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.

[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.

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.

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.

Autoimmune T lymphocytes in myasthenia gravis. Determination of target epitopes using T lines and recombinant products of the mouse nicotinic acetylcholine receptor gene.

Oligoclonal and cloned T lines from peripheral blood or thymuses of patients with myasthenia gravis (MG) were selected for reactivity against nicotinic acetylcholine receptors (AChR) from Torpedo california, or against a recombinant fusion peptide, X4, representing the extracellular portion of the mouse AChR alpha-chain. All cell lines expressed the CD4 membrane phenotype, and their antigen reactivity was blocked by antibodies against monomorphic HLA DR/DP determinants. Using a panel of fusion proteins of different, overlapping mouse AChR alpha-chain sequences, a major T cell epitope was localized between amino acid positions 85 and 142. This determinant was distinct from the humoral main immunogenic region, which has been identified on the sequence 61-76. The response pattern of uncloned T lines from three patients with different HLA haplotypes suggests, however, that in any one MG patient T lymphocytes may recognize more than one autoantigenic epitope on the AChR alpha-chain, and that the T lymphocyte response profiles vary among individual patients.

Thymus in myasthenia gravis. Isolation of T-lymphocyte lines specific for the nicotinic acetylcholine receptor from thymuses of myasthenic patients.

The thymus is believed to play a central role in the pathogenesis of Myasthenia gravis (MG). According to a previous hypothesis, MG is initiated within the thymus by immunogenic presentation of locally produced nicotinic acetylcholine receptor (AChR) to potentially autoimmune T cells. Data of 10 consecutive MG patients demonstrate two critical features of MG thymuses that support the concept of intrathymic activation of autoreactive, AChR-specific lymphocytes. Morphologically, the thymuses showed lympho-follicular hyperplasia in nine cases and benign thymoma in one case. The paramount feature revealed by immunohistological double marker analyses was the intimate association of myoid cells (antigen producing) with interdigitating reticulum cells (potentially antigen presenting cells), both of which were surrounded by T3+ lymphocytes in thymus medulla. All 10 thymuses contained T lymphocytes reactive with AChR. This was in contrast to the peripheral immune compartment (blood) where in only 3 of 10 patients, significant T cell responses to AChR were observed. AChR-specific T cell lines could be established from 8 of 10 thymuses, all members of the helper/inducer subset as indicated by the expression of markers T3 and T4.

Specific immune complexes augment in vitro acetylcholine receptor-specific T-cell proliferation.

We investigated the interaction between acetylcholine receptor (AChR)-specific T-helper cells from patients with myasthenia gravis and murine monoclonal anti-AChR antibodies. At optimal antigen concentration, anti-AChR antibodies neither enhanced nor impaired T-cell responses. However, at substimulatory antigen concentration, addition of anti-AChR antibodies substantially enhanced the proliferation of AChR-specific T cells. In spite of low amounts of antigen, immune complex formation allowed highly efficient capture and uptake of antigen via Fc receptors on antigen-presenting cells, which could be inhibited by an antibody to Fc receptors. Immune complex-mediated stimulation of sensitized AChR-specific T lymphocytes in vivo may contribute to the exacerbation of the disease, and demonstrates the interaction between T and B lymphocytes in myasthenia gravis.

Multiple symmetric lipomatosis: abnormalities in complex IV and multiple deletions in mitochondrial DNA.

Multiple symmetric lipomatosis (MSL) is a rare disorder of middle life characterized by large nonencapsulated lipomas distributed around the neck, shoulders, and other axial regions. Neurologic involvement, particularly peripheral neuropathy, is frequent. The pathogenesis of the syndrome is still unknown, but ragged-red fibers are occasionally present in muscle of affected patients, suggesting a mitochondrial abnormality. We studied 11 unrelated patients with MSL by means of neurophysiology, muscle morphology, muscle biochemistry, Southern blot, and PCR analysis of mitochondrial DNA. All patients were men aged 41 to 63 years. Clinical or electrophysiologic signs of a sensorimotor polyneuropathy were present in nine patients, eight of whom had a history of alcoholism. In muscle biopsy specimens, the most prominent feature was pathologic subsarcolemmal aggregates of mitochondria. Biochemical analysis of respiratory chain enzymes revealed a moderate but significant decrease of cytochrome c oxidase activity as compared with age-matched controls. In one patient, Southern blot analysis showed multiple deletions of mitochondrial DNA. We conclude that mitochondrial dysfunction is common in MSL and may be based on identifiable defects in the mitochondrial genome.

