Christoph Busemann

Composition of molecular cardiolipin species correlates with proliferation of lymphocytes.

The mitochondrial phospholipid cardiolipin (CL) is required for oxidative phosphorylation. Oxidation of CL results in the disruption of CL-cytochrome c binding and the induction of apoptosis. Large variations in the acyl-chain residues of CL have been reported, but evidence as to whether these variants exert distinct biological effects has been limited. We have studied the acyl-chain composition of CL in lymphocytes, and found marked differences between highly and slowly proliferating cells. In fast growing cells, we detected a decreased number of double bonds, and a higher amount of C16 acyl-chain residues in CL, compared with slower growing cells. However, fewer C18 acyl-chain residues were found in CL from fast growing cells compared with slower proliferating cells. Our results suggest a functional link between acyl-chain composition of CL and cell proliferation.

Efficacy of Trabectedin in Patients with Advanced or Metastatic Alveolar Soft-Part Sarcoma

Background: Alveolar soft-part sarcoma (ASPS) is a rare sarcoma often occurring in young patients that is characterized by the unbalanced translocation der(17)t(X;17) (p11;q25). Although itusuallyshowsan indolent clinical course, the prognosis is usually poor in advanced disease. Since standard chemotherapy regimens used in soft-tissue sarcomas lack efficacy in ASPS, new therapeutic options are needed. We investigated the efficacy of trabectedin, which has demonstrated activity in a variety of cancer types including some of the most prevalent translocation-related sarcomas. Patients and Methods: 7 patients with metastatic or advanced ASPS treated with trabectedin in the Sarcoma Center Berlin-Brandenburg and the University Hospital of Greifswald were analyzed for median progression-free survival (mPFS), overall survival (OS), and therapy-related toxicity. Results: In 6 patients with documented disease progression, disease stabilization was reached with trabectedin; only 1 patient experienced progressive disease. The mPFS and OS were 7 months and 21 months, respectively, since the start of trabectedin treatment. Overall, no severe Common Toxicity Criteria (CTC) grade 3 or 4 toxicity was observed. Conclusions: The poor prognosis of patients with ASPS has so far been due to the unavailability of effective systemic treatments. Trabectedin can be considered the only currently registered drug with clinical activity in this disease.

Myocardial and aortal involvement in a case of disseminated infection with Fusarium solani after allogeneic stem cell transplantation: report of a case.

We describe a 57‐year‐old woman suffering from acute erythroblastic leukaemia. After the first course of high‐dose Ara‐C containing consolidation therapy, the patient developed multiple skin lesions on the left foot. A skin biopsy revealed a Fusarium infection. The lesions regressed under therapy with caspofungin and voriconazole. Leukaemia relapsed after 1 year and an allogeneic stem cell transplantation was performed for consolidation of leukaemia in second remission. Again, the patient developed macular skin lesions located on the trunk and the extremities with central pallor. Clinical examination showed fever, tachyarrhythmia and a systolic murmur. Fusarium spp. was cultured from blood samples. An antimycotic therapy with amphotericin B, voriconazole and posaconazole failed completely. The patient died in a septic shock with consecutive multiple organ failure. The autopsy (SN 1/06, Institute of Pathology, University of Greifswald) revealed a disseminated infiltration with Fusarium solani including myocardial, endocardial and aortal infection. The involvement of the cardiovascular system is uncommon in fusariosis and has not been described so far. This case confirms other reports describing the high mortality of fusariosis after allogeneic stem cell transplantation. A rapid diagnosis and antimycotics with higher activity against Fusarium spp. are necessary for successful therapy of this severe mould infection in the immunocompromised host.

Complete remission and early relapse of refractory plasma cell leukemia after bortezomib induction and consolidation by HLA-mismatched unrelated allogeneic stem cell transplantation.

