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J Thiele

Publications and source records attributed to J Thiele.

At least 37 records · Page 2Linked to original sources
PubMed2004

[Regression of the Philadelphia chromosome (bcr/abl)-positive myelo- and megakaryopoiesis after Imatinib (STI571) therapy in chronic myelogenous leukemia (CML)].

In chronic myeloid leukemia following therapy with Imatinib (STI571) hematologic and cytogenetic response is associated with conspicuous changes of bone marrow morphology. However, it is not known to which extent these alterations are accompanied by a loss of the bcr/abl translocation. To study regression of the leukemic cell population we recruited 14 patients lacking pretreatment. Therapy resulted in a reduction of CD61(+) megakaryopoiesis. Dwarf megakaryocytes characteristic for this disorder were replaced by large, normally appearing cells of this lineage. Morphometric analysis confirmed the significant decrease in the number of micromegakaryocytes and yielded planimetric parameters in keeping with normalization. Moreover, a fluorescence in-situ hybridization study in five patients of this cohort revealed that before therapy 70% of all myeloid cells exhibited the bcr/abl gene. Regarding megakaryopoiesis about 65% of the micromegakaryocytes displayed positive signals. Following treatment these bcr/abl(+) cell populations decreased significantly while the emerging large megakaryocytes lacked a proper labeling. Because cytogenetic response and reduction of atypical micromegakaryocytes are linked, this feature may be useful to monitor therapeutic efficacy.

Biopsy↗
PubMed2004

Prefibrotic chronic idiopathic myelofibrosis--a diagnostic enigma?

To analyze precursor lesions of chronic idiopathic myelofibrosis (CIMF) 21 patients were recruited who developed manifest myelofibrosis after about 70 months, preceded by a prefibrotic stage but without interference by cytoreductive therapy. Prodromal bone marrow lesions included a prominent granulocytic and megakaryocytic proliferation with megakaryocytes showing conspicuous abnormalities associated with a borderline to slight anemia, thrombocytosis, and minimal splenomegaly. Comparison of this cohort with 211 additional patients at this precursor stage revealed no differences concerning clinical findings and bone marrow histopathology. Relative incidence of prefibrotic CIMF was 24% and median survival 143 months, thus contrasting overt CIMF (82 months). In CIMF progressive myelofibrosis occurred in more than 50% of patients according to the last biopsy specimen; however, this figure increased according to relevant clinical data in the follow-up period.

Bone Marrow Examination↗
PubMed2004

Bone marrow angiogenesis: methods of quantification and changes evolving in chronic myeloproliferative disorders.

Until now little information is available about bone marrow (BM) angiogenesis in chronic myeloproliferative disorders (CMPDs). Amongst the various immunohistochemical markers for endothelial cells CD34 and CD105 have proven to be most reliable since they exhibit no relevant co-staining. Determination of vascularity has to include pathophysiological aspects of perfusion. Therefore, quantification of the microvascular density (MVD) by the so-called hot spot method has to be improved by parameters that characterize blood flow more properly like microvessel area (luminal distension), shape (form factor), tortuosity, and branching (maximal vessel length). In comparison to the normal BM chronic myeloid leukemia (CML) revealed a significant increase in MVD which was functionally associated with elevated levels of angiogenic cytokines. Structure of vessels was significantly altered by showing an enhanced irregularity of shape and tortuosity and increase in fibers was conspicuously accompanied by a higher degree of MVD. Contrasting the group of patients with Imatinib (STI571) therapy interferon failed to reduce the number of vessels. Following bone marrow transplantation a significant enhancement of the MVD was found in the early post-transplant period, but after about 6 months normalization occurred. Anomalies of microvascular architecture were easily demonstrable by three-dimensional reconstruction and consisted of a complex branching network of irregular shaped sinuses. Chronic idiopathic myelofibrosis displayed a significant increase in the MVD only in the advanced fibrosclerotic stages. This feature was accompanied by an enhanced luminal distension and tortuosity, thus contrasting the prefibrotic and early fibrotic phases of this disorder. Similar to CML a relationship between evolving myelofibrosis and change in vascular architecture was encountered. This feature may present a possible target for future anti-angiogenic therapy. In essential thrombocythemia there is only a mild increase in MVD detectable while in polycythemia vera besides an enlarged number, a luminal dilation due to the densely packed erythrocytes is recognizable. In conclusion, contrasting the usually applied quantification technique more elaborate morphometrical methods are warranted to obtain a better insight into the vascular architecture of the BM. In CMPDs angiogenesis is significantly associated with the evolution of myelofibrosis and may be altered by therapeutic regimens probably due to changes in cytokine release.

