Cardiac death after autologous stem cell transplantation (ASCT) for treatment of systemic sclerosis (SSc): no evidence for cyclophosphamide-induced cardiomyopathy.

In patients with systemic sclerosis (SSc) treatment-related mortality after autologous stem cell transplantation (ASCT) appears to be increased as compared to patients with hematological malignancies. In our phase I/II study on ASCT in autoimmune diseases a patient with SSc died on day 2 after ASCT. Here we report the results of the autopsy which revealed advanced pulmonary and cardiac fibrosis as the most probable cause of death. In spite of detailed technical examination before enrollment, the cardiopulmonary function tests did not reflect the advanced stage of the disease. We conclude that in selected patients with SSc, biopsies should be performed to reduce mortality after ASCT.

Grading of tumors and tumorlike lesions of bone: evaluation by FDG PET.

UNLABELLED: Clinical diagnosis of skeletal tumors can be difficult, because such lesions compose a large, heterogeneous group of entities with different biologic behaviors. The aim of this prospective study was to assess the value of PET in grading tumors and tumorlike lesions of bone. METHODS: Two hundred two patients with suspected primary bone tumors were investigated using FDG PET. Uptake of FDG was evaluated semiquantitatively by determining the tumor-to-background ratio (T/B). All patients underwent biopsy, resulting in the histologic detection of 70 high-grade sarcomas, 21 low-grade sarcomas, 40 benign tumors, 47 tumorlike lesions, 6 osseous lymphomas, 6 plasmacytomas, and 12 metastases of an unknown primary tumor. RESULTS: All lesions, with the exception of 3 benign tumors, were detected by increased FDG uptake. Although sarcomas showed significantly higher T/Bs than did latent or active benign lesions (P < 0.001), aggressive benign lesions could not be distinguished from sarcomas. Using a T/B cutoff level for malignancy of 3.0, the sensitivity of FDG PET was 93.0%, the specificity was 66.7%, and the accuracy was 81.7%. CONCLUSION: FDG PET provides a promising tool for estimating the biologic activity of skeletal lesions, implicating consequences for the choice of surgical strategy.

Langerhans cell deficiency in reticular dysgenesis.

Reticular dysgenesis is a rare inherited immunodeficiency characterized by the lack of blood monocytes and neutrophils and low lymphocyte counts, contrasting with normal red blood cell counts and normal or decreased platelet counts. Whether dendritic cells or macrophages, both of which derive primarily from blood monocytes, are affected in this condition remains unknown. We studied 7 patients with reticular dysgenesis. Macrophages were present in normal numbers in the dermis and in the atrophic lymphoid tissues of these patients, proving that at least some subsets of macrophages can differentiate despite very low monocyte counts. By contrast, Langerhans cells, which are CD1a-positive epidermal dendritic cells, were absent in all (n = 5) patients before bone marrow transplantation. After bone marrow transplantation, Langerhans cells were present (n = 2), suggesting that the defect is not related to keratinocyte dysfunction. A split chimeric reconstitution, characterized by the presence of autologous blood monocytes able to differentiate in vitro into CD1a-positive dendritic cells, was observed in a patient who underwent successful engraftment. These results suggest that an intrinsic cell defect is unlikely and that a bone marrow-derived factor may be defective in reticular dysgenesis; it may be responsible for the Langerhans cell defect but not involved in macrophage differentiation.

Fluorodeoxyglucose positron emission tomography of soft tissue tumours: is a non-invasive determination of biological activity possible?

