[Radical pleurectomy and hyperthermic intrathoracic chemotherapy for treatment of thymoma with pleural spread]. / Radikale Pleurektomie und hypertherme intrathorakale Chemotherapie zur Behandlung pleural metastasierter Thymome.

INTRODUCTION: Patients with pleural thymoma spread (Masaoka stage IV a) should be treated within a multimodal treatment regime. However, the extent of local surgical resection to achieve optimal tumour control remains controversial. PATIENTS AND METHODS: Prospective analysis between September 2008 and April 2013 of all patients with a Masaoka stage IV a thymoma, who underwent radical pleurectomy/decortication (P/D) followed by hyperthermic intrathoracic chemotherapy (HITHOC). RESULTS: A total of 11 patients (male n = 7; mean age 46.5 ± 11.4 years) with a primary stage IV a thymoma (n = 3) or thymoma with pleural relapse (n = 8) were included after successful transsternal thymoma resection. WHO histological classification was: B1 n = 1, B2 n = 6, B3 n = 3 and C n = 1. A radical P/D (5/11; 45 %) was extended with resection of the pericardium and diaphragm in 6/11 (55 %) patients. After surgical resection (91 % complete macroscopic R0/R1-resection) the HITHOC with cisplatin (100 mg/m2 body surface area (BSA) n = 7; 150 mg/m2 BSA n = 4) was performed for one hour at 42 °C. Operative revision was necessary in two patients (chylo- and hematothorax) with one patient also requiring temporary renal replacement therapy due acute renal failure (cisplatin 150 mg/m2 BSA). 30-day mortality was 0 %. Local recurrence (pulmonary n = 1, paravertebral n = 2) was documented in 3/10 (30 %) patients after R0/R1 resection. After a mean follow-up of 23 months the overall median survival was 27 months and 82 % (9/11) patients are still alive at the end of the study period. CONCLUSIONS: Masaoka stage IV a thymoma could be safely treated with lung-sparing radical P/D and HITHOC with cisplatin in a multimodality treatment regime. Early results with respect to recurrence and survival are encouraging, but further studies are warranted and we have to await long-term results.

Local and systemic exposure of cisplatin during hyperthermic intrathoracic chemotherapy perfusion after pleurectomy and decortication for treatment of pleural malignancies.

BACKGROUND: Assessing the pharmacokinetics of intrapleurally administered cisplatin during hyperthermic intrathoracic chemotherapy perfusion (HITHOC) following pleurectomy/decortication in patients with malignant pleural mesothelioma or advanced thymoma with pleural spread. METHODS: Pharmacokinetic analysis (ICP-MS) of intrapleural cisplatin with a dosage of 100 mg/m(2) (n = 5) or 150 mg/m(2) (n = 5) at 42°C perfusate temperature. Simultaneous pleural perfusion fluid and serum samples were collected at the beginning and every 15 min. Serum samples were collected at the end of the operation, 6, 12, and 24 hr postoperative. RESULTS: Mean cisplatin levels in the perfusate slightly decreased during the HITHOC. The mean area under the curve ratios (AUC perfusate :AUC serum ) of cisplatin were nearly similar. The mean AUCs of cisplatin in the perfusate were approximately 58 and 55 times greater than detected in the serum. The mean peak of cisplatin in the serum was reached after 1 hr of HITHOC. The AUC of cisplatin in the serum did not significantly differ (P = 0.18) between both groups up to 24 hr after perfusion. CONCLUSIONS: HITHOC with cisplatin provides a pharmacological advantage of high local intrapleural cisplatin concentrations. Elevation of the cisplatin dosage to 150 mg/m(2) did not lead to a significant increase of the systemic cisplatin concentration.

Surgical resection of thymoma still represents the first choice of treatment.