Bone Marrow↗
PubMed2004

Effects of the tyrosine kinase inhibitor imatinib mesylate (STI571) on bone marrow features in patients with chronic myelogenous leukemia.

Preliminary data are available about bone marrow (BM) changes in patients with chronic myeloid leukemia (CML) who received the molecularly targeted and highly effective tyrosine kinase inhibitor Imatinib mesylate (STI571). This review is focused on a systematic assessment of BM features detectable at different stages of CML (stable, accelerated, blastic) following long-term (more than 10 months) treatment. By applying enzyme- and immunohistochemistry including monoclonal antibodies visualizing proliferating cell nuclear antigen (PCNA) and apoptosis (anti-apostatin), a more elaborate insight into alterations affecting hematopoiesis and the stroma compartment was gained. In patients with stable-phase CML therapy resulted in a significant reduction in cellularity, neutrophil granulopoiesis and number of megakaryocytes, accompanied by a retrieval of erythroid precursors. In patients with Imatinib as the only treatment morphometric analysis of CD61+ megakaryopoiesis was in keeping with a significant decrease in maturation defects implying a lesser amount of atypical micromegakaryocytes almost consistent with normalization. Moreover, a reduction of the initially enhanced (CD34+) microvessel density was detectable associated with a decrease in luminal distension. Regression of marked to moderate myelofibrosis was recognizable in about 70% of patients especially in the accelerated and blastic phases. The amount of myeloblasts, CD34+ progenitor cells and lysozyme-expressing immature myelomonocytic cells declined with treatment, but recurred in about 19% of patients that developed a leukemic relapse after 21+/-6 months of therapy. Data on proliferative activity and apoptosis in general supported in vitro findings concerning the inhibitory effect of this agent on growth associated with a tendency for stimulated apoptosis, at least in responding patients.

Apoptosis↗
PubMed2004

Regeneration of heart muscle tissue: quantification of chimeric cardiomyocytes and endothelial cells following transplantation.

Persuasive evidence has been recently provided that adult bone marrow (BM) cells exert greater plasticity than previously assumed. This review is focused on the quantification of mixed chimerism (mCh) in the hearts (cardiomyocytes and endothelial cells) of patients after orthotopic heart to heart transplantation (HHT) in comparison to full (unmanipulated) allogeneic BM and peripheral blood stem cell (PBSC) transplants. Following a sex-mismatched transplantation constellation heart muscle tissue obtained at autopsy was examined. Evaluation of mCh was most often performed by immunophenotyping combined with fluorescence in-situ hybridization (FISH) applying x- and y-chromosome-specific DNA probes. When comparing our data with the results of former studies that were regularly based on the detection of the y-chromosome alone, the quantity of chimeric cardiomyocytes after HHT ranged from 0% to 9%. On the other hand, after full BM transplantats (chimeric) cardiomyocytes of donor-type origin appeared at an incidence between 0.23% to 6.4%. These disturbing inconsistencies were assumed to be related to methodology: the restriction to the y-chromosome, disregard of the plane of section (detection sensitivity ranging between 35% and 67%) and state of tissue preservation (cadaver hearts). Therefore, when strictly applying dual color FISH and limiting the recognition of chimeric cardiomyocytes and endothelial cells to the presence of two distinctive signals detection sensitivity was significantly enhanced. Contrasting a total congruence with the genotyping in control specimens of normal cadaver hearts, a striking disparity in the extent of mCh was found depending on the different modes of transplantation. After allografting with PBSC a considerably low incidence (1.6%) of chimeric cardiomyocytes was determined contrasting with 5.3% of donor-derived cells after full BM transplants. Following HHT host-type endothelial cells (16.2%) of the intramural and subepicardial vessel walls were more often encountered than following BM and PBSC allografting. These findings are in keeping with the assumption of a sprouting and migration of vascular structures into the donor heart from the site of surgical aligment and injury between retained host and donor atrial walls. When considering the other methods of transplantation (BM, PBSC) the data on chimeric endothelial cells support the hypothesis of a common hemangioblast. Concerning the cardiomyocytes it seems most reasonable to assume that primitive mesenchymal stem cells of the BM play a pivotal role in the development of mCh. This phenomenon is more extensively expressed than previously expected and may be related to an enforced repair of the damaged myocardium during the post-transplant period as the sequel of myeloablative (cardiotoxic) conditioning.