Since musculoskeletal tumours comprise a large heterogeneous group of entities with different biological behaviour, clinical diagnosis of such lesions can be very difficult. The aim of this prospective study was to assess the usefulness of 2-[F-18]-fluoro-2-deoxy-d-glucose (FDG) positron emission tomography (PET) in the non-invasive evaluation of soft tissue tumours. One hundred and two patients with suspected soft tissue neoplasms were investigated by FDG-PET. The uptake of FDG was evaluated semiquantitatively by determining the tumour to background ratio (TBR). All patients underwent biopsy, resulting in the histological detection of 39 high-grade sarcomas, 16 intermediate-grade sarcomas, 11 low-grade sarcomas, 25 benign tumours, 10 tumour-like lesions such as spontaneous myositis ossificans (n = 6) and one non-Hodgkin lymphoma. All lesions except for two lipomas disclosed an increased FDG uptake. Sarcomas showed significantly higher TBR values than latent or active benign lesions (P<0.001) and aggressive benign lesions (P<0.05). Using a TBR cut-off level of 3.0 for malignancy, sensitivity of FDG-PET was 97.0%, specificity 65.7% and accuracy 86. 3%. From our data there are three main conclusions: (1) Except for patients with pseudotumoral myositis ossificans, lesions with a TBR >3 were sarcomas (91.7%) or aggressive benign tumours (8.3%). (2) Tumours with a TBR <1.5 were latent or active benign lesions, exclusively. (3) The group with intermediate TBR values (<3 and >1. 5) comprised primarily latent or active benign lesions, but also four aggressive benign tumours and two low-grade sarcomas. Our data suggest that FDG-PET represents a useful tool for the evaluation of the biological activity of soft tissue neoplasms.

Anaemia, thrombocytopenia and coagulopathy due to occult diffuse infantile haemangiomatosis of spleen and pancreas.

UNLABELLED: Diffuse infantile haemangiomatosis of the spleen is a very rare lesion. Large haemangiomas may cause trapping of platelets and coagulation disorders known as Kasabach-Merrit syndrome. We here report the case of an infant with splenic and pancreatic haemangiomatosis presenting with life-threatening thrombocytopenia, anaemia and intravascular coagulation. Diagnosis was hampered by reactive erythroblastosis and non-conclusive radiological findings. While treatment with corticosteroids was ineffective, administration of antithrombin III improved coagulation parameters. After splenectomy the child recovered promptly and has remained free of disease for 3 years to date. CONCLUSION: Occult visceral haemangiomatosis without visible cutaneous haemangiomas should be included in the differential diagnosis of thrombocytopenia, anaemia and consumption coagulopathy. Antithrombin III treatment may be considered to overcome bleeding problems in patients with Kasabach-Merrit syndrome.

[Color Doppler controlled needle biopsy in diagnosis of soft tissue and bone tumors]. / Die farbdopplersonographisch gesteuerte Nadelbiopsie in der Diagnostik von Weichteil- und Knochentumoren.

In a prospective study we investigated 168 patients with musculoskeletal tumors, including 71 sarcomas, by core needle biopsy using the high-speed device Autovac. Monitoring with colour-coded duplex sonography allowed a well-aimed puncture of smaller or deeply localized lesions and also permitted the discrimination of necrotic and viable parts of the tumor. Adequate material for histologic diagnosis including grading and determination of tumor subtype was obtained from soft tissue sarcomas, soft tissue metastases, malignant lymphomas, plasmacytomas, and osteolytic skeletal secondaries. In contrast, in benign soft tissue and bone tumors the diagnosis could be established in only 66% of cases. Although skeletal sarcomas were identified as malignant mesenchymal lesions, a complete histologic classification of tumor subtype frequently was not possible due to an insufficient tissue specimen. With an accuracy of 97% for the diagnosis of malignancy and of 94% for the diagnosis of soft tissue sarcoma the results of core needle biopsies were comparable to those of incisional biopsies, the reference standard in the diagnosis of musculoskeletal tumors. Regarding the known disadvantages and the oncological risks of incisional biopsies, needle biopsy should replace the open procedure as the primary means of diagnosis in soft tissue and osteolytic bone tumors.

Clonal origin of tumor cells in a plexiform neurofibroma with LOH in NF1 intron 38 and in dermal neurofibromas without LOH of the NF1 gene.