OBJECTIVE: The aim of this study was to analyze the clinicopathological factors, treatment strategies and survival rates after surgical resection of thymoma. METHODS: Between 12/1997 and 5/2010, 42 patients underwent surgical resection of the thymus. The presence of a thymoma was determined by histological examination in 23 patients, while patients with hyperplasia of the thymus (n = 19) were excluded from further analysis. RESULTS: Myasthenia gravis coexisted in 9/23 (39.1%) patients. Thymomas were classified according to the Masaoka staging system (I: n = 6 [26.1%], IIa: n = 7 [30.4%], IIb: n = 2 [8.7%], III: n = 1 [4.4%], IVa: n = 7 [30.4%]) and the WHO histological classification (A: n = 4 [17.4%], AB: n = 5 [21.7%], B1: n = 1 [4.4%], B2: n = 8 [34.8%], B3: n = 3 [13%], C: n = 2 [8.7%]). Recurrence of thymoma was documented in three (13%) patients. After a mean follow-up of 58.4 months, 21 (91.3%) patients are alive. The overall survival rate was 95% and 87.8%, at 2 and 5 years, respectively. The disease-free interval at 5 years was 85% for the 17 (73.9%) patients with complete resection. CONCLUSIONS: Surgical resection of thymoma is the preferred treatment, because it is safe and effective with a low rate of recurrence and a good long-term survival. Advanced and invasive thymomas require a multimodal approach for better local tumor control and further improvement of prognosis.

Thymoma and paraneoplastic myasthenia gravis.

Paraneoplastic autoimmune diseases associate occasionally with small cell lung cancers and gynecologic tumors. However, myasthenia gravis (MG) occurs in at least 30% of all patients with thymomas (usually present at MG diagnosis). These epithelial neoplasms almost always have numerous admixed maturing polyclonal T cells (thymocytes). This thymopoiesis-and export of mature CD4(+)T cells-particularly associates with MG, though there are rare/puzzling exceptions in apparently pure epithelial WHO type A thymomas. Other features potentially leading to inefficient self-tolerance induction include defective epithelial expression of the autoimmune regulator (AIRE) gene and/or of major histocompatibility complex class II molecules in thymomas, absence of myoid cells, failure to generate FOXP3(+) regulatory T cells, and genetic polymorphisms affecting T-cell signaling. However, the strong focus on MG/neuromuscular targets remains unexplained and suggests some biased autoantigen expression, T-cell selection, or autoimmunization within thymomas. There must be further clues in the intriguing serological and cellular parallels in some patients with late-onset MG but without thymomas-and in others with AIRE mutations-and in the contrasts with early-onset MG, as discussed here.

The PTPN22gain-of-function+1858T(+) genotypes correlate with low IL-2 expression in thymomas and predispose to myasthenia gravis.

Protein tyrosine phosphatase, non-receptor type 22 (PTPN22) inhibits T-cell activation and interleukin-2 (IL-2) production. The PTPN22(gain-of-function)+1858T(+) genotypes predispose to multiple autoimmune diseases, including early-onset (non-thymomatous) myasthenia gravis (MG). The disease association and the requirement of IL-2/IL-2 receptor signaling for intrathymic, negative T-cell selection have suggested that these genotypes may weaken T-cell receptor (TCR) signaling and impair the deletion of autoreactive T cells. Evidence for this hypothesis is missing. Thymoma-associated MG, which depends on intratumorous generation and export of mature autoreactive CD4(+) T cells, is a model of autoimmunity because of central tolerance failure. Here, we analyzed the PTPN22 +1858C/T single nucleotide polymorphism in 426 German Caucasian individuals, including 125 thymoma patients (79 with MG), and investigated intratumorous IL-2 expression levels. Unlike two previous studies on French and Swedish patients, we found strong association of PTPN22 +1858T(+) genotypes not only with early-onset MG (P=0.00034) but also with thymoma-associated MG (P=0.0028). IL-2 expression in thymomas with PTPN22 +1858T(+) genotypes (P=0.028) was lower, implying weaker TCR signaling. We conclude that the PTPN22(gain-of-function) variant biases towards MG in a subgroup of thymoma patients possibly by impeding central tolerance induction.