Animals↗
PubMed2004

Therapy-related changes of the bone marrow in chronic idiopathic myelofibrosis.

In chronic myeloproliferative disorders (CMPDs) a conflict of opinion exists regarding therapy-induced bone marrow (BM) changes and the evolution of myelofibrosis during the lengthy course of the disease. For a more elaborate study of these features chronic idiopathic myelofibrosis (IMF) seems to be a most suitable condition. Therefore this review is focused on this CMPD and amongst other findings analyzes data from a series of 340 patients with a long follow-up including 893 biopsies (median interval of 32 months). The ensuing results were compared with those communicated in the relevant literature. In addition to a control group of 153 patients with IMF who received only symptomatic treatment, therapy groups included busulfan, hydroxyurea, interferon and various combinations. In all groups hypoplasia of a varying degree was a frequent finding (6%) and often accompanied by a patchy arrangement of hematopoiesis. Most conspicuous was a gelatinous edema showing a tendency to develop a discrete reticulin fibrosis (scleredema). Aplasia developed in 7.7% of patients, usually at terminal stages of the disease independently of treatment. Minimal to moderate maturation defects of hematopoiesis involved especially megakaryocytes and erythroid precursors, but overt myelodysplastic features were most prominent following hydroxyurea and busulfan therapy. Acceleration and blastic crisis were characterized not only by increasing dysplastic changes, but also by the appearance of blasts including CD34+ cells. Semiquantitative grading of the fiber content revealed that 183 patients (54%) without or with moderate fibrosis at the beginning showed a significant progression and therefore contrasted with the 66 patients with a stable state. Following this calculation no relevant differences in the evolution of myelofibrosis were evident in the various therapy groups especially not following interferon treatment. In a few patients a regression was found which was accompanied by a severe hypoplasia or aplasia compatible with a myelo-ablative effect. In conclusion, peculiar BM changes, in particular conspicuously expressed myelodysplastic features are consistent with therapy-related lesions. Development of myelofibrosis in IMF is obviously due to disease progression unrelated to stage at diagnosis and not significantly influenced by treatment modalities.

Animals↗
PubMed2003

Chronic myeloproliferative disorders with thrombocythemia: a comparative study of two classification systems (PVSG, WHO) on 839 patients.

A multicenter observational study was performed on 839 adult patients with a chronic myeloproliferative disorder and a platelet count in excess of 600 x 10(9)/l to compare the updated criteria of the Polycythemia Vera Study Group (PVSG) with the recently published WHO classification. Essential thrombocythemia (ET) was diagnosed in 483 patients according to the PVSG; however, when considering histopathology as a major diagnostic feature of the WHO criteria, (true) ET could be established in only 162 patients. The remaining cases were found to represent either initially prefibrotic (184 patients) or early fibrotic (137 patients) chronic idiopathic myelofibrosis (IMF). On the other hand, both classification systems enabled a clear-cut distinction of patients showing overt IMF and polycythemia vera. Follow-up examinations in 140 patients with ET according to the PVSG criteria included also sequential bone marrow biopsies (interval: 38+/-30 months). A transition into mild reticulin fibrosis occurred in only 2 of 49 patients with (true) ET in contrast to 45 of 91 patients with initial and early IMF where a progression into overt myelofibrosis was encountered. Survival patterns for ET displayed significant differences because according to the PVSG a 16.5% disease-specific loss of life expectancy was calculable compared to a value of only 8.9% when following the WHO criteria. Contrasting this finding, initial and early IMF mimicking ET was characteriZed by a reduction of life expectancy ranging between 21.6% and 32.3 %. In conclusion, a more accurate classification of ET is warranted by regarding the WHO criteria that include histopathology as a major feature for diagnosis.

