Biomedical subjects

Petr Starostik

Publications and source records attributed to Petr Starostik.

18 recordsLinked to original sources

PubMed2025

Reconciling competencies in undergraduate medical genetics education: APHMG versus PCME competencies.

PURPOSE: We wanted to understand whether there were gaps within and/or between the Association of Professors of Human and Medical Genetics (APHMG) and the Association of Pathology Chairs (APC) published competencies for undergraduate medical education pertaining to topics in medical and/or laboratory genetics. METHODS: This study compared and contrasted the APHMG and APC competencies related to genetics to identify gaps between and within each to inform the closure of those gaps in undergraduate medical education curriculum development for medical and laboratory genetics at the University of Florida. RESULTS: Gaps were identified within and between both documents, many relating to neoplasia for nonheritable cancers and various topics related to laboratory genetics, such as interpretation of results, principles of laboratory diagnostics, and explaining results to others. CONCLUSION: APHMG and APC should consider the gaps identified in this study in future updates to their respective competencies. Additionally, medical school curriculum committees may also wish to consider addressing these gaps in the development of medical genetics curricula.

Humans↗

PubMed2006

Clinical efficacy of lenalidomide in patients with relapsed or refractory chronic lymphocytic leukemia: results of a phase II study.

PURPOSE: Patients with relapsed or refractory chronic lymphocytic leukemia (CLL) have profound immune defects and limited treatment options. Given the dramatic activity of lenalidomide in other B-cell malignancies and its pleotropic immunomodulatory effects, we conducted a phase II trial of this agent in CLL. PATIENTS AND METHODS: Patients with relapsed or refractory B-cell CLL (B-CLL) were eligible if they required treatment as per the National Cancer Institute Working Group 1996 guidelines. Lenalidomide was administered orally at 25 mg on days 1 through 21 of a 28-day cycle. Response was assessed after each cycle. Patients were to continue treatment until disease progression, unacceptable toxicity, or complete remission. Rituximab was added to lenalidomide on disease progression. RESULTS: Forty-five patients were enrolled, with a median age of 64 years. Sixty-four percent of the patients had Rai stage III or IV disease, and 51% were refractory to fludarabine. The overall response rate was 47%, with 9% of the patients attaining a complete remission. Fatigue, thrombocytopenia, and neutropenia were the most common adverse effects noted in 83%, 78%, and 78% of the patients, respectively. CONCLUSION: Lenalidomide is clinically active in patients with relapsed or refractory B-CLL. These findings are encouraging and warrant further investigation of this agent in the treatment of this disorder.

Adult↗

PubMed2005

Amplification of NOTCH1 and ABL1 gene loci is a frequent aberration in enteropathy-type T-cell lymphoma.

We have shown previously that amplification of chromosomal region 9q34 is the most frequent aberration in enteropathy-type T-cell lymphoma (ETL). To determine the minimum amplified 9q34 region and identify possible candidate gene(s), we performed a detailed microsatellite screening and quantitative real-time PCR (QPCR) on 26 ETL cases. Microsatellite analysis revealed allelic imbalance in both ABL1 and NOTCH1 gene loci (microsatellites D9S290-D9S1847 and D9S158 flanking the former and latter genes, respectively) localized in the band 9q34. The results were confirmed by TaqMan-based QPCR showing amplification of ABL1 and NOTCH1 exons in 50% and 65% of cases, respectively. Amplifications of the NOTCH1 gene were more frequent than of the ABL1 gene; moreover, the analyzed NOTCH1 exon consistently displayed higher levels of amplification than ABL1 coding sequences. From 9q34 known genes, NOTCH1 could thus be the primary target of genomic DNA amplification in ETL.

Chromosomes, Human, Pair 9↗

PubMed2003

Human ependymomas reveal frequent deletions on chromosomes 6 and 9.