Deficiency of the autoimmune regulator AIRE in thymomas is insufficient to elicit autoimmune polyendocrinopathy syndrome type 1 (APS-1).

Thymomas are thymic epithelial neoplasms, associated with a variety of autoimmune disorders (especially myasthenia gravis), that apparently result from aberrant intra-tumourous thymopoiesis and export of inefficiently tolerized T-cells to the periphery. The autoimmune regulator (AIRE) drives the expression of self-antigens in the thymic medulla and plays an essential role in 'central' tolerance in both humans and mice. However, while inactivating AIRE mutations result in the 'autoimmune polyendocrinopathy syndrome type 1' (APS-1), its major features are not well reproduced in AIRE-knock-out mice. Therefore, alternative human disease scenarios with concomitant AIRE deficiency may be valuable tools to test conclusions drawn from mouse models. Here we show, in a large series, that approximately 95% of thymoma patients are 'chimeric'; expression of AIRE and major AIRE-related autoantigens (eg insulin) were undetectable in their tumours but maintained in their remnant thymic tissue and lymph nodes. Notably, despite the AIRE-deficient thymopoiesis in thymomas, disorders and autoantibodies typical of APS-1 were distinctly uncommon in these patients. The one striking similarity was in the recently observed neutralizing anti-type I interferon (IFN) antibodies, which are found at diagnosis in 100% of patients with APS-1 and in approximately 60% of patients with thymomas, as we show here. We conclude that APS-1 type autoantigens must be protected from autoimmunity by mechanisms that do not extend to the muscle autoantigens so frequently targeted in thymoma patients but so rarely recognized in APS-1. Thus our findings argue strongly for a tolerogenic function of AIRE beyond its role in negative T-cell selection in human thymopoiesis, and/or for specific autoimmunization against muscle in thymomas.

Dynamic and three-dimensional transcranial ultrasonography of an arachnoid cyst in the cerebral convexity. Technical note.

Structural imaging of the brain, such as cerebral computerized tomography (CT) and magnetic resonance (MR) imaging, is state-of-the-art. Dynamic transcranial (dTC) ultrasonography and three-dimensional (3D) transcranial color-coded duplex (TCC) ultrasonography are complementary, noninvasive procedures with the capacity for real-time imaging, which may aid in the temporary management of space-occupying lesions. A 16-year-old woman presented with recurrent tension-type headaches. A space-occupying arachnoid cyst in the cerebral convexity was demonstrated on MR images. The patient underwent an examination for raised intracranial pressure. which was performed using a standard color-coded duplex ultrasonography system attached to a personal computer-based system for 3D data acquisition. Transcranial ultrasonography was used to identify the outer arachnoid membrane of the cyst, which undulated freely in response to rotation of the patient's head (headshake maneuver). Three-dimensional data sets were acquired and, using a multiplanar reformatting reconstruction algorithm, the authors obtained high-resolution images that corresponded to the initial MR image and a follow-up cranial CT scan. No detectable differences were observed on dTC or 3D TC ultrasonograms obtained at follow-up examinations performed 9 and 28 months later. Three-dimensional TCC and dTC ultrasonography may complement conventional diagnostic procedures such as MR and CT imaging. This report represents evidence of the high resolution and good reproducibility of 3D TC methods. Ultrasonography is a mobile and inexpensive tool and may be used to improve management and therapeutic strategies for patients with space-occupying brain lesions in selected cases.

Thymomas alter the T-cell subset composition in the blood: a potential mechanism for thymoma-associated autoimmune disease.

