Biomedical subjects

S Braun

Publications and source records attributed to S Braun.

At least 55 records · Page 3Linked to original sources

PubMed2001

Recent advances in technologies for the detection of occult metastatic cells in bone marrow of breast cancer patients.

Approximately half of breast cancer patients with stage I-III disease will suffer metastatic disease despite resection with tumour-free margins. In 30-40% of these patients, individual carcinoma cells can already be detected at the time of primary therapy in cytological bone marrow preparations using immunocytochemistry. Numerous prospective clinical studies have shown that the presence of occult metastatic cells in bone marrow is prognostically relevant to patient survival. Only a few studies failed to do so, thus stimulating a critical discussion on the methodology and clinical value of bone marrow analysis. The potential for obtaining improved prognostic information on patient outcome, for monitoring tumour cell eradication during adjuvant and palliative systemic therapy, and for specifically targeting tumour biological therapies are intriguing clinical opportunities that may be afforded by bone marrow analysis. Standardized and robust methodology is a prerequisite for clinical application of these techniques, however.

Bone Marrow Cells↗

PubMed2001

Comparative analysis of micrometastasis to the bone marrow and lymph nodes of node-negative breast cancer patients receiving no adjuvant therapy.

PURPOSE: In node-negative patients, of whom up to 30% will recur within 5 years after diagnosis, markers are still needed that identify patients at high enough risk to warrant further adjuvant treatment. In the present study we analyzed whether a correlation exists between microscopic tumor cell spread to bone marrow and to lymph nodes and attempted to determine which route is clinically more important. PATIENTS AND METHODS: According to a prospective design, bone marrow aspirates and axillary lymph nodes of level I (n = 1,590) from 150 node-negative patients with stage I or II breast cancer were analyzed immunocytochemically with monoclonal anticytokeratin (CK) antibodies. We investigated associations with prognostic factors and the effect of micrometastasis on patients' prognosis. RESULTS: CK-positive cells in bone marrow aspirates were present in 44 (29%) of 150 breast cancer patients, whereas only 13 patients (9%) had such positive findings in lymph nodes; simultaneous microdissemination to bone marrow and lymph nodes was seen in merely two patients. No correlation of bone marrow micrometastases with other risk factors was assessed. Reduced 4-year distant disease-free and overall survival were each associated with a positive bone marrow finding (P =.032 and P =.014, respectively) but not with lymph node micrometastasis. Multivariate analysis revealed an independent prognostic effect of bone marrow micrometastasis on survival, with a hazards ratio of 6.1 (95% confidence interval, 1.2 to 31.3) for cancer-related death (P =.031) in our series. CONCLUSION: Immunocytochemical detection of micrometastatic cells in bone marrow but not in lymph nodes is an independent prognostic risk factor in node-negative breast cancer that may have implications for surgery and stratification into adjuvant therapy trials.

Bone Marrow Neoplasms↗

PubMed2001

ErbB2 overexpression on occult metastatic cells in bone marrow predicts poor clinical outcome of stage I-III breast cancer patients.

Occult hematogenous micrometastases are the major cause for metastatic relapse and cancer-related death in patients with operable primary breast cancer. Although sensitive immunocytochemical and molecular methods allow detection of individual breast cancer cells in bone marrow (BM), a major site of metastatic relapse, current detection techniques cannot discriminate between nonviable shed tumor cells and seminal metastatic cells. To address this problem, we analyzed the relevance of erbB2 overexpression on disseminated cytokeratin-18-positive breast cancer cells in the BM of 52 patients with locoregionally restricted primary breast cancer using immunocytochemical double labeling with monoclonal antibody 9G6 to the p185erbB2 oncoprotein. Expression of p185erbB2 on BM micrometastases was detected in 31 of 52 (60%) patients independent of established risk factors such as lymph node involvement, primary tumor size, differentiation grade, or expression of p185erbB2 on primary tumor cells. After a median follow-up of 64 months, patients with p185erbB2-positive BM micrometastases had developed fatal metastatic relapses more frequently than patients with p185erbB2-negative micrometastases (21 versus 7 events; P = 0.032). In multivariate analysis, the presence of p185erbB2-positive micrometastases was an independent prognostic factor with a hazard ratio of 2.78 (95% confidence interval, 1.11-6.96) for overall survival (P = 0.029). We therefore conclude that erbB2 overexpression characterizes a clinically relevant subset of breast cancer micrometastases.

