We have isolated and characterized the human cardiac mast cell (CMC) and compared this novel mast cell (MC type with MC obtained from uterus, skin, and lung. Heart tissue was obtained from 14 patients with cardiomyopathy (CMP, heart transplantation). CMC were isolated by enzymatic digestion using collagenase, pronase-E, hyaluronidase, and DNAse. Substantial amounts of CMC (0.5% to 1.5% of isolated cells) were found in the atrial appendages but not in ventricular digests or other sites of the heart (< 0.1%). In situ staining of atrial tissue revealed the presence of CMC in the myocardium (2.16 +/- 0.7 MC/mm2), endocardium (2.24 +/- 0.9 MC/mm2), and epicardium. As assessed by combined toluidine blue/immunofluorescence staining with monoclonal antibodies (MoAbs), isolated CMC expressed surface IgE, the receptor for stem cell factor (c-kit receptor/CD117), the p24 antigen (CD9), the Pgp-1 homing receptor (CD44), the pan leukocyte antigen (CD45), and the ICAM-1 antigen (CD54). CMC were not recognized by MoAbs to lymphocyte function associated antigen 2 (LFA-2; CD2), T-cell receptor (TcR; CD3), T4 antigen (CD4), LFA-1 alpha-chain (CD11a), C3biR alpha-chain (CD11b), CR4 alpha-chain (CD11c), LPS-R related Ag (CD14), 3-FAL/x-hapten (CD15), Fc gamma RIII (CD16), lactosylceramid (CDw17), the B-cell antigen CD19, or CR1 (CD35). In situ expression of leukocyte antigens on CMC was demonstrable by indirect immunoperoxidase staining technique and double-labeling immunohistochemistry. Almost all CMC (90%) reacted with MoAbs against tryptase and chymase and thus were MCTC. Cardiac mast cells were also stained by the heparin-binding dye Berberine sulfate and expressed measurable amounts of histamine (4.6 +/- 1.4 pg per cell). Cross linking of either IgE receptor or SCF receptor (c-kit) on CMC resulted in histamine secretion (non-specific release: < 6% of total histamine, alpha IgE induced: 12% to 52%; SCF-induced release: 9% to 18%), whereas neither substance P (a skin MC agonist) nor the basophil agonist FMLP showed an effect on CMC. Together, the CMC is an MCTC primarily located in the appendage of the atrium. This novel type of MC exhibits surface membrane antigen and functional properties similar to those of lung and uterus MC.

Autonomous, factor-independent growth and differentiation of malignant cells in preleukemic and leukemic disease states is a well-recognized phenomenon and is often associated with a poor prognosis. Mast cells are distinct hematopoietic cells and express a unique profile of antigens. Growth and differentiation of normal mast cells is dependent on mast cell growth factor (MGF), the ligand of the c-kit protooncogene product. In this study, we screened for mast cell-lineage involvement in 52 patients suffering from myeloid leukemias, myelodysplastic syndromes (MDS), systemic mastocytosis, or other diseases by probing for mast cell-related molecules (c-kit, tryptase, histamine, and MGF) and by analyzing kit ligand/MGF-independent growth of mast cells in long-term suspension culture. Of the 52 patients tested, 2 patients with refractory anemia with excess of blast cells in transformation and 1 patient suffering from chronic myeloid leukemia blast crisis (CML-BC) were diagnosed as mastocytic disease. These patients were characterized by complex chromosomal abnormalities, splenomegaly, high percentages of circulating metachromatic cells (5% to 25%), high levels of cellular tryptase (> 10 ng/10(5) peripheral blood mononuclear cells/mL) and a tryptase/histamine (ng:ng) ratio greater than 1. The metachromatic cells expressed the mast-cell-related surface antigen c-kit, but not basophil-related antigens (CD11b, CDw17). Furthermore, in these 3 patients, spontaneous, MGF-independent growth of mast cells along with spontaneous synthesis of tryptase was demonstrable in long-term culture. No autocrine production, paracrine production, or overproduction of MGF was found. The spontaneous growth of mast cells could neither be abbrogated by addition of monoclonal antibodies (MoAbs) to c-kit nor by MoAbs against MGF (< 5% inhibition), whereas factor (MGF)-dependent differentiation of mast cells in these patients could be abbrogated by MoAbs to c-kit or MoAbs to MGF (> 70% inhibition, P < .001). In addition, serum MGF levels in these patients were within the normal range and MGF could not be detected in cell-free culture supernatants. All 3 patients showed rapid progression of disease and had a survival time of less than 1 year. In conclusion, we describe a unique form of transformation in MDS and CML-BC characterized by mast cell lineage involvement and factor-independent differentiation of mast cells. This form of leukemic transformation has to be delineated from chronic myeloid leukemia with basophilia or basophil crisis, from primary mast cell leukemia, and from monocytic leukemias and myelodysplastic disorders associated with basophilia.

Summary:A 52-year-old female underwent autologous BMT because of acute myeloid leukaemia FAB M4 in second remission. Since the patient had no HLA-identical sibling she received a purged autologous BM transplant. On day +5 she developed signs of a sepsis syndrome with fluid retention and was treated with broad-spectrum antibiotic therapy. However, her body weight remained high, ascites and an increase of total serum bilirubin and alkaline phosphatase developed. The icterus worsened to a total bilirubin level of 25 mg/100 ml. Sonographic and endoscopic imaging showed a dilated gall bladder but disclosed a post-hepatic cause for the icterus. A transjugular liver biopsy on day +71 revealed severe cholestasis and siderosis. The patient remained aplastic with constantly increased bilirubin levels. On day +73 septic shock syndrome occurred and the patient died of multiorgan failure 3 days later. At autopsy, a highly differentiated bile duct adenocarcinoma at the porta hepatis, so-called Klatskin tumour, was found, explaining the fatal course with intractable cholestasis. Keywords: hepatic VOD; cholestasis; bile duct adenocarcinoma Hepatic veno-occlusive disease (VOD) is a syndrome consisting of weight gain, ascites, increase of bilirubin level, and right upper abdominal quadrant pain with a high rate of lethality. Occasionally it can be accompanied by refractoriness to platelet transfusion. In most cases VOD occurs after allogeneic BMT, and occasionally after high-dose chemotherapy with or without autologous stem cell rescue. Despite a range of prophylactic and therapeutic approaches with administration of heparin and tissue plasminogen activator (tPA), 1 transjugular intrahepatic portosystemic stent- shunt (TIPS) 2-4 and even liver transplantation 5 the prognosis has remained poor.We describe a patient who presented clinically with the signs of severe VOD after autologous BMT for AML with an atypical chronic course and a surprising diagnosis post mortem. Case reportA 52-year-old female patient was referred to our department for BMT. She had AML FAB M4 in second remission. The disease had been diagnosed 16 months earlier and the patient had received induction therapy consisting of DNR, vepeside and Ara-C. Complete remission was achieved. Consolidation therapy with Ara-C followed. Two months after the third consolidation cycle the patient had a relapse. She received reinduction therapy with idarubicin and Ara-C and one course of consolidation therapy prior to BMT. Because the patient had no HLA-identical sibling, autologous BM for transplantation was harvested in second remission 2 months before BMT. The BM was purged by mafosfamide. The CD34 + count after purging was 1.44 × 10 6 /kg. On admission for autologous BMT the patient presented with a Karnofsky score of 100. Clinical examination revealed no pathologic findings. The liver and kidney function was normal.Conditioning consisted of BU 4 mg/kg orally daily divided into four doses, total dose 16 mg/kg and vepeside 60 mg/kg. The patient tolerated the conditioning regi...