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Biomedical subjects

M Reichel

Publications and source records attributed to M Reichel.

At least 19 recordsLinked to original sources
PubMed2001

Biased distribution of chromosomal breakpoints involving the MLL gene in infants versus children and adults with t(4;11) ALL.

Derivative chromosomes of 40 patients diagnosed with t(4;11) acute lymphoblastic leukemia (ALL) were analysed on the genomic DNA level. Chromosomal breakpoints were identified in most cases within the known breakpoint cluster regions of the involved MLL and AF4 genes. Due to our current knowledge of the primary DNA sequences of both breakpoint cluster regions, specific features were identified at the chromosomal fusion sites, including deletions, inversions and duplications of parental DNA sequences. After separation of all t(4;11) leukemia patients into two age classes (below and above 1 year of age), the analysis of chromosomal fusion sites revealed significant differences in the distribution of chromosomal breakpoints and led to the definition of two hotspot areas within the MLL breakpoint cluster region. This may point to the possibility of different age-linked mechanisms that were leading to t(4;11) chromosomal translocations.

Adult↗
PubMed2000

Prognostic factors in the operative treatment of ductal pancreatic carcinoma.

BACKGROUND AND AIMS: The average 5-year survival rate following resection of a ductal adenocarcinoma of the pancreas is 10%, worldwide. Despite increasing resection rates, only about 20% can be operated on with curative intent. A differential histopathological analysis of the resected tumors may help to justify expanding the surgical procedure by extended lymph-node dissection. PATIENTS/METHODS: Between January 1986 and December 1995, a total of 113 patients underwent resection with curative intent for a ductal pancreatic carcinoma with regional lymph-node dissection. All histological findings were reviewed and reclassified in accordance with the 1997 Union Internationale Contra la Cancrum (UICC) classification. Survival data for all of these patients were obtained from family doctors and registration offices. Independent prognostic factors were statistically analyzed. RESULTS: Of the 113 patients, 93 received an R0 resection. The postoperative mortality rate was 2.2% (2 of 93). More than one-half of the tumors had a diameter of between 2.1 cm and 4 cm. Among the 22 tumors measuring up to 2 cm in diameter, 41% already had lymph-node metastasis and 86% invasion of the lymphatic vessels. Carcinomas measuring between 4.1 cm and 6 cm were all associated with lymph-vessel invasion. Perineural invasion was present in 50% of the tumors. A noteworthy finding was the fact that 64% of the 25 tumors with negative lymph nodes had lymph-vessel invasion, and 48% perineural invasion. The cumulative 5-year survival rate of the R0-resected patients was 10. 5%. Patients with lymph-node-negative stages survived significantly longer (26.5%) than patients with lymph-node-positive stages (5%). Furthermore, a significant difference was seen between pN1a and pN1b (16.7% vs 2.2%). Multivariate analysis identified tumor grading, tumor size and lymph vessel invasion as independent prognostic factors. CONCLUSIONS: Apart from the factors tumor size and tumor grading, lymph-vessel invasion appears to be of special significance for the long-term prognosis. Already in the pN0 stage, the latter was present in 64% of the cases and must be considered a precursor of lymphogenic metastasization. Since lymph-vessel invasion was demonstrated in 86% of tumors measuring less than 2 cm, the therapeutic consequence for all ductal pancreatic tumors is an extended lymphatic and soft tissue dissection that goes beyond the regional lymph-node stations.

Aged↗
PubMed2000

Pathomorphological and histological prognostic factors in curatively resected ductal adenocarcinoma of the pancreas.

The fate of patients with potentially resectable carcinomas is not only determined by the pTNM tumor stage, but also possibly by tumor-biological factors. The aim of this study was to identify these prognostic factors in patients undergoing primary curative (R0) resection. The study retrospectively analyzed 113 patients with ductal adenocarcinoma who were operated on between 1986 and 1995. R0 resection was able to be performed in 93 patients. Lymph node metastases were found in 73%. The rates of lymph vessel and perineural invasion were 83.5% and 45%, respectively. Among the 25 carcinomas without lymph node metastases, 64% already had lymph vessel invasion and 48% had perineural invasion. The cumulative 5-year survival rate of the 91 surviving patients analyzed was 10.5%. Depending on the tumor stage we found a significant difference in 5-year survival rates between patients without lymph node metastases (26.5%) and those with lymph node involvement (5%) (P = 0.008). A multivariate analysis only identified lymph vessel invasion (L0/1), tumor size (< or = or < or =2 cm), and tumor grading (G) to have significant and independent prognostic value. Lymph vessel invasion, tumor size, and tumor grading proved to be independent factors determining long-term prognosis.