Thymomas are the only tumors that are proven to generate mature T cells from immature precursors. It is unknown, however, whether intratumorous thymopoiesis has an impact on the peripheral T-cell pool and might thus be related to the high frequency of thymoma-associated myasthenia gravis. This study shows, using fluorescence-activated cell sorting-based analyses and T-cell proliferation assays, that thymopoiesis and T-cell function in thymomas correspond with immunologic alterations in the blood. Specifically, the proportion of circulating CD45RA(+)CD8(+) T cells is significantly increased in patients with thymoma compared with normal controls, in accordance with intratumorous T-cell development that is abnormally skewed toward the CD8(+) phenotype. Moreover, it is primarily the proportion of circulating CD45RA(+)CD8(+) T cells that decreases after thymectomy. The results also demonstrate that T cells reactive toward recombinant autoantigens are distributed equally between thymomas and blood, whereas T-cell responses to foreign antigen (ie, tetanus toxoid) are seen only among circulating T cells and not among thymoma-derived T cells. These functional studies support the hypothesis that thymopoiesis occurring within thymomas alters the peripheral T-cell repertoire. Because many thymomas are enriched with autoantigen-specific T cells, a disturbance of circulating T-cell subset composition by export of intratumorous T cells may contribute to paraneoplastic autoimmune disease arising in patients with thymoma. (Blood. 2000;96:3872-3879)

Acute deterioration of Charcot-Marie-Tooth disease IA (CMT IA) following 2 mg of vincristine chemotherapy.

BACKGROUND: Severe up to life-threatening neuropathy has been observed in patients with hereditary neuropathies receiving vincristine. CASE REPORT: A 52-year-old female painter suffering from high-grade non-Hodgkin's lymphoma (stage IVB) was treated with a total of 4 mg of vincristine during two courses of CHOP chemotherapy (cyclophosphamide, vincristine, adriamycin, prednisone). At onset of treatment no neurological problems were reported. There was good lymphoma response to chemotherapy. At the same time, however, the patient gradually developed dysphagia, dysarthria, muscular weakness of both lower and upper extremities, areflexia, paraesthesia of the fingertips and bilateral sensory impairment of feet and lower legs. These symptoms continually worsened over a period of seven weeks until she was unable to walk or to perform her work. Electrophysiological studies showed peripheral axonal and demyelinative sensorimotor neuropathy in correlation to histological findings. Molecular analysis revealed 17p11.2 duplication typical for Charcot-Marie-Tooth disease IA. While continuing chemotherapy without the use of vincristine the patient's neurologic symptoms slowly recovered within six months. CONCLUSION: Prior to administration of vincristine family and patient history as well as physical examination should be performed carefully to look for underlying hereditary neuropathy. For those patients with a clinical history or symptoms suggestive for CMT nerve conduction velocity studies and on an individual base even molecular genetic analysis are necessary to prevent serious neurologic complications. worsened significantly resulting in dependency on a wheelchair and inability to perform her work as a painter. Finally she consulted a neurologist and was admitted to hospital for further diagnostic studies and continuation of treatment for her lymphoma in March 1998 with a provisional diagnosis of severe vincristine-induced neuropathy. Medical history at time of admission included hyperthyroidism, that was currently treated with propylthiouracil, a MALT lymphoma 1983, that was treated surgically only, and a meningoencephalitis in 1968. No further medication was taken. In addition she had a history of Lyme disease since 1993 with positive IgM-titer until December 1997, when antibiotic therapy with doxycycline and ceftriaxone was administered successfully. Family history obtained on admission revealed that her mother had non-specific neuropathic symptoms as well as a poorly defined foot deformities of the mother's father. The patient's brother does not show any neurologic impairment and is in good physical health.

Somatostatin receptor scintigraphy in thymoma imaging method and clinical application.

Somatostatin receptor scintigraphy with 111In-[DTPA-D-Phe1]-octreotide has the potential for visualizing primary and recurrent thymomas in patients with myasthenia gravis, whereas thymic hyperplasias fail to accumulate somatostatin analog peptides. We demonstrate somatostatin receptor imaging findings in a patient with a mixed encapsulated thymoma which exhibited intense 111In-[DTPA-D-Phe1]-octreotide uptake in early and late scans. In another patient with a history of malignant thymoma 111In-[DTPA-D-Phe1]-octreotide accumulation was clearly seen in a mass suspected to be a recurrence. This paper describes the imaging protocol including Single Photon Emission Computed Tomography (SPECT) and discusses the clinical applications of this feasible functional imaging method in patients with thymomas.