LOH at the NF1 locus was investigated in 38 neurofibromas of 26 NF1 patients. Only in one of these tumors LOH was observed. In this plexiform neurofibroma of a NF1 patient with a constitutional one base-pair insertion in NF1 exon 4b, a non-random X-inactivation pattern was found, strongly suggesting a clonal origin of the tumor cells. The analysis of X-inactivation patterns allowed the classification of some of the other neurofibromas with regard to the detectability of clonal LOH. In 3 of 6 neurofibromas without LOH amenable to this analysis, a comparable X-inactivation pattern was found in constitutional and neurofibroma derived DNA. A clonal LOH would not have been detected in these tumors. However, we observed a nonrandom pattern in 3 of the 6 neurofibromas, suggesting a clonal origin of the tumor cells. LOH was not detected in these tumors, but could, however, have occurred by mutational events below the level of large somatic deletions, loss of a whole chromosome 17 or somatic recombination.

[A case of sarcoidosis of the mastoid]. / Ein Fall von Sarkoidose im Mastoid.

BACKGROUND: Sarcoidosis is a common granulomatous systemic inflammatory disease mainly affecting the interstitial lung tissue and perihilar lymph nodes. Since its first description by Bernier 1889 its etiology has remained obscure. METHOD: Sarcoidosis of the right middle ear in a 38-year-old woman was diagnosed by biopsy. RESULT: After mastoidectomy and treatment with prednisolone the patient has been free of relapse for two years. CONCLUSION: According to our knowledge this is the second reported case of sarcoidosis of the middle ear. In both cases the interstitial lung tissue has been involved as well. This finding increases the importance of excluding sarcoidosis in differential diagnosis of chronic otitis media.

Histomorphological examination of endoluminal stent grafting in the descending aorta in a sheep model.

Experiments were designed to examine the wound healing characteristics at the aorta-endograft interface. Thoracic aneurysms were induced in sheep and excluded by endovascular placement of a selfexpanding stent graft (Corvita Endovascular Graft). After a follow-up of 1, 4, or 12 weeks sheep were sacrificed and the corresponding segments of the aorta were subjected to histological examinations. Histomorphological evaluation of all groups underlined sufficient exclusion of lesions of the aortic wall by endovascular grafting. There was no evidence of proximal or distal leakage, graft dislocation or migration. The results appeared to be evidence that the endoluminal stent graft may be incorporated by the host aortic tissue.

Epstein-Barr-virus-associated lymphoproliferative syndrome in severe combined immunodeficiency: establishment of a lymphoblastoid cell line as an in vitro model for biological and therapeutic studies.

Patients with primary or secondary immunodeficiency are at high risk for B cell lymphoproliferative syndromes (LPS) that are generally Epstein-Barr virus (EBV)-associated. We established a cell line, termed JuWa, from an immunoblastic lymphoma that developed in a child with severe combined immunodeficiency. JuWa cells were representative of the original lymph node as shown by a similar IgH gene rearrangement pattern. The cell line exhibited the typical features of a lymphoblastoid cell line (LCL): (1) growth pattern in large clumps, (2) lack of structural chromosome abnormalities, (3) type III latency with expression of EBV-associated EBNA2 and LMP, as well as B cell activation markers CD23 and CD30, thereby showing characteristics of an EBV producer cell line, i.e. a latent infection with a small subpopulation of cells spontaneously entering the lytic cycle, (4) inducibility of the lytic cycle by IdU and TPA, leading to an increase of early antigen and viral capsid antigen-positive cells from 1 to 15-20%, and (5) elimination of the linear viral genomes by treatment with acyclovir (ACV), without affecting the circular episomal genomes. After withdrawal of ACV, viral replication resumed within 7 days. Thus, JuWa cells support the concept of the LCL-like features of LPS and lymphomas occurring in the setting of immunodeficiency. In our in vitro model, ACV treatment could effectively suppress the viral replication but not cure EBV infection of B cells.

Intestinal cytomegalovirus disease in immunocompromised patients may be ruled out by search for cytomegalovirus DNA in stool samples.

Cytomegalovirus (CMV) PCR from stool specimens was adopted as a diagnostic tool for patients with suspected CMV colitis. After being established, the method was evaluated in 17 AIDS patients and 19 other immunocompromised patients by comparison of PCR results with clinical, histological, and microbiological or virological data. CMV PCR was positive in 4 symptomatic patients with proven CMV colitis and negative in 15 of 16 patients without characteristic histopathology. Neither CMV immunoglobulin G seropositivity nor intestinal symptoms alone were significantly associated with positive PCR results, but severe active systemic CMV infection may lead to a positive PCR. Absence of CMV DNA in stool samples may prove useful in ruling out CMV related colitis.