Ependymomas are glial tumors of the brain and spinal cord. Genetic aberrations associated with the development of these tumors have not been fully identified yet. In previous cytogenetic and comparative genomic hybridization studies, multiple genomic imbalances in ependymomas were found, including partial or whole chromosome losses (1p, 4q, 6q, 9, 10, 11, 13, 16, 17, 19q, 20q and 22q). The aim of this study was to map particularly the commonly affected regions in ependymomas. Thirty-three pairs of matched normal and tumor specimens from ependymoma patients were genotyped using 34 polymorphic microsatellite markers distributed over 15 chromosomes. Loss of heterozygosity (LOH) was found in 26 of 33 tumors (78.8%). The most frequent LOHs were found on the long arms of chromosomes 6 (30.3%) and 9 (27.3%). LOH was also detected on 3p14 (13.3%), 10q23 (10.3%) and 11q (18.2%). Because of the high percentage of LOH on chromosome 6 and 9, we conclude that important tumor suppressor genes are situated on these two chromosomes.

Adult↗

PubMed2003

Correlating genetic aberrations with World Health Organization-defined histology and stage across the spectrum of thymomas.

Thymomas are thymic epithelial tumors. Because most of them are rich in nonneoplastic T-cells, recurrent genetic aberrations have been reported only in the rare, lymphocyte-poor WHO types A, B3, and C. We have now investigated virtually the whole spectrum of thymomas, including the commoner types AB and B2, microdissecting or culturing neoplastic cells from these lymphocyte-rich thymomas and applying 41 microsatellite markers covering 17 loci on 10 chromosomes. In 28 cases, comparative genomic hybridization data were available. Apart from type A, there was striking heterogeneity between thymomas. Allelic imbalances were seen in 87.3% of the 55 cases, and MSI in 9.9%. Losses of heterozygosity (LOHs) were much the commonest aberration. Overall, they were most prevalent at four regions on chromosome 6. Aberrations elsewhere, affecting mainly 8p11.21 and 7p15.3, suggested a cortical footprint because they recurred only in the thymopoietically active type AB and B thymomas. LOHs were also seen at the adenomatous polyposis coli (APC) locus (5q21-22) in subsets of these thymomas, whereas combined LOHs at the APC, retinoblastoma (13q14.3), and p53 (17p13.1) loci were confined to a subset of B3 thymomas that had possibly evolved from APC-hemizygous B2 thymomas by tumor progression; indeed, thymomas combing B2 plus B3 features are common. Notably, some AB and B thymomas shared LOHs despite their nonoverlapping morphology and different clinical behavior. Finally, allelic imbalances at 8p11.21 and 16q22.1 (CDH1) were significantly more frequent in stage IV metastatic thymomas. We conclude that the WHO-defined histological thymoma types generally segregate with characteristic genetic features, type A thymomas being the most homogeneous. Many findings support the view that B2 and B3 thymomas form a continuum, with evidence of tumor progression. However, other findings imply that types A and AB are biologically distinct from the others, any potential invasiveness being severely restricted by a medullary commitment in the precursor cell undergoing neoplastic transformation.

Cells, Cultured↗

PubMed2003

Allelic losses on chromosome 6q25 in Hodgkin and Reed Sternberg cells.

We established a molecular cytogenetic approach to identify consistent genetic aberrations in classical Hodgkin lymphoma. Single laser-micromanipulated Hodgkin and Reed Sternberg (H-RS) cells and the respective germ line tissue were PCR-amplified using highly polymorphic microsatellite probes. Loss of heterozygosity and genomic imbalances of the fluorochrome-labeled microsatellites were determined by fragment length analysis. Eleven cases of in classical Hodgkin lymphoma (cHL) were initially screened with 21 microsatellite markers scattered over the entire genome. Loss of heterozygosity was detected in >40% of informative loci in most cases indicating a deletion of a substantial part of the genome of H-RS cells. Allelic losses and imbalances on chromosome 6q were detected in most of these cases. A deletion mapping of 6q was performed in 16 cases of cHL. This detailed analysis of 6q led to the identification of a 3.3-Mbp region around D6S311 flanked by D6S978 and D6S1564 that was altered in 11 of 14 cases of cHL analyzed. In conclusion, allelotyping of single H-RS cells revealed monoallelic chromosomal deletions and genomic imbalances on 6q that might affect genes critically involved in the pathogenesis of H-RS cells.

Alleles↗

PubMed2003

Semiquantitative and qualitative assessment of B-lymphocyte V H repertoire by a fluorescent multiplex PCR.