Bone Marrow Neoplasms↗

PubMed2001

[Schonlein-Henoch purpura associated with hepatitis B in a patient with HIV infection].

HISTORY AND CLINICAL FINDINGS: A 23-year-old man with HIV-infection and recently diagnosed hepatitis B infection developed painful swelling and palpable purpura in the limbs. In addition, relapsing diarrhoea, arthralgia and pain at the level of the right kidney were noted. The liver, the palpable lymph nodes and the tonsils were enlarged. INVESTIGATIONS: The following laboratory parameters were abnormal: sedimentation rate 64/70 mmHg, CD4+ cells 462/ml, CD4/CD8 ratio 0.3, serum CRP 16 mg/l, antistreptolysin titre 542 kU/l, complement C3 < 0.1 g/l, GPT 37 U/l, albumin 49.5% and gamma-globulin 28.5%, in urine, leukocytes 25/microliter and protein 0.25 g/l. Hepatitis serology: anti-HBc, HBs-Ag and HBe-Ag positive, anti-HBs and anti-HBe negative, hepatitis A-Ab (IgG) positive, hepatitis A-Ab (IgM) negative, hepatitis C-Ab negative. Pharyngial swab: beta-haemolytic streptococci of group A. Stool examination: amoeba cysts, corona virus and fungi 10(4)-10(5)/ml (control specimen negative). Abdominal sonography showed minor hepatomegaly, splenomegaly and two 0.8 cm-large lymph nodes near the liver entrance. The histology of a skin lesion revealed a florid leukocytoclastic vasculitis at the upper and middle dermal vessels. The immunohistological examination detected IgA, IgM and C3 deposits. TREATMENT AND COURSE: The multiple bacterial infections had initially been considered as triggering the Schönlein-Henoch purpura. However despite successful treatment of these infections severe relapses of both the skin lesions and the systemic manifestations occurred. A drug reaction, autoimmune diseases and tumours were excluded. Only after treatment of hepatitis B infection with recombinant interferon alpha together with administration of zidovudine (treatment of choice at that time) the lesions quickly disappeared without further relapses. During the 5-year-follow-up, recurrent bacterial infections did not induce relapses of the disease, whereas the hepatitis B infection was seroconverted. CONCLUSION: It is likely that the hepatitis B may have been the trigger for the Schönlein-Hennoch-purpura.

Adult↗

PubMed2001

Occult tumor cells in bone marrow of patients with locoregionally restricted ovarian cancer predict early distant metastatic relapse.

PURPOSE: Based on conventional tumor staging, primary ovarian cancer is viewed as an intraperitoneal disease that rarely spreads to extraperitoneal organs. However, autopsy studies reveal a much higher rate of occult metastasis, indicating that extraperitoneal spread occurs with much greater frequency than previously appreciated. Consequently, we investigated the incidence of early hematogenous dissemination and its association with distant disease-free and overall survival. PATIENTS AND METHODS: Bone marrow aspirates from 108 patients newly diagnosed with International Federation of Gynecology and Obstetrics stage I to III ovarian cancer were prospectively analyzed with the novel anti-cytokeratin (CK) antibody A45-B/B3. We investigated the frequency of CK-positive tumor cells in bone marrow and their effect on prognosis in relation to established risk factors for tumor progression. RESULTS: Tumor cells in bone marrow were detected in 32 (30%) of 108 patients. A CK-positive finding was unrelated to established risk parameters, except for poor nuclear grading of the primary tumor. At a median follow-up of 45 months (range, 12 to 77 months), the presence of occult metastatic cells in bone marrow was associated with the occurrence of clinically overt, extraperitoneal (predominantly extraskeletal) distant metastasis (relative risk [RR], 16.5; 95% confidence interval [CI], 6.2 to 56.9; P < .0001) and death from cancer-related causes (RR, 2.3; 95% CI, 1.2 to 4.3; P = .01). Multivariate analysis identified a positive bone marrow finding as an independent prognostic factor of reduced distant disease-free survival for all patients (RR, 13.8; 95% CI, 5.4 to 52.9; P < .0001) and for the 64 stage R0-1 patients (RR, 7.3; 95% CI, 1.5 to 56.8; P = .0021). CONCLUSION: Our data signal that hematogenous dissemination of tumor cells occurs early and throughout all stages of ovarian cancer. The clinical significance of our findings is supported by the unfavorable prognosis in association with the presence of occult metastatic cells, especially in those patients who received an effective locoregional therapy.

