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Biomedical subjects

K M Müller

Publications and source records attributed to K M Müller.

At least 127 records · Page 7Linked to original sources

[Carcinoid tumors of the lung and asbestos. Clinical aspects for insurance medicine].

Lung dust analyses were performed on tumor-free lung tissue from surgical samples of 28 carcinoid tumors. The measured levels in one surgical sample may easily be correlated with the increased asbestos load of the lung due to the patients' occupation as stone mason. No evidence supporting the correlation of increased chronic asbestos load of the lungs and the development of typical carcinoid tumors of the lung was found.

Adolescent↗

[Synovial sarcoma of the pericardium].

A precordial tumor of the pericardium was radiologically diagnosed as the cause of an untypical clinical picture of heart disease in a 41-year-old soldier. As the patient had an increased asbestos exposure due to his profession, he was admitted to operation under the tentative diagnosis of a pericardial mesothelioma and the question of an occupational disease (BK 4105). Microscopic and immunohistochemical findings are compatible with the diagnosis of a synovial sarcoma of the pericardium. The present immunohistochemical marker spectrum allowed a reliable differentiation between synovial sarcoma and pericardial mesothelioma, which is more frequent than synovial sarcoma. The epithelioid component was determined using the following antibodies: MNF 116, CK 19, CK 7, EMA and Ber EP-4 were positive while Factor VIII, Calretinin, S100, Vimentin, CEA, CD 31, bcl-2 and HBA-71 were negative. The sarcomatous component was determined with antibodies to Vimentin, bcl-2 and HBA-71 which were positive, and to MNF 116, CK 19, CK 7, Factor VIII, Calretinin, S100, EMA, CEA, Ber EP-4 and CD 31 which were negative. Synovial sarcomas of the pericardium in the lower anterior mediastinum or the myocardium are exceedingly rare. A causal relationship between tumor formation and an increased asbestos exposure--similar to the epidemiologically based experiences with pericardial mesothelioma--is not likely. Primary extrapericardial synovial sarcoma could be excluded.

Adult↗

Exposure to carbon black: a cancer risk?

Lung cancer is one of the most serious health problems in the industrial nations and is therefore of great public and scientific interest. Although inhalative cigarette smoking is without doubt the main cause for the increasing frequency of lung cancer, during recent years there has been more and more public interest in other substances in the environment or at the work place that are assumed to be potentially carcinogenic especially due to experiences with fibrous particles such as asbestos and their effects. Enhanced attention is also directed to inert or nuisance dusts such as carbon black. Evaluation of the possibly increased risk for humans should first be based on exact epidemiology data. In the absence of those data--as in the case of carbon black--experimental data in animals serve as the point of orientation, especially results gained in rats in long-term inhalation studies. Pathologic anatomy investigations of human lungs under similar exposure conditions, however, render results quite different from those obtained in rats and, thus, preclude ready interpretation of animal results to human risk assessment. This is particularly true for the development of lung tumors in rats under overload conditions as well as for certain tumor types not observed in human lung tissues. It is therefore quite understandable that many researchers propose to interpret the changes observed in rat lung tissues after inhalation of carbon black as rat-specific reaction mechanisms that cannot be applied to human tissues, which in the past have led to the wrong conclusions regarding human risk assessment due, among other factors, to incorrect experimental design and inaccurate nomenclature of tumorous lesions in rats.

Animals↗

Expression and localization of vascular endothelial growth factor and its receptor flt in pulmonary sarcoidosis.

Vascular endothelial growth factor (VEGF) is a multifunctional cytokine, which has recently been reported to enhance the activation and migration of monocytes through the flt receptor in vitro, which are key events in granuloma formation of granulomatous disorders and in sarcoidosis. Since activated macrophages and monocytes are known to be involved in sarcoid granuloma formation in sarcoidosis, we investigated the expression of VEGF and its receptor flt in 33 paraffin-embedded lung tissue biopsies of patients with pulmonary sarcoidosis. VEGF-mRNA was localized by nonradioactive in situ hybridization, VEGF and flt expression were visualized immunohistochemically. We found an increased transcription and protein production of VEGF and an overexpression of flt in activated alveolar macrophages, in epitheloid cells, and in multinuclear giant cells of pulmonary sarcoid granulomas.

Adult↗

Expression of c-Met receptor and hepatocyte growth factor/scatter factor in synovial sarcoma and epithelioid sarcoma.