Adenocarcinoma↗
PubMed1999

A DNA damage repair mechanism is involved in the origin of chromosomal translocations t(4;11) in primary leukemic cells.

Some chromosomal translocations involved in the origin of leukemias and lymphomas are due to malfunctions of the recombinatorial machinery of immunoglobulin and T-cell receptor-genes. This mechanism has also been proposed for translocations t(4;11)(q21;q23), which are regularly associated with acute pro-B cell leukemias in early childhood. Here, reciprocal chromosomal breakpoints in primary biopsy material of fourteen t(4;11)-leukemia patients were analysed. In all cases, duplications, deletions and inversions of less than a few hundred nucleotides indicative of malfunctioning DNA repair mechanisms were observed. We concluded that these translocation events were initiated by several DNA strand breaks on both participating chromosomes and subsequent DNA repair by 'error-prone-repair' mechanisms, but not by the action of recombinases of the immune system.

Adolescent↗
PubMed1999

Rapid isolation of chromosomal breakpoints from patients with t(4;11) acute lymphoblastic leukemia: implications for basic and clinical research.

Chromosomal translocations t(4;11)(q21;q23) are associated with a group of acute lymphoblastic leukemias with very poor prognosis. From the complete sequences of the breakpoint cluster regions of the human MLL and AF-4 translocation partner genes, a novel set of 66 oligonucleotides that facilitates the rapid identification of translocation breakpoints by PCR analysis of genomic DNA was designed. For each breakpoint, a pair of optimally snited primers can be assigned, which improves the monitoring of the disease during treatment. Comparison of the breakpoints with the corresponding parental sequences also contributes to our better understanding of the illegitimate recombination events leading to these translocations.

Alu Elements↗
PubMed1999

Computer simulation of field distribution and excitation of denervated muscle fibers caused by surface electrodes.

In the course of this study, 2 submodels have been developed and combined, the 2-D finite element modeling of the electrical potential distribution in the human thigh and a Hodgkin and Huxley (HH) type model to calculate fiber excitation and action potential propagation. To determine the excitation of the target muscle fiber with the help of the activating function, the fiber's orientation within the muscle has to be known. The electric field along the fiber has to be calculated as a function of the applied electric current and the potential at the electrodes, respectively. The excitement of the muscle fibers varies across a wide range depending on the active and passive membrane parameters and the intracellular and extracellular mediums. Persisting denervation leads to a decay of muscle cells, and a partial substitution by fibroblasts occurs. The electrical activation of these tissues is more difficult, and biphasic stimulation pulses up to 200 ms in duration and 60-100 V in amplitude are needed to cause a contraction of the denervated muscle. An example shows the field distribution and the simulated activity in one representative muscle fiber of a well trained m. rectus femoris.

Action Potentials↗
PubMed1999

Hypergranulotic dyscornification: a distinctive histologic pattern of maturation of epidermal epithelium present in solitary keratoses.

Hypergranulotic dyscornification is an appellation proposed to designate a newly recognized distinctive pattern of epidermal maturation that is analogous to other epithelial reaction patterns such as epidermolytic hyperkeratosis, focal acantholytic dyskeratosis, cornoid lamellation, pale-cell acanthosis, and follicular mucinosis. The name "benign hypergranulotic keratosis with dyscornification" is proposed to specify solitary keratoses with digitated epidermal hyperplasia that exhibit this exceptional pattern of cornification. This abnormal type of cornification is characterized by hypergranulosis. A pale-staining basophilic substance is present intercellularly within the upper spinous layer and the hyperplastic granular layer. Overlying the thickened granular layer in foci at tips of epidermal papillations are orthokeratotic mounds of large, dull, eosinophilic staining corneocytes that are sharply demarcated from the thickened granular layer. Basophilic keratohyalin granules are focally retained within these corneocytes. There is overlying compact orthokeratosis that extends across the entire lesion. The compact orthokeratosis is slightly basophilic, and lies below a laminated and basket-weave orthokeratotic stratum corneum. There is a predominantly lymphocytic infiltrate at the base of these neoplasms with some spongiosis. There is parakeratosis focally present in the stratum corneum overlying these individual areas of abnormal cornification. The histopathologic and clinical findings in eight lesions that exhibit hypergranulotic dyscornification, a heretofore undescribed unique pattern of epidermal cornification, are presented.