[Inflammatory pseudotumors of the lung and trachea]. / Inflammatorische Pseudotumoren der Lunge und Trachea.

Inflammatory pseudotumors (synonym: plasma cell granulomas) of the lung and trachea are a group of non-neoplastic lesions of unknown etiology which may occur at any age. The complex histomorphology und proliferative capacity of these pseudotumors may result in diagnostic difficulties during intraoperative frozen section analysis. Four cases of inflammatory pseudotumors of the respiratory tract (three pulmonal, one tracheal pseudotumors) are reported. One patient (16 years, female) suffered from sudden chest pain with dyspnoe, caused by obstruction of the right main bronchus due to an intraluminal pseudotumor. Because of the intraoperative diagnosis of a malignant histiocytoma, sleeve resection of the right main bronchus with bronchotracheal anastomosis was performed. Eight years postoperative, the patient is still disease-free. Another patient (52 years, male) developed multiple inflammatory pseudotumors in both lungs with direct infiltration of the mediastinum. After three thoracotomies, there is still residual disease in the mediastinum. The third patient (52 years, male) developed an inflammatory pseudotumor in the right upper lobe after irradiation therapy for hypopharyngeal carcinoma several years before. The last case in this series is a patient (43 years, male) with suspected bronchial carcinoma in the left lower lobe. The intraoperative frozen section analysis interpreted this lesion as an bronchioloalveolar carcinoma, but the diagnosis was corrected in the paraffin embedded specimens. Clinical presentation, size and number of these tumors are very variable. Despite their rarity, inflammatory pseudotumors should be considered in the differential diagnosis.

A fatal infection with Alternaria alternata and Aspergillus terreus in a child with agranulocytosis of unknown origin.

Alternaria alternata and Aspergillus terreus were isolated from cutaneous nodules in a 5-year-old girl with agranulocytosis of unknown origin. Histopathological examination supported the diagnosis of an infection with two opportunistic moulds. Aspergillus terreus was also isolated from the secretions of the maxillary sinuses of the patient. In spite of antimycotic therapy, the child eventually died from respiratory failure.

Hepatitis C virus infection is a risk factor for liver failure from veno-occlusive disease after bone marrow transplantation.

The contribution of hepatitis C virus (HCV) infection to liver disease after bone marrow transplantation (BMT) was retrospectively evaluated in 61 patients treated with BMT. HCV genome, as well as antibodies to HCV, was analyzed in sera collected before and serially after BMT. Six patients had been infected with HCV before BMT and three patients acquired the infection during or shortly after BMT. All patients infected before BMT died within 10 weeks after transplantation. Five of these six patients (83%) died of veno-occlusive disease (VOD), compared with nine of 52 patients (17%) not infected with HCV (P < .005). Risk factors for VOD other than HCV were not more prevalent in these patients compared with uninfected patients. Parallel to the development of VOD, replication of HCV increased, as demonstrated by rising concentrations of viral RNA in serum. HCV infection acquired during or after BMT caused only mild acute hepatitis C, which progressed to chronic hepatitis C in one patient surviving 10 years after BMT. These data suggest that patients with liver disease caused by HCV infection are at high risk of developing lethal VOD after BMT.

A symptomatic papillary fibroelastoma of the left ventricle removed with the aid of transesophageal echocardiography.

A papillary fibroelastoma, causing amaurosis fugax and paresis of the right arm, was detected by echocardiography as a free floating mass in the left-ventricular outflow tract. Based on the exact localization of the tumor by intraoperative transesophageal echocardiography the initial indication for ventriculotomy was disregarded and an atraumatic transvalvular approach was chosen.

Experimental Yersinia enterocolitica infection in euthymic and T-cell-deficient athymic nude C57BL/6 mice: comparison of time course, histomorphology, and immune response.