Overexpression of c-Met receptor/hepatocyte growth factor (scatter factor) system (c-Met/HGF/SF) as a physiologically paracrine cellular signaling system is thought to be involved in the progression of malignant tumours. In 26 synovial sarcomas and epithelioid sarcomas, c-Met and HGF/SF expression was analysed immunohistochemically. There were 10 biphasic synovial sarcomas, 7 of which showed moderate to strong c-Met expression in epithelial areas compared with the fibrous component, with corresponding expression of HGF/SF. Six of 9 monophasic fibrous synovial sarcomas showed only very faint c-Met and corresponding HGF/SF expression. In 7 epithelioid sarcomas strong expression of c-Met and HGF/SF was observed within epithelioid tumour cells. Non-radioactive in situ hybridization demonstrated the synthesis of c-Met receptor in tumor cells by detecting c-met-mRNA. This analysis shows that in synovial sarcomas and epithelioid sarcomas, tumour entities with epithelial and mesenchymal structures, c-Met and HGF/SF overexpression can be detected, indicating a role of this signaling system in these subtypes of sarcoma, and especially in the more epithelioid tumour phenotype. An autocrine interaction between overexpressed c-Met receptor and HGF/SF may be hypothesized.

Hepatocyte Growth Factor↗

Hepatocyte growth factor/scatter factor and its receptor c-Met are overexpressed and associated with an increased microvessel density in malignant pleural mesothelioma.

Hepatocyte growth factor/scatter factor (HGF/SF) stimulates cell proliferation, motility and invasiveness via its receptor c-Met during embryogenesis and repair processes. It induces angiogenesis, promoting endothelial cell migration and capillary-tube formation in vivo. Co-expression of HGF/SF and c-Met receptor results in enhanced tumour growth, invasiveness and a mesenchymal-epithelial transition in some experimental tumours. Since mesothelioma cells have been reported to express c-Met receptor and to migrate in response to HGF/SF, we investigated human malignant pleural mesotheliomas for the demonstration of possible co-expression of the growth factor and its receptor. The microvessel density of the tumours was also analysed in order to assess the influence of HGF/SF expression on tumour angiogenesis. Thirty-nine paraffin-embedded specimens of malignant pleural mesotheliomas were immunostained by anti-HGF/SF and anti-c-Met antibodies and semiquantitatively evaluated. c-Met mRNA expression was visualised in ten tumour samples by a fluorescent in situ hybridisation method. Microvessel density was calculated by counting microvessels with a high-power field (200x) on von-Willebrand-factor-stained slides. We found an increased production of HGF/SF in 33/39 tumours and a corresponding overexpression of c-Met receptor in 29/39 specimens. The FISH method detected increased transcription of c-Met mRNA in malignant cells and in neighbouring vascular endothelial cells. HGF/SF-positive mesotheliomas had significantly higher microvessel densities compared to their HGF/SF-negative counterparts. The observed co-expression of HGF/SF and c-Met in malignant pleural mesotheliomas suggests a possible self-stimulation (autocrine loop) of tumour cells. On the basis of the significantly higher microvessel density values of malignant mesotheliomas overexpressing HGF/SF, we postulate, that HGF/SF may be an additional relevant factor in tumour angiogenesis in malignant pleural mesotheliomas.

Hepatocyte Growth Factor↗

Hyperventilation induces release of cytokines from perfused mouse lung.

Artificial mechanical ventilation represents a major cause of iatrogenic lung damage in intensive care. It is largely unknown which mediators, if any, contribute to the onset of such complications. We investigated whether stress caused by artificial mechanical ventilation leads to induction, synthesis, and release of cytokines or eicosanoids from lung tissue. We used the isolated perfused and ventilated mouse lung where frequent perfusate sampling allows determination of mediator release into the perfusate. Hyperventilation was executed with either negative (NPV) or positive pressure ventilation (PPV) at a transpulmonary pressure that was increased 2.5-fold above normal. Both modes of hyperventilation resulted in an approximately 1.75-fold increased expression of tumor necrosis factor alpha (TNFalpha) and interleukin-6 (IL-6) mRNA, but not of cyclooxygenase-2 mRNA. After switching to hyperventilation, prostacyclin release into the perfusate increased almost instantaneously from 19 +/- 17 pg/min to 230 +/- 160 pg/min (PPV) or 115 +/- 87 pg/min (NPV). The enhancement in TNFalpha and IL-6 production developed more slowly. In control lungs after 150 min of perfusion and ventilation, TNFalpha and IL-6 production was 23 +/- 20 pg/min and 330 +/- 210 pg/min, respectively. In lungs hyperventilated for 150 min, TNFalpha and IL-6 production were increased to 287 +/- 180 pg/min and more than 1,000 pg/min, respectively. We conclude that artificial ventilation might cause pulmonary and systemic adverse reactions by inducing the release of mediators into the circulation.