We established a new tool to perform semiquantitative and qualitative screening for V(H) gene usage frequency during IgH rearrangements in human B-lymphocytes. In two separate multiplex PCRs, the rearranged VDJ regions were amplified with V(H) family-specific primers labeled with different fluorescent dyes (FAM, HEX, NED, or ROX). The relative amount of each of the particular V(H) family products and their ratios were determined by fragment analysis on a ABI PRISM 377 sequencer. We verified that the fluorescent multiplex PCR (FMPCR) shows high specificity and sensitivity, acceptable reproducibility and reliability. Data obtained were well in agreement with results revealed by sequencing following single-cell PCR. Ten healthy volunteers showed a comparable semiquantitative V(H) family distribution. The FMPCR also correctly detected a monoclonal peak in a CLL patient. Thus, labeling primers with various fluorescent dyes allows for an assessment of V(H) family usage and an immediate determination of the involved V(H) gene family if any clonal peaks are present. This method provides a quick, easy, and reliable tool for V(H) repertoire screening of larger populations of patients suffering from diseases with changes in the V(H) repertoire allowing for selection of cases worth a more detailed and cumbersome sequence analysis later on.

Adult↗

PubMed2003

Angioimmunoblastic T cell lymphoma is derived from mature T-helper cells with varying expression and loss of detectable CD4.

Angioimmunoblastic T cell lymphoma (AILT) is a rare lymphoma that is regarded as a clinicopathologic entity but shows considerable histomorphologic diversity, variable immunophenotypes and inconsistent T cell receptor (TCR) gene rearrangement. One hundred four paraffin blocks of AILT were investigated defining tumor cell lineage by triple immunostains with a confocal laser scanning microscope and correlating morphology, immunophenotype and TCRgamma gene rearrangement to clinical outcome. Ninety-nine cases were CD4(+), some of them showing a mixture of CD4(+) and CD4(-) tumor cells. The remaining 5 specimens were CD3(+)/CD4(-)/CD8(-). A considerable number of T cells of different subtypes could always be found, but even in 13 cases predominated by CD8(+) cells, proliferation could be attributed to atypical CD4(+) cells. TCRgamma gene rearrangement was monoclonal in 48 cases (69%) among 70 tested. In 29 of these semi-quantitative gene scan analysis resulted in a median proportion of monoclonal peak of 35% of PCR-products. Clinical outcome was identical grouping patients by clonality of TCRgamma, absence or presence of clear cell clusters and international prognostic index. We conclude that AILT is mainly derived from CD2(+)CD3(+)CD4(+)CD5(+)CD7(-) mature T-helper cells with varying expression and partial loss of detectable CD4. A significant number of non-neoplastic T cells (resting CD4(+) T cells and activated small or medium-sized CD8(+) lymphocytes) may coexist with a minor neoplastic T cell population. Clinicopathologic correlation suggests AILT to be a well defined homogeneous entity with poor prognosis. Currently no prognostic factors can be derived.

Adult↗

PubMed2003

High frequency of genetic aberrations in enteropathy-type T-cell lymphoma.

To define genetic aberrations playing a role in the development of enteropathy-type T-cell lymphoma (ETL), we examined 26 such tumors using a battery of 47 microsatellite markers. The most frequent aberration (seen in 40% of informative genotypes) was amplification of genomic material in region 9q34 encompassing c-abl and Notch-1 gene loci. Other frequent amplifications were detected in regions 5q33.3-34 and 7q31 (both in more than 30%). Multiple losses of heterozygosity were detected in 6p24, 7p21, 17q23-25, regions containing putative tumor suppressor genes, and in the p53 locus in 17p13.1. Analysis of the pattern of occurrence of these aberrations revealed existence of two ETL subgroups: one of them characterized by the 9q34 aberration and another smaller one showing allelic imbalances in 3q27. These two aberrations were mutually exclusive. Microsatellite instability (MSI) was detected in 69% of the examined lymphomas; the percentage of MSI-positive genotypes per tumor ranged from 2% to 12%. The spectrum of genetic alterations detected showed patterns dependent on morphology. Monomorpic ETLs displayed frequently biallelic TCR-gamma gene rearrangement (p = 0078, chi(2) test). They showed a different pattern and fewer allelic imbalances (no 3q27, 4q28, 13q14, fewer 5q21, or 5q33.3-34 aberrations) and a lower frequency of MSI than pleomorphic ETLs.

