Subacute fatal aluminum encephalopathy after reconstructive otoneurosurgery: a case report.

We report a 52-year-old woman who underwent otoneurosurgery to resect acoustic neurinoma. Bone reconstruction was performed with an aluminium (Al)-containing cement. Six weeks later the patient suffered from loss of consciousness, myoclonic jerks, and persistent grand mal seizures, clinical symptoms that resembled those of lethal dialysis encephalopathy of the 1960s and 1970s. She died 6 months later because of septic complications. Light- and electron-microscopic investigation of the central nervous system (CNS) showed pathognomonic Al-containing intracytoplasmic argyrophilic inclusions in choroid plexus epithelia, neurons, and cortical glia. These changes are characteristics of dialysis-associated encephalopathy (DAE), induced nowadays by long-term ingestion of Al-containing drugs (and with benign clinical courses). Atomic absorption spectrometry showed an increase of mean bulk Al concentration of the cortex and subcortex up to 9.3 microg/g (normal range <2 microg/g); laser microprobe showed the increase of Al in subcellular structures. This unique case again shows the extraordinary neurotoxicity of Al, which was, in our patient, initiated by an amount of about 30 mg Al and apparently caused by direct Al access to the brain parenchyma via a cerebrospinal fluid leakage.

Transgenic rat hearts expressing a human cardiac troponin T deletion reveal diastolic dysfunction and ventricular arrhythmias.

OBJECTIVE: Familial hypertrophic cardiomyopathy (FHC) due to mutations of cardiac troponin T (cTnT) is associated with a high frequency of sudden death even in the absence of cardiac hypertrophy. To investigate the causal relationship of cTnT mutations and this particular phenotype, we sought to establish a transgenic rat model for the disease. METHODS: Transgenic rats were generated expressing human wild-type cTnT or two truncated cTnT molecules (del ex16, del ex15/16), resulting from an intron 15 splice donor site mutation previously observed in FHC patients. Transgenic rat hearts were characterized by histology, immunohistochemistry and in the 'working heart'. RESULTS: Human wild-type and del ex16 cTnT were stably expressed and incorporated into the sarcomere of transgenic cardiomyocytes. Del ex16 transgenic rats revealed a lower level of expression (4-5%) than human wt cTnT animals (25-40%). In the 'working heart' model del ex16 hearts exhibited significant systolic and diastolic dysfunction without cardiac hypertrophy. In contrast, human wt cTnT hearts showed improved contractile performance and moderate myocardial hypertrophy. After 6 months of daily physical exercise one del ex16 rat died suddenly and three out of five del ex16 hearts revealed ventricular tachycardia/fibrillation. No arrhythmia was observed in human wt cTnT expressors. Myofibrillar disarray was present in del ex16 hearts after training but not in human wild-type cTnT rats or non-transgenic controls. CONCLUSION: A human cTnT deletion overexpressed in transgenic rats exerts a dominant-negative effect and mimics the phenotype of FHC with diastolic dysfunction and arrhythmias. By contrast, human cTnT wild-type animals reveal a gain of function and cardiac hypertrophy without arrhythmias.

Colonic primary large cell lymphoma with marginal zone growth pattern presenting as multiple polyps.

We report a rare case of primary gastrointestinal lymphoma, stage IE, in a 58-year-old white man who had multiple colonic polyps measuring up to 1 x 1.1 cm. The tumor originated in the marginal zone of the follicles infiltrating the interfollicular spaces. Follicular colonization was frequently seen. The mucosa was spared by the infiltrate. Morphologically, the neoplastic cells were monomorph, intermediate-sized blasts. Rare small to intermediate sized cells, some with centrocyte-like morphology, intermingled the blastic infiltrate. The neoplastic cells expressed CD20 and had a monotypic immunoglobulin of cytoplasmic IgM (kappa) on paraffin sections. Tumor cells stained negative for CD45RO, CD5, CD10, IgD, and CD23. Polymerase chain reaction revealed a clonal V-D-J rearrangement. Bcl-1 and bcl-2 rearrangement were not detected. We therefore suggest the diagnosis of primary large cell lymphoma with marginal zone growth pattern mimicking colonic adenomas.

Bronchoalveolar lavage cell profiles in Wegener's granulomatosis.

Pulmonary involvement due to Wegener's granulomatosis (WG) can present radiologically either as diffuse infiltrates or as nodular and linear opacities. Clinical experience suggest that these radiological patterns are associated with different bronchoalveolar lavage (BAL) cell profiles, but this has not been examined formally. We compared the BAL cell profile in eight WG patients with diffuse infiltrates on chest X-ray, indicative of highly active pneumonitis, with corresponding findings in 37 patients with nodular, linear and focal low-attenuation infiltrates on high-resolution computed tomography (HRCT) which reflected low-grade, mainly interstitial disease. A control group was composed of 11 patients with pulmonary sarcoidosis. Diffuse infiltrates occurred in association with high systemic disease activity and featured a neutrophilic BAL profile in the presence of generally normal BAL lymphocytes. HRCT findings suggestive mainly of interstitial disease were associated with either a lymphocytic BAL cell profile or a normal cell pattern. Patients with a lymphocytic cell profile generally had a preferential elevation of CD4+ cells in the BAL in the presence of a normal CD4/CD8 ratio in the blood. This was a common feature of WG and pulmonary sarcoidosis. In conclusion, highly active pneumonitis and pulmonary disease of low or moderate activity in WG are associated with disparate BAL cell profiles. It remains to be examined whether the preferential elevation of CD4+ cells in the latter condition reflects a common pathogenetic role of this subset of cells in WG and pulmonary sarcoidosis.

