Successful treatment of hyperuricemia with low doses of recombinant urate oxidase in four patients with hematologic malignancy and tumor lysis syndrome.
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Adult↗
Biomedical subjects
M Hummel
Publications and source records attributed to M Hummel.
Design and standardization of PCR primers and protocols for detection of clonal immunoglobulin and T-cell receptor gene recombinations in suspect lymphoproliferations: report of the BIOMED-2 Concerted Action BMH4-CT98-3936.
In a European BIOMED-2 collaborative study, multiplex PCR assays have successfully been developed and standardized for the detection of clonally rearranged immunoglobulin (Ig) and T-cell receptor (TCR) genes and the chromosome aberrations t(11;14) and t(14;18). This has resulted in 107 different primers in only 18 multiplex PCR tubes: three VH-JH, two DH-JH, two Ig kappa (IGK), one Ig lambda (IGL), three TCR beta (TCRB), two TCR gamma (TCRG), one TCR delta (TCRD), three BCL1-Ig heavy chain (IGH), and one BCL2-IGH. The PCR products of Ig/TCR genes can be analyzed for clonality assessment by heteroduplex analysis or GeneScanning. The detection rate of clonal rearrangements using the BIOMED-2 primer sets is unprecedentedly high. This is mainly based on the complementarity of the various BIOMED-2 tubes. In particular, combined application of IGH (VH-JH and DH-JH) and IGK tubes can detect virtually all clonal B-cell proliferations, even in B-cell malignancies with high levels of somatic mutations. The contribution of IGL gene rearrangements seems limited. Combined usage of the TCRB and TCRG tubes detects virtually all clonal T-cell populations, whereas the TCRD tube has added value in case of TCRgammadelta(+) T-cell proliferations. The BIOMED-2 multiplex tubes can now be used for diagnostic clonality studies as well as for the identification of PCR targets suitable for the detection of minimal residual disease.
Chromosome Aberrations↗
[Heart transplantation in Germany 2002].
After the first transplantation thirty-five years ago, heart transplantation has become an established and surgically widely standardized treatment modality for patients with end-stage heart failure. The improved medical therapy and alternative treatment options like revascularisation (CABAG), electrical resynchronization by a three-chamber pacemaker system or the implantation of mechanical assist device systems as well as the development of risk factor score systems to calculate the prognosis of patients with heart failure requires a new assessment of the indication for heart transplantation. The large number of heart transplanted patients and the results of randomized studies with new immunosuppressive drugs allow to calculate the risk, benefit and limitation of transplantation with relatively good reliability. These experiences and knowledge obtained and the German Transplantation Law, which passed the parliament in 1999, led to the establishment of a new heart allocation system. Additionally, by the central documentation of all transplantations in Germany, it becomes possible to compare the results of heart transplantations for better quality control.
Adult↗
Receptor revision of immunoglobulin heavy chain genes in human MALT lymphomas.
BACKGROUND/AIMS: Rearrangement of immunoglobulin gene segments, leading to B cells with functional receptors, is thought to be largely restricted to developing immature B cells in bone marrow. However, accumulating evidence suggests that mature B cells occasionally modify their antigen specificity by VH segment replacements during the germinal centre reaction to enhance antigen affinity, or to overcome self reactive antigen receptors. Although malignant B cells maintain the features of their normal counterparts in most instances, to date, such replacements have not been described for human B cell lymphomas. METHODS: Rearranged immunoglobulin heavy chain genes from two extranodal marginal zone B cell lymphomas were amplified, cloned, and sequenced. Sequences with identical CDR3 regions were selected and aligned to each other and public databases. RESULTS: VH replacements were seen in two extranodal marginal zone B cell lymphomas. In line with the hypothesis that in mature B cells these replacements are associated with active somatic hypermutation, in addition to VH replacement, different mutation patterns were seen in the revised VH portions. In the remaining common 3'-VH regions, these mutations could be used to establish a phylogenetic relation between the sequences, rendering the possibility of artefactual chimaeric polymerase chain reaction products very unlikely. CONCLUSIONS: These results support the view that VH replacements are a further mechanism for reshaping antigen affinity and specificity, and indicate that these receptor modifications are not restricted to normal and reactive germinal centre B cells, but may also occur in close association with the development of malignant B cell lymphomas.