Neurofilament is an autoantigenic determinant in myasthenia gravis.

Intratumorous expression of a 153-kd protein (p153), which contains an acetylcholine receptor-like epitope, is the only tumor marker described to date that significantly associates with thymoma in paraneoplastic myasthenia gravis (MG). Here, we report that p153 is identical to the midsize neurofilament, as verified by immunohistochemistry, immunofluorescence, and western blot analysis. Furthermore, the acetylcholine receptor-like epitope of the midsize neurofilament (NF-M) was identified by peptide epitope mapping. We also show, using T-cell proliferation assays, a significantly increased response of intratumorous T cells to a recombinant midsize neurofilament fragment in thymoma patients with MG compared with MG patients with thymic follicular hyperplasia or thymoma patients without MG. The T cells of thymic follicular hyperplasia and thymoma patients without MG seem to be unresponsive to NF-M. In contrast, we found increased T-cell responses to recombinant acetylcholine receptor fragments in MG patients in general compared with non-MG patients. Increased T-cell responses to NF-M in patients with paraneoplastic MG might be the result of an abnormal positive selection of immature T cells within thymomas, caused by the expression of NF-M in neoplastic thymic epithelial cells. Our results offer further evidence that NF-M expression in thymomas is an autoantigenic determinant in MG.

Association of acetylcholine receptor alpha-subunit gene expression in mixed thymoma with myasthenia gravis.

OBJECTIVE: To investigate the association of MG with the transcription of muscular or neuronal acetylcholine receptor (AChR) subunit genes in thymomas. BACKGROUND: Many steps in the pathogenesis of MG have been elucidated but, with rare exceptions, its etiology is unknown. In patients with MG with thymoma, the tumor probably elicits autoimmunity to AChR, but it is enigmatic why MG develops in some patients but not in others. METHODS: Reverse transcriptase (RT)-PCR, immunohistochemistry, and immunofluorescence studies were carried out to investigate AChR expression in 35 patients with thymoma. Statistical analysis was used to specify significant differences between thymoma subtypes. RESULTS: Considering all thymomas (n = 35), no correlation was found between MG status and AChR gene expression as detected by RT-PCR. However, when histologically defined thymoma subtypes were studied separately, transcription of the muscular AChR P3A- alpha-subunit gene was significantly associated (alpha < 0.01) with the occurrence of MG in mixed thymomas (n = 17), but not in thymomas of the cortical type. For the other muscular AChR subunits (P3A+ alpha isoform, beta, gamma, delta, and epsilon) and the alpha2 and beta4 neuronal AChR subunits, no such correlation was detected. CONCLUSIONS: Expression of the P3A AChR alpha-subunit gene might be important for the pathogenesis of MG in mixed thymomas, suggesting etiologic heterogeneity of paraneoplastic MG among patients with histologically different thymoma subtypes.

Abnormal thymocyte development and generation of autoreactive T cells in mixed and cortical thymomas.

To gain insight into the pathogenesis of thymoma-associated myasthenia gravis, thymocyte maturation was investigated in mixed and cortical thymomas by three-color flow cytometry. Although we detected cells at all recognizable stages, we noted an unusual increased percentage of early CD4+/CD3- thymocytes--especially in mixed thymoma--and a pronounced decreased percentage of mature CD4+/CD3+ cells in cortical thymomas as well. The percentage of CD3+/CD69+ cells that arose after positive selection was reduced in both thymoma subtypes compared with control thymuses, which suggests differences in the rate or efficiency of positive selection particularly in mixed thymomas. Mature T cells in 10 of 11 thymomas were not activated in situ as shown by the absence of CD25 expression. After stimulation with recombinant human acetylcholine receptor alpha-subunit fragments, thymocytes from 8 of 11 thymomas of both subtypes proliferated more strongly than those from controls, regardless of whether the donors were myasthenic. Responses of residual thymus cells to tetanus toxoid correlated well with those of autologous blood T cells, whereas those from the thymomas clearly did not--implying minimal colonization of thymomas by mature recirculating T cells. In conclusion, our results show that cortical and mixed thymomas exhibited differences in thymocyte maturation. Nevertheless, both thymoma subtypes seem to contribute to the pathogenesis of paraneoplastic myasthenia gravis by generating naive but potentially autoaggressive T cells; in some thymomas, these cells may then be actively immunized inside the tumor.

