Dual role of the IL-12/IFN-gamma axis in the development of autoimmune myocarditis: induction by IL-12 and protection by IFN-gamma.

IL-12 and IFN-gamma positively regulate each other and type 1 inflammatory responses, which are believed to cause tissue damage in autoimmune diseases. We investigated the role of the IL-12/IFN-gamma (Th1) axis in the development of autoimmune myocarditis. IL-12p40-deficient mice on a susceptible background resisted myocarditis. In the absence of IL-12, autospecific CD4(+) T cells proliferated poorly and showed increased Th2 cytokine responses. However, IFN-gamma-deficient mice developed fatal autoimmune disease, and blockade of IL-4R signaling did not confer susceptibility to myocarditis in IL-12p40-deficient mice, demonstrating that IL-12 triggers autoimmunity by a mechanism independent of the effector cytokines IFN-gamma and IL-4. In conclusion, our results suggest that the IL-12/IFN-gamma axis is a double-edged sword for the development of autoimmune myocarditis. Although IL-12 mediates disease by induction/expansion of Th1-type cells, IFN-gamma production from these cells limits disease progression.

Human leukocyte antigen G up-regulation in lung cancer associates with high-grade histology, human leukocyte antigen class I loss and interleukin-10 production.

Immune evasion in lung cancer results from both structural and functional alterations of human leukocyte antigen (HLA) class I molecules and the local release of immunosuppressive cytokines. Recent data suggest that HLA-G, a nonclassical class Ib molecule, is involved in immune evasion by tumor cells. We sought to determine whether HLA-G could contribute to immunescape in lung cancer. All of 19 tumor specimens examined demonstrated detectable membrane-bound (HLA-G1), as well as soluble (HLA-G5) isoform transcription. Nine of 34 (26%) tumors were positive by immunohistochemistry using monoclonal antibody (mAb) 4H84, recognizing all denatured HLA-G isoforms, of which six were positive using mAb 16G1, recognizing soluble HLA-G. HLA-G immunoreactivity correlated with high-grade histology, with HLA-G being preferentially expressed on large-cell carcinomas. In these patients, loss of classical HLA class I molecules was observed to associate with HLA-G protein up-regulation. Moreover, we found interleukin-10 expressed in 15 of 34 (44%) tumors, and in most of the HLA-G-positive cases (7 of 9), suggesting up-modulation of HLA-G by interleukin-10. It is conceivable that HLA-G expression in lung cancer might be one of the ways how the tumor down-regulates host immune response, in addition to interleukin-10 production and HLA class I loss.

[Malignant lymphoma of the larynx: a case report and review of the literature]. / Das maligne Lymphom des Larynx: Fallbericht und Literaturübersicht.

BACKGROUND: Malignant lymphoma of the larynx are rare tumors and represent less than 1% of primary malignant laryngeal tumors. CASE REPORT: In this case report we present a case of a diffuse large B-cell lymphoma of the larynx. Clinical presentation, diagnostic approach, staging and differential diagnosis as well as therapy and prognosis are discussed in relation to the available literature. CONCLUSIONS: Lymphomas primary to the larynx are non-Hodgkin-lymphomas and are predominantly located in the supraglottic larynx. The presenting symptoms and signs include dysphagia, dysphonia, dyspnea which on occasion can be severe, and enlarged cervical lymphoma. B-symptoms are mostly not present. Indirect laryngoscopy reveals a globoid submucosal faintly pink tumor mass. The diagnosis rests on histological examination of a biopsy specimen. Benign tumors, squamous cell carcinoma and other lymphoproliferative diseases have to be excluded from the differential diagnosis. Extensive tumor staging is necessary before radiotherapy or chemotherapy. Surgery is not indicated, even in localized disease. Prognosis is good in the most often localized laryngeal non-Hodgkin-lymphomas (stage IE and IIE) and generalization is rare. Hence, supraglottic submucosal laryngeal tumors can represent non-Hodgkin-lymphomas. Biopsy and subsequent histological examination are essential for correct diagnosis.