Base Sequence↗
Clonality and malignancy. PCR assays for the diagnosis of clonal B- and T-cell proliferations: potentials and pitfalls.
The discrimination between lymphomas and reactive lymphoproliferations is difficult or even impossible in a proportion of cases by means of histology and additional immunhistochemistry alone. Therefore, the analysis of the clonality of the rearranged immunoglobulin genes and T-cell receptor genes, respectively, is often employed as an additional diagnostic tool. This analysis is based on the fact that the tumor cells of lymphomas harbor identically (clonally) rearranged antigen receptor genes whereas reactive lymphoproliferations consist of cells with differently (polyclonally or oligoclonally) rearranged antigen receptor genes. Initially Southern blot analysis was used to determine the presence of clonal lymphoid cell populations. Meanwhile polymerase chain reaction (PCR) is the method of choice because of its higher sensitivity and its applicability to DNA extracted from formalin-fixed tissues. Although this PCR approach appears to be simple, there are many pitfalls, which can lead to false negative or false positive results. In a diagnostic setting, these false clonality results could give rise to a wrong final diagnosis and, as a consequence, to the performance of an inadequate therapy. The reasons for the non-detectability of clonal B-cell or T-cell populations or for the detection of false clonality (e.g. clonal rearrangement pattern in the absence of a lymphoma) are manifold. In the following the most frequent reasons are discussed and recommendations are given to avoid false negative and false positive results.
B-Lymphocytes↗
Nifedipine improves blood flow and oxygen supply, but not steady-state oxygenation of tumours in perfusion pressure-controlled isolated limb perfusion.
Isolated limb perfusion allows the direct application of therapeutic agents to a tumour-bearing extremity. The present study investigated whether the dihydropyridine-type Ca(2+)-channel blocker nifedipine could improve blood flow and oxygenation status of experimental tumours during isolated limb perfusion. Perfusion was performed by cannulation of the femoral artery and vein in rats bearing DS-sarcoma on the hind foot dorsum. Perfusion rate was adjusted to maintain a perfusion pressure of 100-140 mmHg throughout the experiment. Following equilibration, nifedipine was continuously infused for 30 min (8.3 microg min(-1) kg(-1) BW). During constant-pressure isolated limb perfusion, nifedipine can significantly increase perfusion rate (+100%) and RBC flux (+60%) through experimental leg tumours. "Steal phenomena" in favour of the surrounding normal tissue and oedema formation were not observed. Despite the increased oxygen availability (+63%) seen upon application of this calcium channel blocker, nifedipine does not result in a substantial reduction of tumour hypoxia, most probably due to an increase in O(2) uptake with rising O(2) supply to the tumour-bearing hind limb. Nifedipine application during isolated limb perfusion can enhance tumour microcirculation and may therefore promote the delivery (pharmacokinetics) of anti-cancer drugs to the tumour and by this improve the efficacy of pressure-controlled isolated limb perfusion.
Animals↗
Molecular genetic diagnosis of a primary central nervous system T cell lymphoma.
Primary central nervous system T cell lymphomas are rare tumors. Histologically, they may be indistinguishable from other entities like inflammatory processes. In such cases, molecular genetic verification of clonal T cell receptor (TCR) gene rearrangements is an indispensable diagnostic tool. Here we present a case where identification of TCR beta and gamma gene rearrangements by polymerase chain reaction was used to differentiate between a vasculitis and a primary CNS T cell lymphoma, which has profound consequences for therapy management and outcome.
Adult↗
Surveillance biopsies in heart and lung transplantation.
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Biopsy, Needle↗
Efficiency and reliability of early postoperative noninvasive rejection monitoring.
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Biopsy, Needle↗
Left ventricular dysfunction during cardiac allograft rejection: early diagnosis, relationship to the histological severity grade, and therapeutic implications.
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Biopsy, Needle↗
Pattern of month of birth in diabetic and non-diabetic adults.
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Adult↗
[Non-invasive monitoring of rejection after cardiac transplantation. The method and retrospective analysis of data on 734 patients].