Adult↗
PubMed1999

Outer root sheath acanthoma.

The term "outer root sheath acanthoma" is proposed to specify a distinctive keratosis exhibiting outer root sheath differentiation. This lesion features anastamosing columns of keratinocytes emanating from the undersurface of the epidermis that respectively demonstrate, with progressive descent into the upper dermis, outer root sheath differentiation characteristic of the infundibulum, isthmus, stem and anagen bulb. In our patient, the lesion was solitary, and no associated systemic disease was evident. Outer root sheath acanthoma is a unique keratosis displaying all four types of tricholemmal differentiation, thus representing a true neoplasm of the entire outer root sheath.

Aged↗
PubMed1998

Fine structure of translocation breakpoints in leukemic blasts with chromosomal translocation t(4;11): the DNA damage-repair model of translocation.

Chromosomal translocations t(4;11) are regularly associated with a specific type of acute leukemias and probably initiate the development of this disease. It has been proposed by others, that these translocations are mediated by recombinases of the immune system. The breakpoints on both derivative chromosomes for three t(4;11) leukemia-derived cell lines and primary blasts from two patients have been analysed here in detail. The results revealed that: (a) multiple double- or single-stranded DNA breaks must have occured near the translocation breakpoints on both participating chromosomes; and (b) DNA fragments flanked by these breaks must have either been deleted, inverted or duplicated during the translocation process. We found no evidence for the involvement of specific target sequences and recombinases of the immune system. Similar characteristic features were observed by re-interpretation of published t(6;11) and t(9;22) translocation data. Therefore we present a new model for the generation of these translocations which poses, that these translocations are reciprocal but not balanced at the fine structure level and that the DNA damage-repair machinery is likely involved in producing the final structure of the translocation breakpoint.

Base Sequence↗
PubMed1998

Continuous hyperfractionated accelerated radiotherapy with/without mitomycin C in head and neck cancer.

PURPOSE: To evaluate the effect of mitomycin C to an accelerated hyperfractionated radiation therapy. The aim was to test a very short schedule with/without mitomycin C (MMC) with conventional fractionation in histologically verified squamous cell carcinoma of the head and neck region. METHODS AND MATERIALS: From October 1990 to December 1996, 188 patients entered the trial. Tumors originated in the oral cavity in 54, oropharynx in 82, larynx in 20, and hypopharynx in 32 cases, respectively. Patients' stages were predominantly T3 and T4 (158/188, 84%) and most patients had lymph node metastases (144/188, 77%) at diagnosis. Only 22 patients were female, 166 were male, the median age of patients was 57 years (range 34 to 76 years). Patients were randomized to one of the following three treatment options: conventional fractionation (CF) consisting of 70 Gy in 35 fractions over 7 weeks (65 patients) or continuous hyperfractionated accelerated radiation therapy (V-CHART; 62 patients) or continuous hyperfractionated accelerated radiation therapy with 20 mg/sqm MMC on day 5 (V-CHART + MMC; 61 patients). By the accelerated regimens, the total dose of 55.3 Gy was delivered within 17 consecutive days, by 33 fractions. On day 1, a single dose of 2.5 Gy was given, from day 2 to 17 a dose of 1.65 Gy was delivered twice: the interfraction interval was 6 hours or more. RESULTS: Mucositis was very intense after accelerated therapy, most patients experiencing a grade III/IV reaction. The mucosal reaction did not differ whether MMC was administered or not. Patients treated by accelerated fractionation experienced a confluent mucosal reaction 12-14 days following start of therapy and recovered (no reaction) within 6 weeks. The skin reaction was not considered different in the three treatment groups. Those patients treated with additional chemotherapy experienced a grade III/IV hematologic toxicity in 12/61 patients. Initial complete response (CR) was recorded in 43% following CF, 58% after V-CHART, and 67% after V-CHART + MMC, respectively (p < 0.05). Actuarial survival (Kaplan-Meier) was significantly improved in the combined treated patients. Local tumor control was 28%, 32%, and 56% following CF, V-CHART, and V-CHART + MMC, respectively (p < 0.05). CONCLUSION: We conclude that our continuous hyperfractionated accelerated radiation therapy regimen is equal to conventional fractionation, suggesting that by shortening the overall treatment time from 7 weeks to 17 days a reduction in dose from 70 Gy to 55.3 Gy is possible, with maintenance of local tumor control rates. The administration of MMC to the accelerated regimen is tolerable and improves the outcome for patients significantly.