Chromosomal deletion of q13 (del q13) and plasma cell leukemia predict both a worse prognosis in myeloma. Experiences with bortezomib in plasma cell leukemia prior to allogeneic stem cell transplantation (SCT) have not yet been reported. Case Report: A 66- year-old male patient was admitted for IgA myelomaIIIA with del q13. The myeloma progressed to plasma cell leukemia. Bortezomib was given, free light chain (FLC) excretion decreased, and myeloma cells disappeared from blood and decreased in marrow. An unrelated, mismatched allogeneic SCT was performed. The patient was discharged after engraftment with full chimerism without signs of GvHD. FLC excretion increased, and immunosuppression was discontinued. From day +84 on, bortezomib was infused again and FLC excretion decreased rapidly. Relapse was confirmed in marrow, and bortezomib was continued. Donor lymphocyte infusions (DLI) had no effect, and a further cycle of bortezomib and thalidomide had only minor effects. On day +209, the patient died from myeloma. Conclusion: This case gives evidence for an excellent initial response of plasma cell leukemia to bortezomib, however, early relapse after SCT clearly indicates limitations of both bortezomib therapy and allogeneic SCT in high-risk myeloma. Future developments are mandatory and could include combination of bortezomib with other cytostatics and early DLI in the absence of GvHD. In addition, there is need to clarify if graft-versus-myeloma effect is diminished by bortezomib therapy after allogeneic SCT.

Treatment of splenic marginal zone lymphoma of the CNS with high-dose therapy and allogeneic stem cell transplantation

Therapy of indolent lymphomas with involvement of the central nervous system (CNS) has not been standardized so far. A 42-year old male patient presented with neurological signs because of leukemic splenic marginal zone lymphoma (SMZL) manifested in bone marrow, lymph nodes and CNS. Due to the aggressiveness of the disease and the young age of the patient, an intensive immunochemotherapy followed by high-dose therapy with busulfan, thiotepa and fludarabine and subsequent unrelated allogeneic stem cell transplantation (alloSCT) was performed. The haemopoietic stem cells engrafted in time and the patient is doing well (ECOG 0) without evidence for active lymphoma three years after transplantation. Highly sensitive tests by specific quantitative real-time polymerase chain reaction for presence of lymphoma cells in blood and bone marrow indicated also a molecular remission. The reported case shows the feasibility of high-dose therapy and allogeneic stem cell transplantation in high-risk patients with CNS-involvement of indolent non-Hodgkin’s lymphoma. In addition, the case supports the hypothesis that the graft-versus lymphoma effect after alloSCT is also active within the CNS.

Erdheim–Chester disease with hemophagocytosis

Dear Editor, A 49-year-old man presented with abdominal distension, weight loss of 6 kg, night sweats, fever, and a compromised condition for about 1 month. A computed tomography (CT) scan revealed a large retroperitoneal mass, and the suspected diagnosis was non-Hodgkins lymphoma. At admission, physical examination revealed hepatosplenomegaly without peripheral lymph node enlargement. Several biopsies for histopathologic evaluation were performed. The diagnosis of soft tissue sarcoma (malignant fibrous histiocytoma) was made and polychemotherapy with epirubicin, ifosfamide, and etoposide (without cisplatinum because of tumorassociated hydronephrosis with concomitant renal impairment) was initiated. Immunohistopathological reevaluation showed xanthogranulomatous inflammation (Figs. 1 and 2) with multinuclear giant cells and foamy histiocytes positive for CD68 (Fig. 3) and CD45, but the absence of CD1a immunoreactivity (excluding a Langerhans cell histiocytosis). The diagnosis of non-Langerhans-histiocytosis Erdheim–Chester disease (ECD) was made and confirmed by an international reference pathologist. A bone scan with 99mTc-MDP showed the typical increased bilateral symmetric uptake within the long bones sparing the epiphyses. Pathognomonic radiographic findings were bilateral symmetric osteosclerosis of the long bones and lytic bone changes localized especially in the metaphyses (Fig. 4). Histological examination of lung and bone marrow confirmed the diagnosis of ECD. Neither treatment with the cytotoxic drug eldesine and prednisolone nor high dose dexamethasone was of any beneficial effects. The patient developed multi-organ failure, severe anemia, and thrombocytopenia. Bone marrow examination showed multiple histiocytic cells showing extensive hemophagocytosis (Figs. 5 and 6). The patient died 4 months after admission. Erdheim–Chester disease is a rare non-Langerhans’ form of histiocytosis first described by William Chester in 1930. Until now, less than 100 cases have been published in the literature. ECD lesions are characterized by infiltrates of xanthomatous histiocytes positive for CD68, in contrast to Langerhans-cell lineage negative for CD1a and S100, Birbeck granules are not found. The presence of a monoclonal cell population cannot be detected by the HUMARA assay [1]. The pathognomonic radiological findings are symmetric. Diaphyseal or metaphyseal sclerotic lesions are found in the long bones, mainly the femur, the tibia, and the fibula. Bone pain is the most frequent symptom. General symptoms such as fever, weight loss, and weakness are reported. Extraskeletal manifestations have been found in the lung (35%), pericardium, myocardium, aorta, orbita (26%), retroperitoneum (37%), skin, and CNS (30%) [2]. The prognosis of ECD is grim. In a retrospective analysis by Veyssier-Belot et al. [2], 22 from 59 patients died after a Ann Hematol (2007) 86:847–849 DOI 10.1007/s00277-007-0324-4