BACKGROUND AND OBJECTIVE: Endomyocardial biopsy is the gold standard for monitoring rejection in cardiac recipients. The death rate due to rejection with this invasive method is 5-6 % in the first postoperative year. The aim of this retrospective data analysis from cardiac recipients was to prove the diagnostic reliability of a non-invasive electrophysiological method for rejection monitoring. PATIENTS AND METHODS: We daily analyzed the QRS-complex amplitude of the intramyocardial electrogram, which we received over a period from one year via a pacemaker with a telemetric capability. The diagnostic guideline for a suspected rejection was the reduction of the QRS-complex amplitude by more than 8 %. Out of 734 patients 558 were included in the study. Biopsy was only performed when the non-invasive rejection monitoring data (QRS-complex amplitude plus echocardiography) showed a discrepancy for rejection. RESULTS: None of the patients died due to rejection, 273 at least once underwent a biopsy, and 285 never had a biopsy. The method reached a sensitivity of 0.9777, a specificity of 0.9634, a negative predictive value of 0.9850, and a positive predictive value of 0.9459. CONCLUSION: Daily electrophysiological non-invasive monitoring of rejection seems to be superior to endomyocardial biopsy. Death of patients due to rejection can be minimised. The number of necessary biopsies can be drastically reduced when compared to the usual number performed.
Adolescent↗
Reliability of tissue Doppler wall motion monitoring after heart transplantation for replacement of invasive routine screenings by optimally timed cardiac biopsies and catheterizations.
BACKGROUND: Invasive screenings at predefined time intervals for acute rejection and transplant coronary artery disease (TxCAD) are standard procedures. However, cardiac biopsies and catheterizations are distressing and risky for the patients and are also costly. We assessed the reliability of pulsed-wave tissue Doppler imaging (PW-TDI) for the timing of invasive examinations in heart recipients in an attempt to avoid unnecessary endomyocardial biopsies (EMBs) and catheterizations. METHODS AND RESULTS: PW-TDI obtained at the basal left ventricular posterior wall before 408 EMBs and 293 catheterizations was tested for its diagnostic value regarding rejection and TxCAD with the use of International Society of Heart and Lung Transplantation biopsy grading, coronary angiography, and intravascular ultrasound as standards. Early diastolic peak wall motion velocity and relaxation time showed high sensitivities for clinically relevant rejection diagnosis (90.0% and 93.3%, respectively). The negative and positive predictive values for rejection of diastolic parameter changes appeared high enough (up to 96% and 92%, respectively) to allow a reliable noninvasive PW-TDI monitoring with efficiently timed, instead of routinely scheduled, EMBs. At definite cutoff values for systolic parameters, the probability for TxCAD reached 92% to 97%. The Fisher classification functions allowed TxCAD exclusion with 80% probability. CONCLUSIONS: Without diastolic parameter changes, acute rejection can be practically excluded, and serial PW-TDI can save patients from routine EMBs. The high specificity and negative predictive value for TxCAD of reduced systolic peak velocities and extended systolic time allow optimized timed catheterizations. Peak systolic velocity and systolic time allow diagnostic classifications that enable patients without known TxCAD but with high risk for catheterization to be spared routine angiographies.
Adult↗
Regulation of the intestinal mucin MUC2 gene expression in vivo: evidence for the role of promoter methylation.
In the present work we investigated the in vivo regulation of the mucin gene MUC2, which is overexpressed in all mucinous colorectal carcinomas. The inhibition of methylation by 5-azadeoxycytidine induces de novo expression of MUC2 in the colon carcinoma cell line COLO 205. The expression is retained in xenograft tissue and the cells give rise to MUC2-expressing tumours in nude mice. The strong expression of MUC2 in the normal human goblet cells and in the tissue of human mucinous colorectal carcinomas is associated with the average methylation of about 50% at every investigated CpG site of the MUC2 promoter. In contrast, MUC2 promoter in the non-expressing normal columnar cells and in the non-mucinous carcinoma tissue is methylated to nearly 100%. These data show that (i) low methylation of MUC2 promoter is associated with MUC2 expression in vivo and (ii) the pattern of MUC2 promoter methylation in the normal goblet or columnar cells most closely resembles that in mucinous or non-mucinous colorectal carcinomas, respectively. They indicate that MUC2 expression in vivo is regulated by promoter methylation and support the hypothesis that cells with goblet-like differentiation give rise to mucinous colonic carcinomas.
Animals↗
T-cell clonality of undetermined significance.