Adult↗
PubMed1998

Verrucous angiosarcoma of the skin: a distinct variant of cutaneous angiosarcoma.

AIMS: Cutaneous angiosarcoma is a malignant vascular neoplasm with well established clinical and histopathological features. Epidermal changes in cutaneous angiosarcoma other than atrophy and necrosis have not been described. In this study, we report three cases of a peculiar variant of angiosarcoma with striking verrucous changes of the overlying epidermis. METHODS AND RESULTS: On light microscopy, verrucous changes characterized by marked pseudocarcinomatous epithelial hyperplasia with hypergranulosis, compact orthokeratosis, and papillomatosis were present overlying an angiosarcoma in the dermis. Clinically the lesions presented as violaceous to brown scaly verrucous nodules or plaques. All lesions developed on an extremity. CONCLUSIONS: Verrucous epidermal changes seem to be a manifestation of pseudocarcinomatous hyperplasia, presumably caused by lymphoedema and the superficial setting of the tumour in the papillary dermis. It is important to be aware of this presentation of angiosarcoma because verrucous epidermal changes may be seen in a wide variety of skin diseases. Furthermore, a biopsy that includes the dermis is necessary to ensure that the angiosarcoma underlying the hyperplastic epidermis is correctly identified. The descriptive appellation verrucous angiosarcoma of the skin is proposed to designate a newly recognized variant of angiosarcoma.

Adult↗
PubMed1997

Identification of a STAT6 domain required for IL-4-induced activation of transcription.

Tyrosine phosphorylation of STAT6 in response to IL-4 results in the formation of STAT6 homodimers that bind specific DNA elements. Although binding sites for STAT6 have been shown to be important for the function of several IL-4-inducible promoters, the role of STAT6 in this activation has not been defined. To determine whether STAT6 is a transcriptional activator, different portions of the carboxyl terminus of STAT6 were fused to the yeast Gal4 protein DNA binding domain. Analysis of these chimeric Gal4-STAT6 proteins demonstrates that a 140-amino-acid proline-rich region of the carboxyl terminus of STAT6 contains a region that activates transcription. Truncation mutants of STAT6 that lack this domain cannot activate transcription and are capable of repressing transcription stimulated by a wild-type STAT6 protein. Strikingly, the ability of IL-4 to induce transcription from the Ig germline epsilon promoter is suppressed by overexpression of a carboxyl-terminal deletion mutant of STAT6. These studies demonstrate that the carboxyl terminus of STAT6 contains an activating domain required for the induction of genes by IL-4.

Amino Acid Sequence↗
PubMed1997

The IL-4 receptor alpha-chain cytoplasmic domain is sufficient for activation of JAK-1 and STAT6 and the induction of IL-4-specific gene expression.

The common gamma-chain (gamma(c)) is a functional component of the IL-4R, yet cells lacking gamma(c) are able to respond to IL-4. This has led to the suggestion that a surrogate gamma'-chain, which can interact with the IL-4R alpha chain to mediate signaling, is expressed on cells lacking gamma(c). An alternative possibility is that in the absence of gamma(c), the IL-4R alpha chain is able to transduce signals by homodimerization. To test this latter possibility, a chimeric receptor containing the extracellular domain of c-kit (the stem cell factor (SCF) receptor) and the cytoplasmic and transmembrane domains of the IL-4R alpha chain was generated. Treatment of cells expressing the chimeric receptor kit/IL-4R alpha with SCF induces activation of the IL-4R alpha-associated kinase JAK-1 and the transcription factor STAT6. However, tyrosine phosphorylation of JAK-3, which associates with gamma(c), is not induced by SCF in these cells. SCF-mediated ligation of kit/IL-4R alpha is sufficient to elicit IL-4-specific gene expression, including up-regulation of CD23 and synthesis of germ-line epsilon transcripts. In the T cell line CTLL2, ligation of kit/IL-4R alpha induces cellular proliferation. Finally, in JAK-1-deficient HeLa cells, STAT6 activation by IL-4 is completely abolished. Together, these data demonstrate that the IL-4R alpha cytoplasmic domain is sufficient to activate JAK-1 and STAT6 and to induce expression of IL-4 target genes, thus identifying a mechanism by which IL-4 signaling can proceed in the absence of JAK-3 and gamma(c).

Antigens, CD↗
PubMed1997

Patterns of chromosomal imbalances in adenocarcinoma and squamous cell carcinoma of the lung.