Adult↗

PubMed2002

Minimal residual low-grade gastric MALT-type lymphoma after eradication of Helicobacter pylori.

Helicobacter pylori eradication is the initial treatment of choice in localised low-grade gastric MALT (mucosa-associated lymphoid-tissue)-type lymphoma. We describe the natural course of seven patients who refused further oncological treatment for persistent lymphoma after successful eradication of H pylori. Despite persistent clonality, neither lymphoma progression nor high-grade transformation arose during a mean observation period of 34 (range 22-44) months. In view of the favourable course of these patients, a watch-and-wait strategy could be a valid approach to management of this disease.

Adult↗

PubMed2002

Loss of heterozygosity on chromosome 22 in human ependymomas.

Ependymomas are glial tumors of the brain and spinal cord. The most frequent genetic change in sporadic ependymomas is monosomy 22, suggesting the presence of an ependymoma tumor suppressor gene on chromosome 22. Thirty-three pairs of matched normal and tumor specimens from ependymoma patients were genotyped using 12 polymorphic microsatellite markers spanning the long arm of chromosome 22. Allelic deletion was found in 12 of 33 tumors (36.4%). Eight tumors showed partial deletions and 4 tumors exhibited loss of the entire arm of 22q. We identified two common regions of deletion: one at 22q11.21-12.2 flanked by markers D22S420 and D22S300, and a second candidate region at 22q13.1-13.3 between D22S274 and D22S1149. The size of each region was 21.1 and 2.4 cM, respectively. Thus, our results suggest that one or more tumor suppressor genes associated with ependymoma may be present on chromosome 22. Comparison of these results with clinicopathological data indicate that allelic losses on 22q tend to occur more frequently in intracranial anaplastic ependymomas in children and intraspinal ependymomas in adults.

Adult↗

PubMed2002

Proficient mismatch repair protein expression in Hodgkin and Reed Sternberg cells.

Hodgkin and Reed-Sternberg (H/RS) cells are characterized by chromosomal instability. Nevertheless, neither specific nor consistent chromosomal alterations could be characterized in H/RS cells. Microsatellite instability (MSI) is another form of genomic instability but its role in the pathogenesis of classical Hodgkin's disease (cHD) has not been investigated so far. We analyzed MSI and mismatch repair (MMR) protein expression in H/RS cells of cHD in order to assess genomic instability in these cells. Using a sensitive single cell approach, MSI-low was detected in a portion of single cells of the H/RS cell line L1236. Mutations of genes encoding for hMSH2 and hMLH1 were excluded by RT-PCR in L1236 cells. An analysis of pooled single H/RS cells of seven primary cases of cHD showed loss of heterozygosity for some allelic markers but absence of MSI in all 7 cases. Owing to a tight correlation between MSI-high, inactivating mutations of MMR genes and MMR protein expression in colon cancer, MMR protein expression commonly is used as a marker for MSI. In order to screen additional primary cases of cHD for MSI, we performed immunohistochemistry for hMSH2 and hMLH1 in 6 of the 7 cases analyzed by single cell PCR and 20 additional cases of cHD. H/RS cells from 25 out of 26 cases showed a nuclear staining pattern for hMSH2 and hMLH1 similar to germinal center B cells of non-malignant lymph nodes. These results indicate a proficient MMR system in most H/RS cells. It is concluded that a defect MMR system is unlikely to contribute to the malignant phenotype and genomic instability of H/RS cells in cHD.

Adaptor Proteins, Signal Transducing↗

PubMed2002

Gastric marginal zone B-cell lymphomas of MALT type develop along 2 distinct pathogenetic pathways.