Adult↗
PubMed2003

Immunoreactivity of cytokeratins (CK7, CK20) and mucin peptide core antigens (MUC1, MUC2, MUC5AC) in adenocarcinomas, normal and metaplastic tissues of the distal oesophagus, oesophago-gastric junction and proximal stomach.

AIMS: Adenocarcinomas of the distal oesophagus and especially the oesophago-gastric junction have shown an increasing incidence during the last decade. Definition of subgroups according to different sites of development, histogenesis or aetiology may prove to be valuable for clinical diagnosis and treatment. Previous studies have shown differences in cytokeratin patterns between Barrett's metaplasia of the oesophagus and intestinal metaplasia in the stomach. The aim of our study was to investigate whether the expression of certain cytokeratins (CK7, CK20) and mucins (MUC1, MUC2, MUC5AC) exhibit clear-cut patterns, thus allowing a subclassification of adenocarcinomas of the oesophago-gastric junction. The possibility of a relationship between antigen expression and the presence or absence of Barrett's metaplastic epithelium was also studied. METHODS AND RESULTS: CK7, CK20, MUC1, MUC2 and MUC5AC were visualized in six adenocarcinomas of the distal oesophagus, 29 adenocarcinomas of the oesophago-gastric junction and eight adenocarcinomas of the proximal stomach. CK7, CK20 and MUC1 were strongly expressed in the great majority of all neoplasms under study, whereas MUC2 and MUC5AC were absent or only faintly detectable. CK20 exhibited a significantly stronger expression in poorly differentiated tumours (G3) and MUC1 immunoreactivity correlated with tubular and papillary versus signet-ring cell histopathology. Other statistically significant correlations between antigens and histopathological features (pTNM stage, grading, histopathological subtype, presence/absence of Barrett's epithelium) were not observed. CONCLUSIONS: According to our results, most adenocarcinomas of the oesophago-gastric junction show a CK7+, CK20+, MUC1+ phenotype irrespective of the presence or absence of Barrett's epithelium. The immunohistochemical data suggest a similar histogenesis of these tumours.

Adenocarcinoma↗
PubMed2003

Bone marrow histopathology following cytoreductive therapy in chronic idiopathic myelofibrosis.

AIMS: To analyse systematically therapy-induced lesions of haematopoiesis in chronic idiopathic myelofibrosis (IMF). METHODS AND RESULTS: A total of 759 sequential bone marrow (BM) biopsies (median interval 32 months) were performed in 261 patients with IMF. Besides a control group (symptomatic treatment), monotherapies included busulfan, hydroxyurea and interferon. In all therapy groups hypoplasia of varying degree was a frequent finding and often accompanied by a patchy distribution of haematopoiesis. Most conspicuous was gelatinous oedema showing a tendency to develop discrete reticulin fibrosis (scleroedema). Minimal to moderate maturation defects of megakaryopoiesis and erythroid precursors occurred, but overt myelodysplastic features were most prominent following hydroxyurea and busulfan therapy. Acceleration and blastic crisis were characterized by the appearance of immature and CD34+ progenitor cells. Concerning the dynamics of fibrosis, no differences were observed between controls and the various therapy groups. In 143 patients (55%) without or with little reticulin at onset, an increase in myelofibrosis was detectable that progressed to overt collagen fibrosis. CONCLUSIONS: Therapy-related bone marrow lesions in IMF comprise a strikingly variable spectrum that may include aplasia with scleroedema and a patchy distribution of myelodysplastic haematopoiesis associated with progressive myelofibrosis.

Aged↗
PubMed2003

Dynamics of fibrosis in chronic idiopathic (primary) myelofibrosis during therapy: a follow-up study on 309 patients.