To elucidate the role of T lymphocytes in primary infection with Yersinia enterocolitica, we investigated the elimination rate of this pathogen, the histomorphology of tissue lesions, and the immune responses of athymic T-cell-deficient C57BL/6 nude mice and their euthymic littermates after parenteral infection with Y. enterocolitica of serotype O:8. While a low inoculum of 3 x 10(2) Y. enterocolitica cells (about 0.01 times the median lethal dose for normal C57BL/6 mice) was cleared by normal C57BL/6 mice within 7 to 10 days, athymic nude C57BL/6 mice developed progressive infections after this inoculum, leading to death on days 20 to 25 postinfection (p.i.). While normal C57BL/6 mice experienced short-term transient infections, nude mice exhibited a biphasic, progressive infectious process. Thus, in the early phase (days 1 to 7 p.i.), a rapid influx of CD11b/18-positive cells (Mac-1 antigen) and natural killer cells was evident in the spleens and livers of the nude mice. The late phase (from day 8 p.i. onward) was characterized by a rapid progression of the infection and a further influx of CD11b/18-positive cells into the liver accompanied by an increase in bacterial counts and development of tissue lesions particularly in the liver and spleen. In normal mice, granuloma-like lesions composed of CD11b/18-, CD4-, and CD8-positive cells could be observed. However, granulomata were not found in nude mice. Yersinia-specific immunoglobulin G antibodies appeared on day 15 p.i. in the sera of normal mice, while nude mice failed to develop significant antibody titers. Adoptive transfer of Yersinia-specific T cells into athymic nude mice mediated resistance to Y. enterocolitica infection and restored both the ability of granuloma formation and the production of specific antibodies. In summary, the data presented herein strongly suggest that T lymphocytes play an essential role in the defense of C57BL/6 mice against Y. enterocolitica.

The cellular immune response against Yersinia enterocolitica in different inbred strains of mice: evidence for an important role of T lymphocytes.

Resistance of mice against infection with Yersinia enterocolitica has been shown to be related neither to the Ity locus coding for resistance against infection with Salmonella typhimurium and other pathogens nor to the H-2 locus. From other mouse infection models, e.g., murine leishmaniasis, there is evidence that a different T cell-dependent regulation of the host immune response in various inbred strains of mice determines the susceptibility to the infectious agent. However, until recently, little was known about the cellular immune response against Y. enterocolitica. Thus, in a first approach we used the highly virulent Y. enterocolitica strain WA of serotype O:8 and different inbred strains of mice (C57 BL/6, Balb/c and athymic T cell-deficient C57 BL/6 nude mice) to investigate the cell-mediated immunity against parenteral infection. Comparison of the median lethal dose and of the net-bacterial growth in the spleens of infected mice indicated that Balb/c mice could be considered as Yersinia-susceptible whereas C57 BL/6 mice were relatively resistant. However, in contrast to normal C57 BL/6, athymic T cell-deficient C57 BL/6 nude mice have proved to be highly susceptible to Yersinia infection suggesting that T cells are required for the elimination of the pathogen. This conclusion was supported by histomorphological and immunohistological results indicating that T lymphocytes were present in Yersinia-induced tissue lesions. Moreover, the adoptive transfer of Yersinia-specific T cell lines and clones into naive animals mediated significant protection against the pathogen in both Yersinia-resistant C57 BL/6 and in Yersinia-susceptible Balb/c mice. These findings emphasize an important role of T lymphocytes in the host response against Y. enterocolitica infection.

[Idiopathic ulcer of the small intestine]. / Idiopathisches Dünndarmulcus.

The authors report on a female patient, 32 years old, suffering for eight years from recurrent and progressive abdominal pain, combined with chronic anemia, due to iron deficiency. Neither anamnesis and clinical course, nor technical examinations elucidated the etiology. Finally an explorative laparotomy with segmental resection of the small intestine led to diagnosis and healing of the rare "idiopathic small bowel ulcer". Possible differential diagnoses were lacking. This case report demonstrates the need of an invasive and aggressive diagnostic approach after excluding all common causes of disease, related to the symptoms, in order to prevent patients from suffering for years.