Adult↗

PubMed2001

Characterization of disseminated tumor cells.

The most prominent secondary organs screened for the presence of occult disseminated tumor cells are regional lymph nodes and bone marrow. The current data suggest that micrometastatic cells represent a selected population of dormant cancer cells, which still express a considerable degree of heterogeneity. The analysis of micrometastatic cells will open a new avenue to assess the molecular determinants of both early tumor cell dissemination and subsequent outgrowth into overt metastases. Moreover, identifying therapeutic target structures (e.g., HER2), monitoring the elimination of bone marrow micrometastases, and assessing treatment-resistant tumor cell clones may help in understanding the current limitations of adjuvant systemic therapy. This review summarizes the current knowledge on the biological characteristics of micrometastatic cancer cells in bone marrow and lymph nodes of cancer patients.

Bone Marrow Neoplasms↗

PubMed2001

Implications of occult metastatic cells for systemic cancer treatment in patients with breast or gastrointestinal cancer.

The early and clinically occult spread of viable tumour cells to the organism is becoming acknowledged as a hallmark in cancer progression, since abundant clinical and experimental data suggest that these cells are precursors of subsequent distant relapse. Using monoclonal antibodies against epithelial cytokeratins or tumour-associated cell membrane glycoproteins, individual carcinoma cells can be detected in cytological bone marrow preparations at frequencies of 10(-5) to 10(-6). Prospective clinical studies have shown that the presence of such immunostained cells in bone marrow is prognostically relevant with regard to relapse-free and overall survival, even in malignancies that do not preferentially metastasise to bone. As current treatment strategies have resulted in a substantial improvement of cancer mortality rates, it is noteworthy to consider the intriguing options of immunocytochemical screening of bone marrow aspirates for occult metastatic cells. Besides improved tumour staging, such screening offers opportunities for guiding patient stratification for adjuvant therapy trials, monitoring response to adjuvant therapies (which, at present, can only be assessed retrospectively after an extended period of clinical follow-up), and specifically targeting tumour-biological therapies against disseminated tumour cells. The present review summarises the current data on the clinical significance of occult metastatic cancer cells in bone marrow.

Bone Marrow Neoplasms↗

PubMed2001

Glycoprotein Ia C807T polymorphism and risk of restenosis following coronary stenting.

Platelets are thought to contribute to development of restenosis following percutaneous coronary interventions. The glycoprotein Ia/IIa complex is a major platelet collagen receptor, its surface expression being influenced by two, linked single nucleotide polymorphisms (C807T and G873A) in the glycoprotein Ia gene. T807 is associated with increased expression of this integrin receptor. We assessed whether T807 is associated with an increased risk of restenosis in 1769 consecutive patients treated with coronary stenting. 6-month follow-up angiograms were available in 82.4% of the patients. C807T genotype distribution was CC in 35.8%, CT in 47.6% and TT in 16.6% of the patients. Restenosis (diameter stenosis > or =50% at follow-up angiography) occurred in 32.9% of CC, 31.5% of CT and 32.1% of TT patients (P=0.87). The rate of major adverse cardiac events (death, myocardial infarction or need of reintervention) within 1 yr was 21.6% for CC, 21.7% for CT and 21.2% for TT patients (P=0.98). Thus, carriage of the GP Ia T807 allele is not associated with an increased risk of restenosis or unfavorable late outcome following coronary artery stenting.