Controversial issues in chronic idiopathic myelofibrosis (IMP) are amongst others the evolution of the disease process and the influence of therapy on the dynamics of fibrosis. For this reason, a multicenter observational study was performed on 309 patients with IMF that had a long follow-up including 822 bone marrow biopsies at a median interval of 32 months. In addition to a control group (156 patients) with symptomatic treatment, monotherapy consisted of busulfan (30 patients), hydroxyurea (52 patients), interferon (26 patients) and various combinations (48 patients). Density and quality (reticulin/collagen) of fibers was determined by a semiquantitative scoring system. Independent of therapeutic regimens at the time of the last bone marrow biopsy 67% of the patients with grades 0-2 fibrosis revealed a progression, 42% stable state and 6% regression of myelofibrosis. Because of significant differences concerning frequencies of biopsies and endpoints of examinations, individual changes in the grades of fibrosis were evaluated with regard to treatment applied at standardized intervals of 20 months. According to this calculation no relevant differences in the dynamics of myelofibrosis (progression, stable state) was detectable in the control group compared to the other therapeutic modalities. The few patients with a regression of myelofibrosis usually presented with severe hypoplasia compatible with a myelo-ablative effect by aggressive chemotherapy. In conclusion, persuasive evidence has been produced that myelofibrosis in IMF is characterized by a stepwise progression and that this process is not significantly influenced by current treatment strategies.

Biopsy↗
PubMed2003

Mixed chimerism of erythro- and megakaryopoiesis following allogeneic bone marrow transplantation.

Until now, studies on mixed chimerism (MCh) after allogeneic bone marrow transplantation (BMT) have predominantly focused on the B- and T-lymphocyte population, but not on distinct myeloid cell lineages like nucleated erythroid precursors and megakaryocytes. To evaluate the lineage-restricted MCh more explicitly in 10 patients with chronic myelogenous leukemia (CML), a quantitative analysis was performed on bone marrow biopsies following a sex-mismatched host/donor constellation. Techniques included immunophenotyping (antiglycophorin C, CD61) for the identification of erythro- and megakaryopoiesis and a simultaneously conducted genotyping with x- and y-chromosome-specific DNA probes. Normal bone marrow and specimens taken before BMT served as controls. Contrasting a total gender-dependent sex-typing in the latter samples in the early and late posttransplant period (up to 586 days), 3-9% erythroid precursors and about 16% megakaryocytes revealed a host-type origin. This significantly higher number of host megakaryocytes is explained by their polyploidy generating an increased probability to detect positive signals at a certain section level of the corresponding biopsies. A striking conversion of MCh to a recipient cell type was found in leukemic relapse with a more than 90% host-derived erythroid and megakaryocytic cell population in 4 patients approximately 643 days after BMT.

Adult↗
PubMed2003

Dynamics of lineage-restricted mixed chimerism following sex-mismatched allogeneic bone marrow transplantation.

Scant knowledge is available about the dynamics of lineage-specific mixed chimerism (Ch) following bone marrow transplantation (BMT). This review is focused on findings derived from bone marrow (BM) biopsies in patients with chronic myeloid leukemia (CML) including a sex-mismatched host/donor constellation. Appropriate techniques involved immunophenotyping by monoclonal antibodies to identify the various cell lineages, dual color fluorescence in situ hybridization (FISH) with x- and y-chromosome-specific DNA-probes and a proper detection system for a simultaneous labeling of the bcr/abl locus. A significant degree of Ch with more than 20% host CD34+ progenitors was found in the early and late (up to 200 days after BMT) posttransplant period. However, only 10% of these cells harbored the bcr/abl translocation gene. This result fits well with corresponding molecular biological findings of so-called minimal residual disease. Conversion of Ch evolved during leukemic relapse with 90% host progenitors of which 50% revealed the bcr/abl locus. A Ch of nucleated erythroid percursors (5%) and CD68+ macrophages (8%) was expressed to a significantly lower degree. The slightly increased frequency found in CD61+ megakaryocytes (16%) was probably due to the polyploid state of these cells. Similar to the CD34+ progenitor cells abrupt changes from donor to host type was associated with an insidious transformation into recurrent leukemia. The CD34+ endothelial cells showed a minor degree of Ch, because donor-derived elements ranged from 18% to 25%. Leukemic relapse was characterized by an almost complete conversion of the endothelial cells to a host type. These findings point towards a CD34+ progenitor cell origin of the (leukemic) endothelial cell layer and suggests that their dysfunction may contribute to an expansion of the neoplastic clone.