[Diagnosis and course of myocarditis: a survey in the medical clinics of Zurich University Hospital 1980 to 1998]. / Diagnose und Verlauf bei Myokarditis: eine Erhebung in den Medizinischen Kliniken des Universitätsspitals Zürich im Zeitraum von 1980 bis 1998.

The clinical picture of myocarditis/myopericarditis is of importance in differential diagnosis, especially in younger patients with suspected myocardial infarction. Myocarditis/myopericarditis commonly presents with chest pain, and the diagnosis is usually established on clinical grounds. However, endomyocardial biopsy is necessary to confirm the diagnosis. We evaluated the characteristics of acute myocarditis over the years 1980-1998 in 54 patients of the Department of Medicine of the University Hospital, Zurich. Two to 6 patients per year were hospitalised with this diagnosis. In most cases the diagnosis was established by a combination of criteria, such as a preceding infection of the upper respiratory tract, thoracic pain, ST segment elevations in different precordial leads followed by T wave inversions, arrhythmias, elevation of cardiac enzymes, reversible hypokinesia by echocardiography and normal coronary arteries. At least 3 of 5 criteria were requested. In a first step we analysed retrospectively all patients with acute myocarditis/myopericarditis in the years 1980-1993. Among 30 cases of acute myocarditis/myopericarditis the following causes could be identified: one influenza B, one Toxoplasma gondii infection, 2 Epstein-Barr infections and one bacterial myocarditis with gram-negative rods. The aetiology of the other 25 cases remained unknown. The majority of myocarditis/myopericarditis healed without complications. One patient with Epstein-Barr myocarditis and one with Toxoplasma gondii infection died. Two patients developed dilated cardiomyopathy. In a second phase we analysed prospectively all cases with acute myocarditis/myopericarditis over the period 1994-1998: 24 patients with acute myocarditis/myopericarditis were hospitalised. At that time coronary angiography and endomyocardial biopsies were performed more frequently. We found 2 patients with giant cell myocarditis and 2 with Toxoplasma gondii infection and HIV, all of whom died. In addition, there were 2 patients with eosinophilic myocarditis, one with Lyme carditis, one with Epstein-Barr myocarditis, one with myopericarditis after Campylobacter enteritis and one histologically proven myocarditis after pneumonia with Haemophilus influenzae. The aetiology of the remaining 13 cases with myocarditis/myopericarditis could not be established. Three patients with probable viral myocarditis developed cardiogenic shock requiring intraaortic balloon pump, and fully recovered. The patient with Lyme carditis manifested with total atrioventricular block and was treated with a temporary pacemaker. One patient with lymphocytic myocarditis required heart transplantation because of terminal heart failure and one female patient with histologically proven diffuse lympho-monocytic myocarditis died of cardiogenic shock. All the other cases healed without complications. Serologies are of little diagnostic value and should be restricted to serologies with therapeutic implications. We believe that the apparent increase in myocarditis/myopericarditis in recent years is a result of better diagnostic tools, such as more specific cardiac enzyme tests, coronary angiography and endomyocardial biopsies. In most cases the therapy remains symptomatic. In elected, severe cases steroids and other immunosuppressive drugs are sometimes used.

Malakoplakia of the colon in an infant with severe combined immunodeficiency (SCID) and charge association.

We report on malakoplakia of the colon observed in a six month old girl in a setting of severe combined immunodeficiency (SCID) and a malformational syndrome termed CHARGE association. By the age of six months, hemorrhagic diarrhea had developed, and multiple ulcers were seen at colonoscopy. The biopsy specimen showed ulcerating malakoplakia. Immunodeficiency was primarily reflected by deprivation of CD4 cells in the peripheral blood, and CT scans failed to detect structures consistent with a normal thymus. There were also polylymphadenopathy and chronic erythroderma. The lymph node showed extreme hypoplasia of the follicular cortex and marked expansion of the paracortex. B cell counts progressively declined, and plasma cells were absent both in intact mucosa of the colon and in a lymph node. The patient died at eighteen months of respiratory failure following recurrent airway infections. Pediatric malakoplakia of the colon, though rare, may be regarded as an example of opportunistic bacterial infection in an immunocompromised host. Combined immunodeficiency (CID) has to be considered in such instances, in particular when malformational syndromes coexist affecting the development of the thymus.