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.

Well-differentiated thymic carcinoma. An organotypical low-grade carcinoma with relationship to cortical thymoma.

Based on a study of 26 cases, the well-differentiated thymic carcinoma is described as a distinct organotypical carcinoma of the thymus with low-grade malignancy. It is characterized by a predominance of epithelial cells with usually low mitotic rate, an epidermoid differentiation with slight to moderate cytological atypia, the constant presence of interepithelial immature cortical thymocytes, lobular growth, and formation of epithelial palisades around perivascular spaces. The tumor occurs at age 14 to 76 years in both sexes. An association with myasthenia gravis is found in 77% of the patients, and 83% of the tumors show invasion of adjacent organs or endothoracic metastasis at primary operation. This rate is higher than in cortical thymomas (47%) but lower than in other thymic carcinomas (92%). Two of 18 patients with follow-up died of tumor recurrence and pleural metastasis. Well-differentiated thymic carcinoma can be related to cortical thymoma by common morphological features and a similar immunophenotype of epithelial cells. It must be differentiated from the lymphocyte-depleted cortical thymomas after corticosteroid treatment and from the benign epithelial-rich medullary thymomas.

Sarcoid myopathy and mitochondrial respiratory chain defects: clinicopathological, biochemical and molecular biological analyses.

We report on a 33-yr-old female patient with myalgia, CK values up to 3500 Ul-1 and proximal weakness. An initial muscle biopsy showed myositis. One year later an enlarged lymph node was investigated and sarcoidosis diagnosed. In a second muscle biopsy inflammatory cells and morphological characteristics of mitochondrial myopathy were found. Biochemical analyses indicated a 50% reduction in complex II activity of the respiratory chain. Due to failure in clinical improvement a third muscle biopsy was performed in 1990 where only 19% of normal complex II activity was present. Southern blot analysis of the mitochondrial genome was normal. Thus for the first time we describe a patient with sarcoid myopathy and a complex II deficiency. Our interpretation is that a pre-existing complex II defect became clinically relevant because of additional sarcoid myopathy.

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.

Splenectomy in myasthenia gravis: a therapeutic concept?

The case histories are presented of five patients with long-diagnosed myasthenia gravis (up to 15 years) who underwent splenectomy. A precondition for the decision to operate was muscle weakness that could not be controlled with standard therapy (e.g. anticholinesterase drugs, immunosuppressive measures). After splenectomy, a considerable improvement took place in three cases; in one case there was moderate improvement, and in another, no improvement. The alleviation of myasthenia gravis may be attributable to the reduction of either the number of immunocompetent lymphocytes in an important storage organ or of the total bulk of the immune system in an immune disease with raised auto-antibody production. The acetylcholine receptor antibody titre was not affected by the operation in a consistent way. After splenectomy, immunosuppressive medication was tolerated better with respect to its haematological side-effects.

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.

Magnetic resonance image findings of spinal intramedullary abscess caused by Candida albicans: case report.

We present the clinical, serological, and radiological features of a patient with a spinal intramedullary abscess caused by Candida albicans. Antimycotic treatment was successful, and no neurosurgical approach was necessary.

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.

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.

[Nuclear magnetic resonance tomography in the diagnosis of muscular diseases]. / Kernspintomographie in der Diagnostik von Muskelerkrankungen.

Forty-nine patients with various systemic muscle diseases were examined by MR using a 1 Tesla magnet and the appearances of different conditions are analysed. Emphasis was placed on the analysis of patients with progressive muscular dystrophies, myositis, myotonia dystrophica and other muscle diseases. The investigation was begun in March 1984 and was continued until September 1985. Certain characteristic patterns of selectively involved muscles could be recognised. The pattern corresponds to our present understanding of the early phases of muscle diseases, whether inflammatory or due to fatty degeneration. The T1 and T2 relaxation times in various patients were quantified and changes in the normal pattern were analysed. Attention is drawn to the value of MR when carrying out a biopsy and for treatment of muscle diseases.

[31P NMR spectroscopy of muscular diseases: correlation with MR imaging]. / 31P-NMR-Spektroskopie bei Muskelerkrankungen: Korrelation zur MR-Bildgebung.

The spectra of normal and abnormal muscle were examined by 31P MR spectroscopy using a 2 Tesla system. Exercise tests on normal and abnormal muscle were also carried out. Abnormal muscles showed characteristic changes in the phosphorus spectrum, when compared with normal muscles, both at rest and after exercise; these were compared with the data from the MR images. The advantages and limitations of the method are discussed.

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.