Aged↗

PubMed2001

On the possible role of muscle in the pathogenesis of spinal muscular atrophy.

Spinal muscular atrophy (SMA) is a common human inherited disease characterized by degeneration of motoneurons and muscular atrophy. SMA results from deletions or mutations of the SMN (survival motor neuron) gene. A nerve-muscle coculture model, consisting of human muscle cells innervated by rat embryonic spinal cord explants, was used to study the pathogenesis of SMA. Previous studies have shown that myotubes formed by fusion of satellite muscle cells from patients with SMA I or SMA II (but not SMA III) underwent a characteristic degeneration 1-3 weeks after innervation. To correlate this cellular study with a molecular approach, we used reverse transcriptase-polymerase chain reaction (RT-PCR), and showed that SMN mRNAs were expressed throughout the fusion of normal satellite muscle cells with two peaks, the first appearing prior to the onset of fusion and the second one or two days before innervation. When satellite muscle cells from patients with SMA I or II were used, only the first peak was observed. Because in these cases the SMN telomeric gene (SMNtel) is deleted, it was concluded that the contribution of SMNtel-dependent mRNAs to the second peak is predominant in normal myogenesis and involved in maturation of myotubes. In addition, diseased satellite muscle cells did not fuse at the same rate as normal satellite muscle cells. Studies on myf-5, a muscle specific transcription factor family, showed that its expression was impaired during the fusion of satellite muscle cells from patients with SMA I or II compared with normal satellite muscle cells. Taken together, these observations suggest that (a) there is a muscle specific expression pattern of SMN, and (b) SMN probably plays a crucial role in maintenance of a functional motor unit, by allowing muscle cells to correctly differentiate and to allow motoneuron survival.

Animals↗

PubMed2001

Hepatic autoantigens in patients with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy.

BACKGROUND & AIMS: Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is caused by mutations of both copies of the autoimmune regulator (AIRE) gene. It is characterized by susceptibility to mucocutaneous candidiasis and multiple autoimmune lesions. A serious disease component is hepatitis. To identify diagnostic autoantibodies for APECED hepatitis, sera from 64 patients with APECED were screened for autoantibodies established in the diagnosis of idiopathic autoimmune hepatitis, and for autoantibodies against 10 cytochrome P450s. METHODS: Screening methods were indirect immunofluorescence, Western blot, Ouchterlony gel diffusion, enzyme-linked immunosorbent assay, and immunoprecipitation. RESULTS: Anti-liver microsomal antibodies were detected in 50% of the patients with APECED hepatitis and 11% of those without hepatitis. Prevalences of antinuclear, smooth muscle, anti-liver cytosol, anti-soluble liver protein/liver pancreas, and anti-CYP2D6 autoantibodies were 9%, 6%, 3%, 0%, and 0%, respectively. CYP1A1, CYP2B6, CYP1A2, and CYP2A6 were identified as autoantigens. Thirty percent of patients with anti-CYP2A6 and 100% of patients with anti-CYP1A2 were affected by hepatitis. Despite the high specificity of anti-CYP1A2 for APECED hepatitis, its sensitivity was low (50%). Anti-CYP2A6 and anti-CYP1A2 were not detected in patients with autoimmune hepatitis (N = 68) or nonhepatitic controls (N = 81). CONCLUSIONS: Anti-CYP1A2 is a highly specific but insensitive marker for APECED hepatitis. No clinical correlation was observed for anti-CYP2A6. Autoimmune hepatitis and APECED hepatitis are characterized by different molecular targets of autoantibodies with no overlap.

Adolescent↗

PubMed2001

Taking the guesswork out of mandibular symphyseal distraction osteogenesis.

