

Gene expression profiling of human plasma cell differentiation and classification of multiple myeloma based on similarities to distinct stages of late-stage B-cell development.

To identify genes linked to normal plasma cell (PC) differentiation and to classify multiple myeloma (MM) with respect to the expression patterns of these genes, we analyzed global mRNA expression in CD19-enriched B cells (BCs) from 7 tonsils, CD138-enriched PCs from 11 tonsils, 31 normal bone marrow samples, and 74 MM bone marrow samples using microarrays interrogating 6800 genes. Hierarchical clustering analyses with 3288 genes clearly segregated the 4 cell types, and chi-square and Wilcoxin rank sum tests (P <.0005) identified 359 and 500 previously defined and novel genes that distinguish tonsil BCs from tonsil PCs (early differentiation genes [EDGs]), and tonsil PCs from bone marrow PCs (late differentiation genes [LDGs]), respectively. MM as a whole was found to have dramatically variable expression of EDGs and LDGs, and one-way analysis of variance (ANOVA) was used to identify the most variable EDGs (vEDGs) and LDGs (v1LDG and v2LDG). Hierarchical cluster analysis with these genes revealed that previously defined MM gene expression subgroups (MM1-MM4) could be linked to one of the 3 normal cell types. Clustering with 30 vEDGs revealed that 13 of 18 MM4 cases clustered with tonsil BCs (P =.000 05), whereas 14 of 15 MM3 cases clustered with tonsil PCs when using 50 v1LDG (P =.000 008), and 14 of 20 MM2 cases clustered with bone marrow PCs when using 50 v2LDG (P =.000 09). MM1 showed no significant linkage with normal cell types studied. Thus, genes whose expression is linked to distinct transitions in late-stage B-cell differentiation can be used to classify MM.

Antigens, CD19↗
PubMed2002

Sperm protein 17 (Sp17) is a suitable target for immunotherapy of multiple myeloma.

Sperm protein 17 (Sp17) is a protein recently identified as a novel cancer-testis (CT) antigen in multiple myeloma (MM). Because this tumor antigen demonstrates a very restricted normal tissue expression, Sp17 may be an excellent target for tumor vaccine of MM. In this study, we determined the ability to generate Sp17-specific HLA class I-restricted cytotoxic T lymphocytes (CTLs) from the peripheral blood of 4 patients with MM, 3 consecutive Sp17(+) patients, and 1 Sp17(-) patient. Dendritic cells were generated from monocytes of 4 patients with MM and used to present a recombinant Sp17 protein to autologous T cells. Following 4 rounds of antigen stimulation, the CTLs were tested for their ability to kill autologous targets in an Sp17-dependent and HLA-class I- restricted manner in standard cytotoxicity assays. Despite previous chemotherapy and the immunosuppression so often associated with MM, CTL generation was successful in all 4 patients, irrespective of the Sp17 status of their tumors. Most importantly, the CTLs were able to lyse autologous tumor cells that expressed Sp17. Tumor cell lysis in all cases appeared to be mainly mediated by perforin and could be blocked by concanamycin A. We conclude that Sp17 is a suitable target for immunotherapy of MM. Our findings provide the basis for a clinical study aimed at inducing a cellular immune response directed at Sp17(+) MM.

Antigen Presentation↗
PubMed2002

Global gene expression profiling of multiple myeloma, monoclonal gammopathy of undetermined significance, and normal bone marrow plasma cells.

Bone marrow plasma cells (PCs) from 74 patients with newly diagnosed multiple myeloma (MM), 5 with monoclonal gammopathy of undetermined significance (MGUS), and 31 healthy volunteers (normal PCs) were purified by CD138(+) selection. Gene expression of purified PCs and 7 MM cell lines were profiled using high-density oligonucleotide microarrays interrogating about 6800 genes. On hierarchical clustering analysis, normal and MM PCs were differentiated and 4 distinct subgroups of MM (MM1, MM2, MM3, and MM4) were identified. The expression pattern of MM1 was similar to normal PCs and MGUS, whereas MM4 was similar to MM cell lines. Clinical parameters linked to poor prognosis, abnormal karyotype (P =.002) and high serum beta(2)-microglobulin levels (P =.0005), were most prevalent in MM4. Also, genes involved in DNA metabolism and cell cycle control were overexpressed in a comparison of MM1 and MM4. In addition, using chi(2) and Wilcoxon rank sum tests, 120 novel candidate disease genes were identified that discriminate normal and malignant PCs (P <.0001); many are involved in adhesion, apoptosis, cell cycle, drug resistance, growth arrest, oncogenesis, signaling, and transcription. A total of 156 genes, including FGFR3 and CCND1, exhibited highly elevated ("spiked") expression in at least 4 of the 74 MM cases (range, 4-25 spikes). Elevated expression of these 2 genes was caused by the translocation t(4;14)(p16;q32) or t(11;14)(q13;q32). Thus, novel candidate MM disease genes have been identified using gene expression profiling and this profiling has led to the development of a gene-based classification system for MM.

Bone Marrow Cells↗
PubMed2002

CGO: utilizing and integrating gene expression microarray data in clinical research and data management.

Clinical GeneOrganizer (CGO) is a novel windows-based archiving, organization and data mining software for the integration of gene expression profiling in clinical medicine. The program implements various user-friendly tools and extracts data for further statistical analysis. This software was written for Affymetrix GeneChip *.txt files, but can also be used for any other microarray-derived data. The MS-SQL server version acts as a data mart and links microarray data with clinical parameters of any other existing database and therefore represents a valuable tool for combining gene expression analysis and clinical disease characteristics.

Computational Biology↗