Animals↗

[Intracellular distribution of beta-catenin in soft tissue tumors].

AIMS: beta-Catenin originally known as an intracellular mediator of epithelial cell-to-cell adhesion is also involved in signal transduction processes. Since its important function in colorectal carcinogenesis has recently been recognized, the aim of our study was to investigate whether a similar intracellular distribution of beta-catenin can be detected in sarcomas and sarcoma-like lesions. METHODS: 45 soft tissue tumors were examined by immunohistochemistry. RESULTS: Different types of beta-catenin-distribution were observed: A more continuous localization at the cell membrane was evident especially in epithelioid-like sarcomas. In contrast only focal staining of cell membranes could be found in different tumors as well. Further on increased cytoplasmatic beta-catenin levels were detected in various types of tumors. CONCLUSIONS: The localization of beta-catenin at the cell membrane serves as a hint for a function of beta-catenin in cell adhesion of mesenchymal tumors apart from epithelial tissues. A nuclear and intracellular accumulation of beta-catenin has been observed in progression of colorectal tumors. The findings of increased levels of beta-catenin in soft tissue tumors may indicate a similar important function in the pathogenesis of these neoplasias.

Cell Adhesion↗

[Basic principles of LIFE--autofluorescence bronchoscopy. Results of 194 examinations in comparison with standard procedures for early detection of bronchial carcinoma--overview].

BACKGROUND: Conventional bronchoscopy in the identification of preneoplasias and carcinoma in situ (CIS) has been inadequate to date. Tissue autofluorescence was found to differentiate normal mucosa from dysplastic or carcinomatous bronchial mucosa. This principle resulted in the development of the LIFE System (Light Imaging Fluorescence Endoscope, Xillix Techn., Vancouver, BC), now in routine use worldwide at 35 centres. In a prospective multicentric study in North America the relative sensitivity for diagnosing intraepithelial neoplasias of combined white light (WLB) and LIFE bronchoscopy in 173 at-risk patients was 6.3 as compared to WLB alone. A similar European multicentric study will be completed by spring of 1998. PATIENTS AND RESULTS: We report on our experience with the routine use of the LIFE System over 23 months. 194 examinations (165 patients) were performed. Moderate to severe dysplasias and in situ carcinomas were diagnosed with a relative sensitivity of 2.7 by the combined WLB-LIFE examination as compared to WLB alone. CONCLUSION: Autofluorescence bronchoscopy as a routine investigation without need of photosensitizers in patients with a high risk for lung cancer can lead to a substantial increase in the detection rate of CIS and moderate to severe dysplasias compared to white light bronchoscopy alone.

Adult↗

Static DNA cytometry as a diagnostic aid in effusion cytology: I. DNA aneuploidy for identification and differentiation of primary and secondary tumors of the serous membranes.

OBJECTIVE: To determine whether DNA aneuploidy is a sensitive and specific marker for the identification of tumor cells in effusions and whether the pattern of DNA aneuploidy can provide important information for the differential diagnosis of primary and secondary tumors of the serous membranes. STUDY DESIGN: One hundred eight malignant mesotheliomas as well as 102 metastatic carcinomas of the serous membranes were obtained from routine cytologic and histologic material. One hundred reactive effusions were investigated as controls. Nuclear DNA contents were measured after Feulgen staining using a TV image analysis system. RESULTS: DNA aneuploidy was assumed if abnormal DNA stemlines, a coefficient of variation of the first DNA stemline > or = 10%, or cells > 9c were observed. On this basis the prevalence of DNA aneuploidy in mesotheliomas was 83% for cytologic and 84% for histologic material. In effusions of metastatic carcinomas it was 100%. None of the 100 reactive effusions revealed DNA aneuploidy (prevalence, 0%). Positive predictive value for mesotheliomas was 100%; negative predictive value was 88% for cytologic and 82% for histologic material. Positive predictive value for metastatic carcinomas was 100%; negative predictive value was 100%. Seventy-two percent of the mesotheliomas revealed their greatest stemline within the range 1.80c-2.20c, whereas none of the metastatic carcinomas showed this stemline position. CONCLUSION: DNA image cytometry might be a very sensitive and highly specific, additional tool for identification of neoplastic cells in effusions as well as for the differential diagnosis of mesothelioma vs. metastatic carcinoma of the serous membranes.

Aneuploidy↗

[Jaundice and progressive liver failure: delayed diagnosis of autoimmune hepatitis due to abrupt termination of steroid therapy?].