Mandibular symphyseal distraction osteogenesis has recently been introduced as a means of resolving arch length deficiencies in the anterior segment and as a method of reducing large vestibular spaces related to a narrow mandible. Accurately relating the required distraction for a given anterior tooth mass and desired future anteroposterior location of the central incisors has not been possible until recently. The relationship between these 3 controlling factors has been mathematically described by the hyperbolic cosine function and a computer program designed for easy use by the clinician. Two clinical cases illustrate the application of the program. A Web site where the program can be downloaded at no cost is mentioned.

Algorithms↗

PubMed2001

Doppler microembolic signals in patients with two different types of bileaflet valves.

OBJECTIVES: This study was performed to evaluate the prevalence and counts of Doppler microembolic signals in patients with St Jude Medical valves (St Jude Medical, Inc, St Paul, Minn) and patients with ATS valves (ATS Medical, Inc, Minneapolis, Minn) and their relation to clinical parameters. METHODS: A total of 179 outpatients of the department of cardiothoracic surgery were examined. They included 98 men and 81 women, aged 61 +/- 11 years, with ATS (n = 91) or St Jude Medical (n = 88) valves in the aortic (n = 110), mitral (n = 39), or both positions (n = 30). Neurologic examination was followed by transcranial Doppler monitoring for microembolic signals. Monitoring was performed bilaterally over the middle cerebral arteries for 1 hour per session. RESULTS: Microembolic signal counts and prevalence were significantly higher in patients with St Jude Medical as compared with ATS valves. Valve type and presence of diabetes mellitus were the only predictors of microembolic signal prevalence on multivariate analysis. No influence of microembolic signals on cerebral embolic complications was established. Additionally, patients with a postoperative history of cerebral embolic complications did not have a higher number of microembolic signals than remaining patients. Interobserver variability was satisfactory. CONCLUSIONS: Patients with St Jude Medical valves were shown to have significantly higher microembolic signal counts than patients with ATS valves. However, our results suggest that microembolic signal counts cannot be used to predict cerebral embolic complications. Their relation to neuropsychologic deficits remains to be evaluated.

Aged↗

PubMed2001

Low preoperative antithrombin activity causes reduced response to heparin in adult but not in infant cardiac-surgical patients.

UNLABELLED: We evaluated the interaction of preoperative antithrombin (AT) activity and intraoperative response to heparin in cardiac surgery. Heparin anticoagulation is essential during cardiopulmonary bypass (CPB). Heparin itself has no anticoagulant properties, however it causes a conformational change of the physiologic plasma inhibitor AT that converts this slow-acting serine protease inhibitor into a fast acting one. Thus, adequate AT activity is a prerequisite for sufficient heparin anticoagulation. AT activity is reduced by long-term heparin therapy. This prospective, observational study investigated 1516 consecutive cardiac-surgical patients (1304 patients >1 yr (Group A) and 212 patients < or = 1 yr (Group I)). AT activity was measured the day before surgery by a chromogenic substrate assay. The celite-activated activated clotting time (ACT) was used to guide intraoperative heparin administration. Heparin sensitivity was calculated and the postoperative blood loss and perioperative blood requirement was recorded. Infant patients had significantly less preoperative AT activity compared with older patients: 84 (33)% vs 97 (17)%, median (interquartile range) (P < 0. 05). The subgroup of patients aged <1 mo (n = 64) demonstrated a preoperative AT activity of 56 (27)% as compared with 90 (23)% in infant patients between one month and one year (n = 148). In adult patients, preoperative AT activity depended predominantly on preoperative heparin treatment: 62% of the patients with an AT activity <80% were pretreated with heparin. Five minutes after heparin but before CPB the ACT was 587 (334) s in Group A patients with AT activity > or = 80%, and 516 (232) in patients with AT activity < or = 80% (P < 0.05). The target ACT of 480 s was achieved in 70% of patients with normal AT activity in Group A compared with only 54% of patients with AT activity <80% (P < 0.05). In Group A patients with decreased AT activity, 18% demonstrated an inadequate ACT response-defined as ACT <400 s-to the first bolus injection of heparin. In Group I, preoperative AT activity did not influence the ACT response (ACT 5 min after heparin: 846 [447] s in patients with AT activity > or = 80% vs 1000 [364] s in patients with decreased AT activity). The heparin sensitivity was 2.4 (1.1) s/unit heparin/kg compared with 1.5 (0.8) s/unit heparin/KG in group A (P < 0.05). These results suggest that preoperative diminished AT activity causes reduced response to heparin in adult but not in infant patients. Infant patients demonstrate a higher heparin sensitivity despite lower preoperative AT activity. Measurement of preoperative AT activity identifies adult patients at risk of reduced sensitivity to heparin. IMPLICATIONS: In patients less than one year of age, low antithrombin (AT) activity is caused by the immature coagulation system. Despite low AT activity, these young patients demonstrate a normal or increased response to heparin anticoagulation before cardiopulmonary bypass (CPB). In contrast, in patients older than one year of age and adult patients decreased preoperative AT activity is mainly caused by preoperative heparin therapy and causes insufficient response to heparin anticoagulation with a standard heparin dosage. Measurement of preoperative AT activity identifies patients at risk of inadequate anticoagulation during CPB.