[Follow-up of myasthenia gravis. Results of a longitudinal study of the significance of psychosocial predictors]. / Krankheitsverlauf bei Myasthenia gravis. Ergebnisse einer Längsschnittstudie zur Bedeutung psychosozialer Prädiktoren.

Forty-two patients suffering from myasthenia gravis were examined in a longitudinal study design. The aim of the study was to investigate possible psychosocial predictors for the course of the disease. At the time of the first examination (T1) the diagnosis myasthenia gravis had been established for no longer than 1 year. Two further examinations were done at 6 months (T2) and 18 months (T3) after T1. Methods consisted of a personality questionnaire (FPI), a coping questionnaire (FKV), an assessment of neurotic symptoms by interviewers (PSKB) and an assessment of the doctor-patient relationship by the attending physicians. Two different severity scores (Oosterhuis Index, Myasthenia Score) served as criteria for the course of the disease. There was no connection between the course of myasthenia gravis and neurotic symptoms like anxiety or depression and the quality of the doctor-patient relationship (both assessed at T1). Also demographic data were independent from the development of severity scores. The personality factor extraversion was associated with a positive course of the disease, aggressiveness and worrying about health with a negative one. Among the coping behaviors religiousness and looking for sense were associated with a favorable course but that was shown only regarding the Oosterhuis Index and not the Myasthenia Score. As several T1 personality factors were predictive for the severity scores at T3, these results may suggest a causal influence of personality factors on the severity of the illness. Whether or not this relationship is actually in operation, however, remains ellusive. Further studies using an experimental design are needed to strengthen this hypothesis.

Chronic inflammatory demyelinating polyradiculoneuropathy: superiority of protein A immunoadsorption over plasma exchange treatment.

We present a patient with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) who was treated regularly with plasma exchanges (PE) because response to other therapies including i.v. immunoglobulins was not adequate. To reduce nonspecific protein losses due to repeated PE and increase IgG-removal, immunoadsorption (i.a.)-therapy using sepharose-bound protein A was initiated. Retrospective analysis of clinical data including muscle strength and walking distance shows that IA led to more rapid and greater functional improvement than PE in this patient with no relevant side effects. After 3 years of therapy lymphoma was diagnosed and treated. The patient had no relapses of CIDP for 17 months, when his functional status deteriorated again necessitating further IA-therapy. It is concluded that IgG removal by IA in CIDP is more effective and has fewer complications than PE. Due to the chronic course of CIDP requiring repeated interventions IA is also not more expensive than PE.

Outcome in juvenile-onset myasthenia gravis: a retrospective study with long-term follow-up of 79 patients.

Randomised and controlled treatment studies of juvenile-onset myasthenia gravis have not been published. We therefore report our retrospective analysis of 79 patients with juvenile-onset myasthenia gravis observed for as long as 30 years. The mean age at onset was 13.7 years and median follow-up 7.7 years. The initial presentation was generalised disease in 90% and ocular disease in the remaining patients. Sixty-five patients (82%) were thymectomised. In 14 of these, treatment consisted of a combination of azathioprine (2-3 mg/kg), corticosteroids (prednisolone up to 60 mg for a maximum duration of 12 months with subsequent tapering) and acetylcholinesterase (AChE) inhibitors, and of azathioprine and AChE inhibitors in 27 patients. One patient received azathioprine and 22 AChE inhibitors only; in another no further medication was necessary. In the severely affected group (n = 16), plasmapheresis was performed additionally before thymectomy and continued for some time after the operation. Treatment was started between 1 and 14 months (mean 2.4 months) after the onset of myasthenic symptoms. No thymectomy was done in 14 patients, and immunosuppressive treatment and AChE inhibitors were given in 9 of these cases. One patient received azathioprine only; 4 patients received AChE inhibitors only. The histology of the thymus gland showed follicular hyperplasia in 89% of the 65 thymectomised patients and normal findings in the remainder. Remission occurred in 60% of patients who underwent thymectomy and in 29% of those who were not thymectomised. Hyperthyroidism (6 patients, 8%), diabetes mellitus (2 patients, 3%) and rheumatoid arthritis (2 patients, 3%) were the most frequent associated immune-mediated diseases. Epileptic seizures and neoplasia were coincident diseases in 2 (3%) and 3 (4%) patients, respectively. There were no deaths from thymectomy or from immunosupression. This open, retrospective analysis suggests that juvenile-onset myasthenia gravis can be treated satisfactorily in most patients by the use of thymectomy and/or immunosupressive medication.