Animals↗
PubMed2003

Diagnostic differentiation of essential thrombocythaemia from thrombocythaemias associated with chronic idiopathic myelofibrosis by discriminate analysis of bone marrow features--a clinicopathological study on 272 patients.

Until now diagnosis of essential thrombocythaemia (ET) is generally performed by following the criteria of the Polycythaemia Vera Study Group (PVSG) that only marginally regards morphological features. Bone marrow biopsies were studied from 272 patients with ET in strict accordance with the PVSG guidelines and also from 35 control patients with reactive thrombocytosis. To define morphological features of distinctive impact more accurately, we performed a stepwise discriminant analysis of 16 morphological parameters based on histochemical staining reactions and semiquantitative grading of standardized features. A clear-cut separation into three distinctive histological patterns was accomplished that showed in more than 96% a correct predicted classification. Variables of significant impact included fibre content, quantity and cytological abnormalities of megakaryopoiesis like bulbous (cloud-like) nuclei, degree of nuclear lobulation and presence of giant forms. These changes were not detectable in the control group. The different constellations of histopathological features could be assigned to true ET (98 patients) and false ET, i.e. 136 patients with prefibrotic and 38 patients with early fibrotic chronic idiopathic myelofibrosis (IMF) accompanied by thrombocythaemia. A re-evaluation of clinical findings was in keeping with this classification into three categories that exerted significant differences to develop myelofibrosis during observation time and also different survival patterns. Contrasting IMF true ET is characterized by a pronounced proliferation of the megakaryocyte lineage showing large to giant cells without maturation defects and no relevant increase in reticulin fibres. Discrimination between these entities is warranted, because of a significant difference in presenting haematological data, follow-up and life expectancy.

Bone Marrow Cells↗
PubMed2002

[Quantification and morphometric analysis of vascular structures in the bone marrow. A critical review].

The important role of angiogenesis for invasion, tumor growth, metastasis and progression of solid tumors is well established. Only recently, the clinical significance of neovascularization in hematological neoplasms has come into the focus of scientific efforts. Emerging data from these studies suggest that the vascular architecture exerts a pivotal role in acute leukemias and multiple myeloma as well as myeloproliferative disorders. Thus, angiogenesis seems to maintain a general condition for malignant growth and the progression of hematological diseases. However, a major shortcoming is that most of the previous studies include only a simple quantitative evaluation of the microvessel density, and applied methods which were developed primarily for the characterization of angiogenesis in solid tumors. In this context it should not be overlooked that solid neoplasms and the bone marrow reveal significant differences regarding the vascular structures and the distribution of microvessels. Therefore, the usually applied, so-called hot-spot techniques, should be amended by an appropriate and more elaborate computer-assisted morphometric analysis of the microvessel structures. This additional spectrum of information regarding quantity and quality of angiogenesis, enables a further understanding of the morphological changes in the course of diseases, and in particular the effect of various therapies on bone marrow vascularization.

Blood Vessels↗
PubMed2002

[Anagrelide-induced changes of megakaryopoiesis during therapy of chronic myeloproliferative disorders with thrombocythemia].

Thrombocythemia in the course of chronic myeloproliferative disorders like chronic idiopathic myelofibrosis (cIMF) and of course essential thrombocythemia (ET), are characterized by life-threatening complications. In a number of clinical trials the recently introduced drug Agrylin((R)) has proven to be very effective. The normalization of the platelet count was related to an interference with megakaryocyte maturation leading to a left-shifting of this cell lineage and/or a reduced proliferation. However, until now no systematic study has been performed on the relationship between development of megakaryopoiesis and proliferative activity. In this investigation we included 10 patients with cIMF and 5 patients with ET that had received Agrylin((R)) for a period ranging between 6 and 70 months. Following therapy this cohort revealed a decrease in the platelet count from 1,104x10(9)/l at diagnosis to 485x10(9)/l. In this context we focused on an immunohistochemical and morphometric analysis of the CD61(+) megakaryopoiesis involving also endomitotic reduplication, by applying a double-immune incubation technique with the proliferating cell nuclear antigen (PCNA). Moreover, we determined the changes of fiber density during observation time. According to our results, the thrombocytopenic effect of Agrylin((R)) is based on an arrest in the dynamics of megakaryocyte maturation towards large (mature) platelet-shedding (polyploid) cells. This pathomechanism causes a significant increase in the number of promegakaryoblasts and megakaryoblasts. On the other hand, the total amount of CD61(+) megakaryocytic cells is not increased. Related to the peculiar cell biology of endomitotic reduplication during the maturation process and its different periods alloted to each single step, PCNA activity (late G1- and S-phase of the cell cycle) is found to be enhanced in the megakaryocyte precursors. Finally, no significant influence of Agrylin((R)) on the evolution of myelofibrosis is detectable and there is a general improvement of hematological data especially in cIMF.