Low-grade marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT) type can transform into high-grade diffuse large B-cell lymphoma (DLBCL). Up to 60% of the MALT lymphomas contain the recently described t(11;18). However, this translocation has not been detected in any DLBCL so far. To elucidate the pathogenesis of these tumors, microsatellite screening of 24 gastric MALT lymphomas was performed and the results were compared with aberrations detected in a previous study on gastric DLBCL. The most frequent aberration, found in 21% of the MALT lymphomas that were exclusively t(11;18)-negative cases, was amplification of the 3q26.2-27 region (harboring the locus of the BCL6 gene). Allelic imbalances in regions 3q26.2-27, 6q23.3-25, 7q31, 11q23-24, and 18q21 were shared by both MALT lymphoma and DLBCL. Loss of heterozygosity in regions 5q21 (APC gene locus), 9p21 (INK4A/ARF), 13q14 (RB), and 17p13 (p53) and allelic imbalances in 2p16, 6p23, and 12p12-13 occurred exclusively in DLBCL. Only one of 10 t(11;18)-positive MALT lymphomas showed an additional clonal abnormality. These tumors thus display features of a clonal proliferation characterized by the presence of the t(11;18). However, they only rarely display secondary aberrations and do not seem to transform into DLBCL. In contrast, t(11;18)-negative MALT lymphomas show numerous allelic imbalances--some of them identical with aberrations seen in DLBCL--suggesting that this group is the source of tumors eventually transforming into high-grade DLBCL.

Adult↗

PubMed2002

Chromosome 6 suffers frequent and multiple aberrations in thymoma.

Thymoma is the most frequent tumor arising in human thymus. In this study, we performed a detailed mapping of deleted regions on chromosome 6 shown previously to harbor the most frequent genetic aberrations in this cancer. We analyzed 40 thymomas using 41 microsatellites. Two hundred ninety-four (23.5%) of 1253 informative genotypes showed loss of heterozygosity (LOH), only 39 (2.4%) were positive for microsatellite instability (MSI). Genetic aberrations on chromosome 6 were found in 31 of 40 cases (77.5%) in five hot spots. The most frequent LOHs (48.6%) occurred in region 6q25.2 within a 0.7-Mb interval flanked by markers D6S441 and D6S290. Another hot spot showing LOH in 32.4% of tumors was located between markers D6S442 and D6S1708 (0.4 Mb apart) on 6q25.2-25.3, just 1.1 Mb from the D6S441-D6S290 deletions. The third hot spot (30%) showing LOH appeared in region 6p21.31 including the MHC locus (markers D6S1666-D6S1560, 1 Mb apart). The fourth hot spot (26.3%) was detected on 6q14.1-14.3 (D6S1596-D6S284, 5.2 Mb apart). Some tumors (21.6%) showed LOHs within a fifth hot spot on 6q21 (D6S447-D6S1592, 0.3 Mb apart). Thus, several tumor suppressor genes on chromosome 6 seem to be involved in the pathogenesis of thymoma.

Chromosome Aberrations↗

PubMed2002

Chromosomal gains at 9q characterize enteropathy-type T-cell lymphoma.

Genetic alterations in enteropathy-type T-cell lymphoma (ETL) are unknown so far. In this series, 38 cases of ETL were analyzed by comparative genomic hybridization (CGH). CGH revealed chromosomal imbalances in 87% of cases analyzed, with recurrent gains of genetic material involving chromosomes 9q (in 58% of cases), 7q (24%), 5q (18%), and 1q (16%). Recurrent losses of genetic material occurred on chromosomes 8p and 13q (24% each), and 9p (18%). In this first systematic genetic study on ETL, chromosomal gains on 9q (minimal overlapping region 9q33-q34) were found to be highly characteristic of ETL. Fluorescence in situ hybridization analysis on four cases of ETL, using a probe for 9q34, indicated frequent and multiple gains of chromosomal material at 9q34 (up to nine signals per case). Among 16 patients with ETL who survived initial disease presentation, patients with more than three chromosomal gains or losses (n = 11) followed a worse clinical course than those with three or less imbalances (n = 5). The observation of similar genetic alterations in ETL and in primary gastric (n = 4) and colonic (n = 1) T-cell lymphoma, not otherwise specified, is suggestive of a genetic relationship of gastrointestinal T-cell lymphomas at either localization.

Adult↗

PubMed2002

A complex DNA-repeat structure within the Selenoprotein P promoter contains a functionally relevant polymorphism and is genetically unstable under conditions of mismatch repair deficiency.