Early recurrence or persistence of autoimmune diseases after unmanipulated autologous stem cell transplantation.

Autologous stem cell transplantation with or without in vitro lymphocyte depletion has been suggested as a new treatment option for severe autoimmune diseases. We describe five patients with autoimmune diseases (CREST syndrome, myasthenia gravis and Hashimoto's thyroiditis, systemic lupus erythematosus, atopic dermatitis, and rheumatoid arthritis) who underwent autologous bone marrow (n = 1) or peripheral blood progenitor cell (n = 4) transplantation with unmanipulated grafts as treatment for the autoimmune disease in one case or as treatment for a malignant disorder with a concomitant autoimmune disorder in four cases. In all patients serological and clinical signs of the autoimmune disease recurred early or persisted. These observations should be regarded as a cautionary note concerning the efficacy of high-dose therapy followed by transplantation of unmanipulated autologous stem cells for treatment of severe autoimmune diseases.

Expression of neurofilaments and of a titin epitope in thymic epithelial tumors. Implications for the pathogenesis of myasthenia gravis.

Autoantibodies against both striated muscle proteins, particularly titin, and the acetylcholine receptor are a hallmark of thymoma-associated myasthenia gravis. However, the stimulus for these responses remains enigmatic as whole titin is not detectable in these tumors. This study reports that in thymomas with cortical differentiation many of the neoplastic epithelial cells expressed low and medium molecular weight neurofilaments detected with several antibodies (on selections and blots) and at the RNA level (by reverse transcriptase polymerase chain reaction). Moreover, higher molecular weight forms sharing at least one epitope with titin were detectable slightly less frequently, as were the more strongly phosphorylated epitopes. In stark contrast, in medullary and mixed thymomas, and especially in the normal thymus, immunoreactivity with anti-neurofilament antibodies was rare. This aberrant overexpression of a titin epitope by epithelial cells with antigen-presenting phenotype in an inappropriate cortical microenvironment suggests that they might autosensitize maturing T cells there and so initiate anti-titin autoimmunity in these patients.

Limited value of cerebrospinal fluid for direct detection of Toxoplasma gondii in toxoplasmic encephalitis associated with AIDS.

The diagnosis of acquired immunodeficiency syndrome-associated toxoplasmic encephalitis (TE), a typically focal disease resulting from reactivation of tissue cysts, relies mainly on indirect diagnostic methods. In a prospective study, we investigated the value of detection of Toxoplasma gondii in cerebrospinal fluid (CSF) by using the polymerase chain reaction and the mouse inoculation test. Twenty-four patients with 26 episodes of TE, 2 HIV-infected patients with primary acute Toxoplasma infection, and 38 HIV-infected control patients with latent Toxoplasma infection were investigated. Detection of T. gondii in CSF by both methods was possible in only 3 of the TE patients (11.5%), the remaining patients being negative with either of the methods. In contrast, T. gondii DNA was detected in both of the acutely infected patients, indicating that in primary acute toxoplasmosis parasites may easily be found in the CSF, whereas in the majority of TE cases in immunocompromised patients, T. gondii parasites do not gain access to the CSF drawn by lumbar puncture.