Adolescent↗

PubMed2001

GRK3 mediates desensitization of CRF1 receptors: a potential mechanism regulating stress adaptation.

Potential G protein-coupled receptor kinase (GRK) and protein kinase A (PKA) mediation of homologous desensitization of corticotropin-releasing factor type 1 (CRF1) receptors was investigated in human retinoblastoma Y-79 cells. Inhibition of PKA activity by PKI(5-22) or H-89 failed to attenuate homologous desensitization of CRF1 receptors, and direct activation of PKA by forskolin or dibutyryl cAMP failed to desensitize CRF-induced cAMP accumulation. However, treatment of permeabilized Y-79 cells with heparin, a nonselective GRK inhibitor, reduced homologous desensitization of CRF1 receptors by approximately 35%. Furthermore, Y-79 cell uptake of a GRK3 antisense oligonucleotide (ODN), but not of a random or mismatched ODN, reduced GRK3 mRNA expression by approximately 50% without altering GRK2 mRNA expression and inhibited homologous desensitization of CRF1 receptors by approximately 55%. Finally, Y-79 cells transfected with a GRK3 antisense cDNA construct exhibited an approximately 50% reduction in GRK3 protein expression and an ~65% reduction in homologous desensitization of CRF1 receptors. We conclude that GRK3 contributes importantly to the homologous desensitization of CRF1 receptors in Y-79 cells, a brain-derived cell line.

Colforsin↗

PubMed2001

Development of the parafollicular cells in recurrent goiter.

OBJECTIVE: To provide more data for the discussion on whether thyroid hormones, iodide and other factors controlling the thyroid also influence the parafollicular (PF) cells, as the answer is of great importance for optimization of the medical treatment of medullary thyroid carcinoma (MTC) after surgery. DESIGN: We compared the density of the PF cells in patients who underwent surgery for the second time due to recurrent goiter with that in normal-sized thyroid glands after the first operation. METHODS: In 20 patients with only one operation, all specimens were taken from morphologically and functionally normal lobular thyroid parenchyma. The second group consisted of 30 patients who had already undergone a nearly total resection of at least one thyroid lobe several years before. Then another surgery of the same side was performed due to recurrent goiter. Immunohistochemical staining of the PF cells was performed using primary antibodies to calcitonin and chromogranin. RESULTS: An average of 78 PF cells (median 12.5) was found in the sections with the highest density of the first group. The average number of PF cells in the second group was just 5 (median 0). The Wilcoxon test revealed a highly significant difference in the total PF cell content between the groups (P < 0.001). CONCLUSIONS: Our study suggests that the stimulating factors that lead to growth of the thyroid parenchyma do not influence the PF cells. Hence a non-suppressive thyroid hormone replacement seems to be sufficient after resection of an MTC.

Adult↗

PubMed2001

Molecular cloning of a functional promoter of the human plakoglobin gene.