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Clone Cells↗
Generation of an immortalized human CD4+ T cell clone inhibiting tumor growth in mice.
Tumor antigen-specific T cell clones represent a useful tool in tumor immunology; however, their long-term culture is limited. To generate an immortalized cytotoxic T cell clone against the human tumor antigen mucin, we exposed a previously generated T cell culture to Herpesvirus saimiri. We obtained an immortalized human CD4+ T cell clone, termed SITAM. Clonality of these cells was shown by analysis of the alpha/beta-T cell receptor (TCR) repertoire. Cytolytic activity was demonstrated against several mucin-expressing tumor cell lines and could not be detected against non-mucin-expressing cells. SITAM cells maintained their features stably for 2 years. Furthermore, growth of the tumor cell line Capan-2 in NOD/SCID mice was inhibited when SITAM cells were coinjected subcutaneously with tumor cells. SITAM cells provide an unlimited source of clonal T cells for analysis of tumor recognition and may be of help in TCR-targeted immunotherapy.
Animals↗
Defective octamer-dependent transcription is responsible for silenced immunoglobulin transcription in Reed-Sternberg cells.
The absence of immunoglobulin (Ig) expression in B-cell-derived Hodgkin and Reed-Sternberg (HRS) cells of classical Hodgkin disease (cHD) was initially suggested to be caused by crippling mutations in the Ig promoter or coding region. More recent investigations have, however, challenged this concept. This study addressed the role of mutations in the Ig promoter region in HRS cells. Nine cases of cHD and 3 B-cell-derived HD lines were analyzed for mutations in the TATA box and octamer motif of the Ig promoter. Mutations in the octamer motif were found in only 1 of the 9 cases and in 1 of the 3 HD cell lines (L1236). Furthermore, in all cases either a complete lack or strong reduction in the expression of the Oct2 transcription factor and the BOB.1/OBF.1 coactivator were found. The relevance of the rare promoter mutations was investigated by assaying the activity of Ig promoter reporter constructs transfected into the HD cell line L1236, which harbors a mutated octamer motif. These Ig reporter constructs were completely inactive in L1236 cells; however, their activity could be reconstituted by the cotransfection of a BOB.1/OBF.1 expression vector. The additional transfection with an Oct2 expression vector did not further enhance the Ig promoter activity. The conclusions drawn from these results are that crippling mutations in the Ig promoter and coding region are not the sole cause for the lack of Ig expression in HRS cells and that defects in the transcription machinery such as absence of BOB.1/OBF.1 are more important for this phenomenon.
Carrier Proteins↗
Analysis of BCL-6 mutations in classic Hodgkin disease of the B- and T-cell type.
BCL-6 is essential for germinal center formation and thus for affinity maturation of immunoglobulin (Ig) genes by somatic mutations. The 5'-noncoding region of the BCL-6 gene is even a target for the mutation machinery. Translocations of the BCL-6 gene to heterologous promoters and mutations of its 5'-noncoding regulatory region were reported to be potential mechanisms for deregulating BCL-6 expression and for playing a role in the genesis of non-Hodgkin lymphoma. In line with this hypothesis is the observation that B-cell lymphoma with somatic mutations, such as diffuse large B-cell lymphoma and follicular lymphoma, also carry BCL-6 mutations, some of which are recurrently detectable. Classic Hodgkin disease (cHD) is also derived from B cells with high loads of somatic mutations and thus a further candidate for BCL-6 mutations. To determine the presence and potential role of BCL-6 mutations in cHD, the 5'-noncoding BCL-6 proportion of single Hodgkin and Reed-Sternberg (HRS) cells from 6 cases of cHD and 6 cases of HD-derived cell lines was analyzed. All B-cell-derived HD cases and cell lines harbored BCL-6 mutations. In contrast, both T-cell-derived HD cases and cell lines were devoid of BCL-6 mutations. With only one exception, there were no lymphoma-specific recurrent BCL-6 mutations detected, and BCL-6 protein was absent from the HRS cells of most cases. In conclusion, (1) somatic BCL-6 mutations are restricted to cHD cases of B-cell origin, and (2) the BCL-6 mutations represent mostly irrelevant somatic base substitutions without consequences for BCL-6 protein expression and the pathogenesis of cHD.
5' Untranslated Regions↗