A 27-year-old woman was successfully treated with a highly dosed steroid therapy over several months during summer 1994 in the event of urticaria. In October 1994, when the patient was complaint free, therapy was abruptly terminated. In November 1994 jaundice, nausea and loss of appetite occurred. Biochemical results showed markedly elevated serum transaminases, negative hepatitis serology, normal immunoglobulins and inconspicious autoantibodies. Histology showed a florid hepatitis. In January 1995 the patient was hospitalized again in very low general and nutritional condition with a marked jaundice, high serum transaminases, insufficient liver synthesis function, established ANA(+), ASMA(+2) and normal immunoglobulins. This time histology painted out an active hepatitis going into liver cirrhosis. Evaluation in view of liver transplantation was carried out in this case of liver failure. At that time, tests showed a distinct gamma globulin fraction increase although the antibody pattern had remainded identical. An immunosuppressive therapy with azathioprine and steroids was decided upon under suspicion of an autoimmune hepatitis leading to a prompt positive response and therefore confirmation of the diagnosis. Complete biochemical remission was attained in April 1995 and a complete histological remission in March 1998.

Adrenal Cortex Hormones↗

[Lymphomatoid granulomatosis--remission induction with interferon-alpha 2b].

HISTORY AND ADMISSION FINDINGS: A 72-year-old woman was admitted to hospital because of nonproductive cough, acrodistal sensorimotor axonal polyneuropathy, fatigue and 10 kg weight loss over the preceding 9 months. INVESTIGATIONS: Chest radiogram showed multiple round foci in both lungs. No organs other than the lungs and the peripheral nervous system were affected. Open lung biopsy revealed a pleomorphic angioinvasive lymphocytic infiltrations. DIAGNOSIS, TREATMENT AND COURSE: The findings indicated lymphomatoid granulomatosis (LG). Wegener granulomatosis was excluded on the basis of the clinical, serological and histopathological findings. Treatment with alpha-interferon (IFN-alpha) produced complete remission within 4 months. Interruption of treatment immediately resulted in a recurrence. CONCLUSION: Together with previously reported cases this patient's response to IFN-alpha suggests that IFN-alpha is a less toxic alternative to cyclophosphamide and corticosteroid administration in the early stages of LG.

Aged↗

Tumour regression in non-small-cell lung cancer following neoadjuvant therapy. Histological assessment.

In the scope of a prospective multi-centre study after neoadjuvant combined chemotherapy (carboplatin, ifosfamide, etoposide, vindesine) and radiotherapy (45 Gy) 40 resection specimens of locally advanced non-small-cell lung cancer were analysed in order to establish reproducible pathological/anatomical results of tumour regression. Resection specimens of 28 squamous cell carcinomas and 12 adenocarcinomas were investigated using serial sections of the primary lesion. The mean age of the patients was 57 years. The results were compared to spontaneous regressive changes in a control group of 50 untreated non-small-cell lung cancers. Marked scarry fibrosis in the region of the former primary tumour, concentric foci of fresh tumour necroses and surrounding foam cell clusters with transition into vascular granulation tissue could be established as characteristic features of therapy-induced tumour regression, whereas untreated carcinomas revealed necroses with adjoining vital tumour tissue. Using a three-step regression system, 3 tumours could be classified as grade I (no or only slight tumour regression), 10 tumours as grade IIA (marked but incomplete tumour regression, more than 10% vital tumour tissue), 20 tumours as grade IIB (less than 10% vital tumour tissue) and 7 tumours as grade III (complete tumour regression without vital tumour tissue). After a median follow-up period of 32.3 months in patients with grade IIB or III tumour regression ("responders") the median survival time of 27.9 months was found to be significantly longer than in patients with grade I or IIA tumour regression ("non-responders") with a median survival period of 13.7 months (log-rank test, P = 0.020). The resection specimens analysed, which were obtained 7 weeks (on average) after the end of radiochemotherapy, did not show specific changes due to preoperative therapy, but quite characteristic histological alterations in the former tumour area were registered, which had been induced by combined neoadjuvant radiation and chemotherapy. The grade of therapy-induced tumour regression could be shown to be a significant prognostic factor in non-small-cell lung cancer.

Adenocarcinoma↗

Expression and localization of thrombomodulin in preneoplastic bronchial lesions and in lung cancer.