Comparative genomic hybridization was used to screen 25 adenocarcinomas and 25 squamous cell carcinomas of the lung for chromosomal imbalances. DNA copy number decreases common to both entities were observed on chromosomes 1p, 3p, 4q, 5q, 6q, 8p, 9p, 13q, 18q, and 21q. Similarly, DNA gains were observed for chromosomes 5p, 8q, 11q13, 16p, 17q, and 19q. Adenocarcinomas showed more frequently DNA overrepresentations of chromosome 1q and DNA losses on chromosomes 3q, 9q, 10p, and 19, whereas squamous cell carcinomas were characterized by increased overrepresentations of chromosome 3q and 12p as well as deletions of 2q. For the first time, we used a histogram representation and statistical analysis to evaluate the differences between both tumor groups. In particular, the overrepresentation of the chromosomal band 1q23 and the deletion at 9q22 were significantly associated with adenoid differentiation, whereas the DNA loss of chromosomal band 2q36-37 and the overrepresentations at 3q21-22 and 3q24-qter were statistically significant markers for the squamous cell type. The study strengthens the notion that different tumor subgroups of the respiratory tract are characterized by distinct patterns of chromosomal alterations.

Adenocarcinoma↗
PubMed1997

Primary small-cell lung carcinomas and their metastases are characterized by a recurrent pattern of genetic alterations.

Small-cell lung cancer (SCLC) represents a group of highly malignant tumors giving rise to early and widespread metastases. We used comparative genomic hybridization in autoptic tumor specimens from 10 patients to discover genetic alterations that are associated with tumor progression and potentially with the metastatic phenotype. Ten primary SCLC and 16 corresponding metastases were investigated with a maximum of 4 tumors per case. Prevalent changes observed in more than 60% of the primary tumors and their metastases included deletions on chromosomes 3p, 4q, 5q, 10q, 13q and 17p, and DNA over-representations on chromosomes 3q and 5p. The number of common alterations in the primary tumors and the related metastases outnumbered the differences, indicating a clonal relationship. Within the lesions of the same patient, differences were found between the primary tumor and the metastases as well as between metastases of distinct organ sites. However, no specific alteration was significantly associated with the metastatic phenotype. We suggest that the high malignancy of SCLC is defined by the above-mentioned pattern of aberrations.

Aged↗
PubMed1997

Exon/intron structure of the human AF-4 gene, a member of the AF-4/LAF-4/FMR-2 gene family coding for a nuclear protein with structural alterations in acute leukaemia.

The AF-4 gene on human chromosome 4q21 is involved in reciprocal translocations to the ALL-1 gene on chromosome 11q23, which are associated with acute lymphoblastic leukaemias. A set of recombinant phage carrying genomic fragments for the coding region and flanking sequences of the AF-4 gene were isolated. Phage inserts were assembled into four contigs with 21 exons, and an intron phase map was produced enabling the interpretation of translocation-generated fusion proteins. The gene contains two alternative first exons, 1a and 1b, both including a translation initiation codon. The translocation breakpoint cluster region is flanked by exons 3 and 6 and two different polyadenylation signals were identified. Polyclonal antisera directed against three different portions of the AF-4 protein were produced and used to detect a 116 kD protein in cellular extracts of human B-lymphoblastoid and proB cell lines. In mitogen-stimulated human peripheral blood mononuclear cells the AF-4 antigen was predominantly located in the nucleus. The AF-4 gene is a member of the AF-4, LAF-4 and FMR-2 gene family. The members of this family encode serine-proline-rich proteins with properties of nuclear transcription factors. Comparison of AF-4 protein coding sequences with the LAF-4 and FMR-2 sequences revealed five highly conserved domains of potential functional relevance.

Amino Acid Sequence↗
PubMed1997

Granular cell basal cell carcinoma.

Granular cell basal cell carcinoma is an unusual histopathologic subtype of basal cell carcinoma in which some or all of the neoplastic cells show cytologic features of granular cells. These distinctive cells contain abundant eosinophilic cytoplasm housing numerous fine and coarse refractile granules. This report documents the first case of granular cell basal cell carcinoma in which the collections of neoplastic granular cells arise in direct contiguity with an otherwise ordinary nodular basal cell carcinoma. Granular cell basal cell carcinoma is a unique histopathologic variant of basal cell carcinoma that is rare, this report representing the sixth case in the world literature.

Adenocarcinoma↗