Alternative diagnosis to heparin-induced thrombocytopenia in two critically ill patients despite a positive PF4/heparin-antibody test

Abstract Thrombocytopenia can cause diagnostic challenges in patients who have received heparin. Heparin-induced thrombocytopenia (HIT) is often considered in the differential diagnosis, and a positive screening can be mistaken as confirmation of the disorder. We present two patients who both received low-molecular-weight heparin for several days. In the first patient, clinical judgment rejected the suspicion of HIT despite a positive screening assay, and treatment for the alternative diagnosis of post-transfusion purpura was correctly initiated. In the second patient, the inaccurate diagnosis HIT was pursued due to a positive screening assay, while the alternative diagnosis of drug-dependent thrombocytopenia caused by piperacillin/tazobactam was rejected. This resulted in re-exposure to piperacillin/tazobactam which caused a second episode of severe thrombocytopenia. A positive screening assay for platelet factor 4/heparin-antibody should be verified by a functional assay, especially in patients with low pretest probability for HIT.

Submicroscopic genomic rearrangements change gene expression in T‐cell large granular lymphocyte leukemia

To better understand the molecular pathogenesis of T‐cell large granular lymphocyte leukemia (T‐LGL), we decided to search for those genetic alterations in T‐LGL patients and MOTN‐1 cell line (established from T‐LGL patient) that have an impact on gene expression and as a result can influence cell biology.

Mucositis after reduced intensity conditioning and allogeneic stem cell transplantation.

Background: Therapyrelated mucositis is associated with considerable morbidity. This complication following allogeneic stem cell therapy (alloSCT) is less severe after reduced intense conditioning (RIC); however, even here it may be serious. Methods: 52 patients (male: n = 35 (67%), female: n = 17 (33%)) at a median age of 62 years (35–73 years) underwent alloSCT after RIC. Conditioning was either total body irradiation (TBI)2Gy/±fludarabine (n = 33, 63.5%) or chemotherapy based. Graftversushost disease (GvHD) prophylaxis was carried out with cyclosporine A ± mycophenolate mofetil (MMF). 45 patients (87%) received shortcourse methotrexate (MTX). Mucositis was graded according to the Bearman and the World Health Organisation (WHO) scale. A variety of parameters were correlated with mucositis. Results: The Bearman and WHO scales showed excellent correlation. Mucositis was significantly more severe after chemotherapybased conditioning compared to conditioning with TBI2Gy/±fludarabine (p < 0.002) as well as in cases with an increase in creatinine levels above the upper normal value (UNV) on day +1 after SCT (p < 0.05). Furthermore, the severity correlated with time to engraftment of leucocytes (correlation coefficient (cc) = 0.26, p < 0.02) and thrombocytes (cc = 0.38, p < 0.001). Conclusions: The conditioning regimen and increased creatinine levels at day +1 were identified as factors predicting the severity of mucositis after RICSCT. Creatinine levels on day +1 after SCT may help identify patients at risk for severe mucositis in the further course of transplantation.

Severe Disseminated Coagulopathy Caused by Adenocarcinoma with Bone Marrow Metastasis

Background: Patients with mucin-producing adenocarcinoma have an increased risk for venous and arterial thrombosis. When these patients present with thrombocytopenia, disseminated intravascular coagulopathy (DIC) is often the underlying cause. Case Report: We report 2 patients who were admitted due to bleeding symptoms of unknown cause, in whom further workup revealed adenocarcinoma-induced DIC. Conclusion: In elderly patients presenting with signs of DIC, such as reduced fibrinogen levels, elevated prothrombin time, elevated D-dimer, and thrombocytopenia, without any obvious reason (e.g., sepsis), adenocarcinoma-associated coagulopathy should be considered as the underlying cause. Paradoxically, in these patients bleeding symptoms improve when the patient is sufficiently anti-coagulated with low molecular weight heparin. Treatment of the underlying disease is of central importance in controlling acute or chronic DIC associated with malignant diseases and chemotherapy should be started as soon as possible.