Epidemiological data, animal studies and interventional studies provide evidence for a potential chemopreventive effect of selenium during development of colorectal cancer. The human glycoprotein Selenoprotein P (SeP) contains up to 50% of plasma selenium content. SeP is expressed in the gastrointestinal tract and the liver, where its expression is downregulated by various proinflammatory cytokines (Il1beta, TGFbeta, IFNgamma). Previously, we have demonstrated dramatically reduced SeP expression in human colon adenomas. Here, we have identified a complex (A)4-C-(A)4-GG-(A)8-GCT-(TC)5-(T)17 (bp -429 to bp - 477) repeat structure within the SeP promoter and we have analysed this regulatory DNA sequence with respect to polymorphisms, genomic instability and functional relevance to promoter activity. As opposed to the (TC)5 variant we identified a novel (TC)3 polymorphism within this repeat in the general population, which conferred significantly reduced basal promoter activity to reporter gene constructs in HepG2 cells. Allelic distribution of this (TC)(n) element was similar in colon carcinoma patients and healthy controls. Additionally, we observed genetic instability within the (T)17 repeat motif in colon cancers of the mutator phenotype. This instability of the (T)17 repeat had no effect on basal promoter activity in reporter gene assays. In conclusion, we characterised a complex repeat structure within the SeP promoter that may be of functional relevance to SeP gene expression. Further studies on the effect of different SeP promoter genotypes on SeP protein expression and disease susceptibility are needed.

Base Pair Mismatch↗

PubMed2002

Spiradenocylindroma of the kidney: clinical and genetic findings suggesting a role of somatic mutation of the CYLD1 gene in the oncogenesis of an unusual renal neoplasm.

We describe the morphology and comparative genomic hybridization findings in a tumor for which we propose the term "spiradenocylindroma" of the kidney. The tumor arose in the wall of a renal cyst in an otherwise healthy male patient who had a favorable clinical course after nephrectomy. Tumor cells formed either large nodules exhibiting a solid or trabecular architecture with conspicuous perivascular spaces or cylindromatous small tumor cell islands arranged in a jigsaw pattern. Focally, there were interspersed tubular structures and tumor cell rosettes with central deposits of periodic acid-Schiff-positive material. A minor tumor component showed epidermoid differentiation. The tumor cells were strongly positive for cytokeratins 5/6, high molecular weight cytokeratins 34betaE12 and AE1/3, and E-cadherin, but only weakly positive for cytokeratins 7, 8, 18, 19, and epithelial membrane antigen. Focal reactivity for actin, vimentin, and S-100 protein or lysozyme and alpha 1 -antichymotrypsin within tubular and cylindromatous areas suggested myoepithelial and apocrine differentiation, respectively. By comparative genomic hybridization, the only abnormality was loss of the long arm of chromosome 16 and gain of genetic material on the short arm of chromosome 16, suggesting isochromosome i(16p). This finding is unique among renal neoplasms and implies loss of heterozygosity at 16q12-13 of the CYLD1 gene that is critically involved in the oncogenesis of familial cylindromatosis and some sporadic spiradenocylindromas. We conclude that somatic mutation of the CYLD1 gene outside the skin can have a role in the oncogenesis of tumors with cylindromatous features.

Carcinoma, Adenoid Cystic↗

PubMed2002

Epstein-Barr virus-associated B-cell lymphoproliferative disorders in angloimmunoblastic T-cell lymphoma and peripheral T-cell lymphoma, unspecified.

Various patterns of Epstein-Barr virus (EBV)-associated B-cell lymphoproliferation occur in patients with immunodeficiency. We studied 17 cases of T-cell lymphoma displaying extensive EBV-driven B-cell lymphoproliferation or simultaneous/subsequent EBV-associated B-cell lymphoma. In 10 cases of angioimmunoblastic T-cell lymphoma, an uncommonly prominent population of EBV+ atypical, activated, focally confluent large transformed B cells was found in the background of T-cell lymphoma. In 4 cases, an EBV-associated B-cell neoplasm (3 diffuse large B-cell lymphomas, 1 plasmacytoma) occurred in patients with T-cell lymphoma. Three cases were composite lymphomas of a peripheral T-cell lymphoma, unspecified, combined with EBV-associated diffuse large B-cell lymphoma. The transformed B-cell population displayed EBV latency types 2 and 3. Monoclonal and oligoclonal B-cell populations were detected in 5 and 6 cases, respectively. Similar to other states of immunodeficiency, disease-related and therapy-induced immunosuppression in T-cell lymphoma may lead to a prominent EBV-associated B-cell lymphoproliferation and to EBV+ B-cell neoplasms.

Aged↗