Tuberous sclerosis with intracardiac rhabdomyoma in a fetus with trisomy 21: case report and review of literature.

A large cardiac rhabdomyoma protruding into the left ventricle was diagnosed in a fetus at 21+2 weeks of gestation by grey-scale echocardiography. Obstruction to left ventricular outflow was ruled out by colour and spectral Doppler echocardiography. No other abnormalities were noted and karyotyping by cordocentesis revealed trisomy 21 (47,XY,+21). Post-mortem examination after termination of pregnancy confirmed the prenatal diagnosis of cardiac rhabdomyoma and in addition revealed fetal tuberous sclerosis. Demonstration of cardiac rhabdomyoma by prenatal ultrasound should raise suspicion of the presence of fetal tuberous sclerosis. Despite the incidental association with aneuploidy, fetal karyotyping is suggested for optimal counselling of parents.

Immunophenotype, proliferation, DNA ploidy, and biological behavior of gastrointestinal stromal tumors: a multivariate clinicopathologic study.

To determine the prognostic impact of clinical, immunohistochemical, and biological parameters, we examined 52 gastrointestinal stromal tumors (GIST) by conventional light microscopy and immunohistochemistry. DNA ploidy was analyzed by image cytometry on cytospin preparation. The proliferative activity was determined by mitosis counting and assessment of Ki-67 reactivity by means of monoclonal antibody Ki-S5. A histopathologic grade was assigned to each tumor according to the French Federation of Cancer Centers (FNCLCC) grading system. Next to vimentin, CD34 was the most prevalent antigen, followed by markers of neural and muscular differentiation. Many tumors exhibited a mixed phenotype. Twenty-one tumors were diploid, eight hypodiploid, and 23 aneuploid. In univariate analysis, tumor grade, Ki-S5 labeling index, mitotic count, atypical mitoses, cellularity, and sex were predictive of both mortality and metastasis risk. DNA ploidy only correlated with overall survival, whereas the tumor location affected the occurrence of metastases. Multivariate analysis selected Ki-S5 scores (P < .0001) and atypical mitoses (P=.012) as independent prognosticators for overall survival, and tumor grade (P=.0036) and size (P=.0055) as predictors of metastatic spread. We conclude that GIST are primitive mesenchymal tumors capable of divergent differentiation, which does not influence their prognosis. The latter appears to be best predicted by histopathologic grading and the Ki-67 labeling index.

Comparative analysis of prognostic indicators for sarcomas of the soft parts and the viscerae.

Purpose of this study was to determine which parameters may be best applied to determine the prognosis of soft tissue and visceral sarcomas, the two groups being regarded as biologically different. In a cohort of 184 soft tissue tumors (STT) and 53 gastrointestinal stromal tumors (GIST), the following factors were examined for their diagnostic and prognostic relevance: patient age, sex, tumor location, histological type, tumor size, tumor grade, DNA ploidy status, mitotic count, and immunohistochemical proliferation index. Tumors were graded according to the FNCLCC system, and antibody Ki-S11 (Ki-67) served as a proliferation marker. Median clinical follow-up time was 48 months. In STT, morphological criteria allowed a ready discrimination between benign and malignant lesions, which was only warranted by histopathological grading in GIST. 178 of all 236 tumors were thus classified as malignant. Whilst most parameters yielded significant results in the univariate analysis, age, sex, and histological type were irrelevant. A proliferation index > 20% predicted a poor outcome in soft tissue sarcomas, in contrast to a threshold of 10% for GIST. In both groups, the Cox multivariate analysis selected the proliferation index as the sole independent predictor of overall survival, whereas it was superseded by the tumor grade with respect to metastatic spread. In conclusion, soft tissue and visceral sarcomas appear to behave basically in a similar manner. Both tumor grade and immunohistochemical proliferation index are of major prognostic value. Concerning the growth fraction, however, different cut-off points should be selected for sarcomas of the soft tissues and those of the digestive tract.

[Prognostic factors for gastrointestinal stromal tumors]. / Prognostische Faktoren Gastrointestinaler Stromatumoren.

AIMS: Stromal tumors of the gastrointestinal tract (GIST) constitute a group of phenotypically heterogenous mesenchymal neoplasms with uncertain biological behaviour. METHODS: We examined 31 cases of paraffin-embedded GIST histologically and immunohistochemically in regard to their proliferation. Mitosis were counted, atypical mitosis were noted. Proliferation was measured immunohistochemically by Ki-S5 expression and cytophotometrically by ploidy. Prognostic factors were evaluated and compared to the clinical behaviour. RESULTS: Mitosis counts with a mean of 6.43/10 HPF (range: 0-51). Eight atypical mitosis were noted of which five had mitosis counts of 10 or less. Proliferation index determined by Ki-S5 was 9.47% (range: 0-30%). Nineteen tumors were aneuploid. Prognostic unfavorable factors included younger age at diagnosis, male sex, muscular differentiation, higher cellularity and site (stomach VS intestine). KAPLAN-MEIER analysis revealed a statistical significance for Ki-S5 index (p = 0.00268) and ploidy (p = 0.0014). Mitosis counts > 10/10 HPF as well as atypical mitosis were associated with an aggressive biological behaviour. CONCLUSIONS: There are different prognostic factors to determine the prognosis of GISTs., e.g. Ki-S5 index, ploidy, mitosis counts and atypical mitosis. Ki-S5 index seems to be the most reliable.