Blood Platelets↗
PubMed2002

[Chimerism of cardiomyocytes and endothelial cells after allogeneic bone marrow transplantation in chronic myeloid leukemia. An autopsy study].

The results of a number of animal experimental studies are in keeping with the finding that hematopoietic progenitors can generate cardiomyocytes and endothelial cells. As a consequence innovative therapeutic strategies have been suggested to possibly ameliorate the outcome of coronary artery disease. However, there is no information available at present whether this pathomechanism is also effective in humans, in particular without prior ischemic lesion of the myocardium. Therefore an autopsy study was performed on cadaver hearts derived from five male patients with chronic myeloid leukemia who received full unmanipulated bone marrow grafts from female donors 21-631 days before death. The purpose of this investigation was to detect and quantify a putative chimerism of cardiomyocytes and endothelial cells (intramural and subepicardial vessels). Genotyping was carried out by applying X- or Y-chromosome-specific DNA probes (fluorescence in-situ hybridisation) on routinely formalin-fixed specimens of the myocardium. To test the sensitivity of our method, cadaver hearts from two males and two females without a history of transplantation served as controls. In contrast to a totally corresponding sex-matched genotyping in 780 cardiomyocytes and 155 endothelial cells of the control group, the five male patients with a previous transplantation revealed significantly different results. A mixed chimerism was identifiable in 57 out of 890 counted cardiomyocytes (6.4%) and in 19 out of 322 endothelial cells (5.8%). These findings support the assumption that in addition to endothelial cells there is also a cardiomyogenic potential of bone marrow stem cells which exists without prior (ischemic) damage to the heart. However, further investigations are necessary to identify, isolate and enrich the cardiomyocytic stem cells more specifically for future curative therapeutic options in patients with severe ischemic cardiomyopathy.

Adult↗
PubMed2002

[Extramedullary initial manifestations of acute myeloid leukemia (AML)].

Extramedullary myeloblastic tumors, so-called myelosarcomas (granulocytic sarcomas, chloromas) have been reported only sporadically in the pertinent literature which reflects their rather infrequent occurrence. These lesions may accompany the initial manifestation or signal relapse of acute myeloid leukemia (AML) or coincide with blastic transformation of a chronic myeloproliferative disorder. However, even more rarely, primary myelosarcomas may precede AML by months or years or may be associated with myelodysplastic syndromes (MDS) that never progress to manifest leukemia. In a retrospective evaluation a clinicopathological study on these latter two variants of isolated extramedullary manifestations of AML was performed to elucidate certain aspects of site involvement and histopathology by application of enzyme and immunohistochemistry. For this reason, we selected 6 patients presenting with a myelosarcoma in combination with MDS and 12 patients revealing only uncharacteristic reactive changes of the bone marrow. Of these patients 8 developed AML following an observation time of up to 2 years. Focal leukemic infiltrates were most often localized in the skin ( n=4), oral mucosa ( n=4), lymph nodes ( n=3), gastrointestinal tract ( n=3) or pleura and retroperitoneum ( n=3 each). Myelosarcomas were usually regarded by the clinicians as putative malignant lymphomas unless further evaluation, especially involving chloroacetate esterase reactions as well as immunostaining with a panel of antibodies reactive with lysozyme, myeloperoxidase, CD68, CD43, CD56, CD117 and CD34 proved their true nature. Although at that time bone marrow findings were inconclusive, a straightforward diagnosis was reached by considering the possibility of a (primary) myelosarcoma in these patients.

Adolescent↗