Primary cutaneous T-cell-rich B-cell lymphoma and Hodgkin's disease in a patient with Gardner's syndrome.

A 50-year-old patient, suffering from familial polyposis (Gardner's syndrome), initially presented with several nodules on his left arm. Histological examination revealed primary cutaneous T-cell-rich B-cell lymphoma (TCRBCL). Staging procedures failed to detect any systemic involvement. Three years after total excision of the tumours, the patient presented with a non-specific dermatitis, enlarged axillary lymph nodes and splenomegaly. Histological and immunohistochemical examination of lymph node and spleen biopsy specimens resulted in the diagnosis of Hodgkin's disease (HD) of the nodular sclerosis type. Sequence analysis of single cells micromanipulated from skin and from lymph node lesions indicated that both lymphoma infiltrates were derived from the same precursor germinal centre B-cell clone. This is a case showing a clonal relationship between TCRBCL and HD, providing support to the B-cell origin of Hodgkin and Reed-Sternberg cells.

Selection and immunomagnetic purging of peripheral blood CD34+ cells for autologous transplantation in B-cell non-Hodgkin's lymphomas.

BACKGROUND: Clonogenic tumor cells in the hematopoietic progenitor cell harvest may contribute to relapse after high dose therapy for B-cell malignancies. Purging of the HPC harvest requires large amounts of anti-B-cell antibodies, whereas CD34-selection enriches self renewing HPC's but malignant cells are still detectable in many CD34+ fractions. PATIENTS AND METHODS: We examined the feasibility and safety of a CD34-selection followed by purging with anti B-cell antibodies in 11 patients with B-cell non-Hodgkin's lymphomas undergoing high-dose therapy with cyclophosphamide, BCNU and etoposide with retransfusion of autologous HPC's. RESULTS: A mean number of 340 x 10(8) mononuclear cells was used for CD34-selection and immunomagnetic purging. CD34+ cells were enriched from a mean of 1.7% (range 0.2%-4.5%) to a mean of 68% (range 49%-87%) with a mean recovery of 27% (range 15%-43%). The mean number of retransfused CD34+ cells was 1.2 x 10(6)/kg (range 0.6-2.2 x 10(6)/kg) body weight with a median of 11 days (range 10-13 days) to neutrophil recovery of 0.5 x 10(9)/l and 17 days (range 13-25 days) to platelet recovery of 50 x 10(9)/l. Mean number of intravenous antibodies and inpatient days were 8 (range 0-14) and 22 (range 19-26) respectively. Major toxicity consisted in four septicemias. CONCLUSIONS: CD34-selected and purged HPC's are safe and mediate rapid hematological recovery after high dose therapy for B-cell non-Hodgkin's lymphomas.

Congenital pancreatic pseudocyst: report of two cases.

Pancreatic pseudocysts have not been reported to occur in the fetus or newborn. The authors report two cases of histologically proven pancreatic pseudocysts in neonates, which were detected using prenatal ultrasonography. Surgical management included external marsupialization followed by internal drainage in one case, and excision in the other. Both patients ultimately did well. The etiology of these lesions remains unclear.

Magnetic resonance imaging and intraoperative frozen sections in intratemporal facial schwannomas.

Seven cases of intratemporal facial schwannoma were assessed by preoperative magnetic resonance imaging (MRI) and intraoperative frozen sections to determine tumor boundaries. These results were then analyzed with respect to gross tumor appearance, under the operating microscope, and final histopathologic diagnosis, with immunostains. Gadolinium-enhanced MRI was helpful in planning the surgical and approach and in defining the extent of tumor involvement relative to the facial nerve. Frozen sections on the other hand were often unreliable in confirming the completeness of resection, frequently overestimating tumor infiltration. Ultimately, tumor-nerve interface, especially in the proximal facial segments, is best judged by its gross intraoperative appearance under high magnification, with the aid of MRI. The difficulty in establishing tumor infiltration in the presence of organized neutral fibers and artifacts is emphasized. Immunohistochemical assays are essential in this regard. Complete tumor removal was achieved in all seven cases, with acceptable functional outcome in those with sufficiently long follow-up.