OBJECTIVE: Plakoglobin (Pg) is the only cytoplasmic protein component common to both junctional complexes mediating cell-cell adhesion, adherens junctions and desmosomes. In these complexes Pg appears to act as a linker protein anchoring transmembrane proteins of the cadherin superfamily to the actin cytoskeleton and intermediate filament system respectively. Intercellular adhesion is frequently disturbed in skin diseases and in carcinomas, enabling tumour progression and metastasis. Whereas Pg expression is lost in some thyroid tumours and carcinoma cell lines, little information on Pg gene regulation is currently available owing to a lack of promoter studies. DESIGN AND METHODS: We have cloned and sequenced genomic DNA from a human library that resulted in 979 bp upstream of the published Pg cDNA. The transcriptional start was mapped by rapid amplification of cDNA ends. Methylation-specific PCR of bisulfite-modified cell line DNA was applied to probe the methylation status of a promoter-associated CpG island. Reporter-gene constructs of various promoter fragments were transiently transfected in thyroid carcinoma cell lines and their activities were determined by luciferase measurements. RESULTS AND CONCLUSIONS: A 1 kb DNA fragment harbouring a functional promoter of the human Pg gene was cloned and characterized. The sequence lacks a canonical TATA box, but contains putative CCAAT boxes as well as various putative binding sites for transcription factors, among them SP1 and AP2, proximal to the transcriptional start. Considerable promoter activity was found in thyroid cell lines and deletion analysis indicated that a 300 bp region proximal to the 5'-untranslated region of the mRNA represents the minimal promoter of the human Pg gene. As cells lacking endogenous Pg expression were found to contain methylated CpG dinucleotides in a CpG island located around the transcriptional start site, it is suggested that epigenetic mechanisms such as DNA methylation contribute to dysregulated Pg expression.

5' Flanking Region↗

PubMed2001

Clinical significance of occult metastatic cells in bone marrow of breast cancer patients.

The early and clinically occult spread of viable tumor cells to the organism is increasingly considered a hallmark in cancer progression, as emerging data suggest that these cells are precursors of subsequent distant relapse. Using monoclonal antibodies to epithelial cytokeratins or tumor-associated cell membrane glycoproteins, individual carcinoma cells can be detected on cytologic bone marrow preparations at frequencies of 10(-5) to 10(-6). Prospective clinical studies have shown that the presence of these immunostained cells in bone marrow, as a frequent site of overt metastases, is prognostically relevant with regard to relapse-free and overall survival. This screening approach may be, therefore, used to improve tumor staging and guide the stratification of patients for adjuvant therapy in clinical trials. Another promising application is monitoring the response of micrometastatic cells to adjuvant therapies, which, at present, can only be assessed retrospectively after an extended period of clinical follow-up. The present review summarizes the current data on the clinical significance of occult metastatic breast cancer cells in bone marrow.

Antibodies, Monoclonal↗

PubMed2001

Molecular determinants of occult metastatic tumor cells in bone marrow.

The success of mammographic screening for breast cancer is that it involves increasingly more patients with small primary tumors formerly thought to have an overall excellent prognosis. Yet, only approximately two thirds of these patients actually have this favorable prognosis, while the remaining third develops metastatic disease. Thus, there is emerging evidence that epithelial tumor cells can disseminate into secondary organs at an earlier stage of primary tumor development than appreciated by current risk classifications. Bone marrow is one of the most prominent secondary organs screened for the presence of disseminated tumor cells. The current data suggest that bone marrow micrometastases represent a selected population of dormant and heterogeneous cancer cells. The analysis of micrometastatic cells opens a new avenue by which to assess the molecular determinants of both early tumor cell dissemination and subsequent outgrowth into overt metastases. Moreover, identifying therapeutic target structures (e.g., HER2/neu), monitoring the elimination of bone marrow micrometastases, and assessing treatment-resistant tumor cell clones might help to understand the current limitations of adjuvant systemic therapy. This review summarizes the current knowledge of the biological characteristics of micrometastatic cancer cells in bone marrow of breast cancer patients.

Antigens, Neoplasm↗