Thrombomodulin (TM) is an endothelial surface glycoprotein that acts as a natural anticoagulant. It inhibits thrombin and accelerates the activation of the anticoagulant protein C. TM has been detected in dermal keratinocytes, where it is associated with terminal differentiation. It can also be detected in various types of squamous malignant neoplasms and in malignancies of endothelial and mesothelial origin, such as Kaposi's sarcoma or malignant mesothelioma, but is absent in pulmonary adenocarcinomas (AC). Seventy-two lung tumour specimens [33 squamous cell carcinomas (SQCC), 23 AC, 1 large cell carcinoma, 8 small cell lung cancers (SCLC) and 7 multidifferentiated tumours (MT)] were analysed immunohistochemically by staining with an anti-TM antibody in order to assess TM expression. All of the SQCC stained positively for TM. In contrast, only 9 AC and 4 MT and none of the SCLC showed positive anti-TM staining. Seven hyperplastic bronchial epithelial specimens and eight preneoplastic bronchial lesions (five cases of moderate dysplasia, two cases of severe dysplasia and one case of carcinoma in situ) were used as controls. Normal or hyperplastic areas of bronchial epithelium revealed no positive reaction. However, a distinct positive anti-TM staining pattern related to the degree of keratiniziation of dysplastic lesions was seen. The present results suggest that anti-TM immunostaining is a useful marker for squamous cell carcinoma in the differential diagnosis of pulmonary carcinoma, also indicating keratinocyte differentiation in dysplastic bronchial epithelium.

Adenocarcinoma↗

[Discontinuous lymph node metastases ("skipping") in malignant lung tumors].

In 50 lung cancers (25 small cell lung cancers, 17 squamous cell carcinomas, 8 adenocarcinomas) pulmonary, mediastinal and cervical lymph node-metastases were analyzed. Lymph-node "skipping" was demonstrated in 46% of the investigated tumors. In seven of these cases the lymph nodes were skipped, which showed complete hyalinization as a consequence of preexisting anthracosilicosis. In 5 other tumors additional lymph nodes with preserved structure were skipped by the metastatic process. Fibrosis of lymphatic tissue after tuberculosis or exposure to ionizing radiation were further reasons for lymph-node skipping. The skipping of intact lymph nodes can be explained by anatomically demonstrable intra- and perinodal short circuit connections. Apart from that, preexisting lymph node changes (silicosis, fibrosis) play an important part.

Adenocarcinoma↗

[Regression grading of neoadjuvant non-small-cell lung carcinoma treatment].

In the scope of a multi-center-study 35 resection specimens from patients with locally advanced non-small cell lung cancer after neoadjuvant chemotherapy and radiation were processed histologically and graded according to the following regression grading system: grade I: no or only slight, in general spontaneous tumor regression, grade IIa: incomplete tumor regression with more than 10% and grade IIb less than 10% vital tumor tissue as well as grade III: complete tumor regression. In 15 patients with grade II a to III tumor regression roughly concentric foci of various size with a sequence of central tumor necrosis, narrow foam cell rim, vascular granulation tissue and peripheral scar formation were demonstrated as characteristic feature of response to neoadjuvant therapy. In patients with grade IIb to III tumor regression ("responders") median survival time of 27.9 months was significantly longer than in patients with grade I to II a tumor regression ("non-responders") with a median survival time of 12.7 months.

Adult↗

[Heart rupture after mitral valve replacement. Pathologic-anatomic findings].

The rupture of the free left ventricular wall is considered a serious complication following mitral valve replacement. We report about 3 cases characterized by similar pathologic-anatomical findings within the region of the left ventricle after mitral valve replacement. Following resection of the original and pathologically altered mitral valve and implantation of a prosthesis, rupture of the left ventricular wall occurred in short time intervals ranging from 1 to 12 h postoperatively. All cases represented a transverse midventricular disruption located between the mitral valve anulus and the resected papillary muscles. The histologic findings included necrotic, damaged myocardial structures with considerable bleeding to the interstitium. Inflammatory infiltration could be detected within the myocardial defects. Abnormal pathologic findings of the coronary arteries or intraoperative lesions could be excluded by thorough autoptic studies. Because of central localization of the ventricular disruption between the mitral valve anulus and the papillary muscles a direct traumatic myocardial injury caused by mitral valve orotheses is to be excluded. When taking into account several reports from literature in combination with our described findings, in autopsy, a loss of contractile integrity of the left ventricle following resection of mitral valve apparatus, especially the chordae tendinaea, should be considered as primary cause for this type of ventricular rupture. This destabilization will lead to a regionally stressec myocardial "stretching" which finally results in rupture of the left ventricular free wall. The described pathogenetic concept seemingly represents the decisive mechanism of this transverse midventricular disruption in all 3 cases. To prevent such post-operative complications, only very limited resection of the mitral valve apparatus should be performed to maintain parts of the chordae tendineae.

Aged↗

[Intravascular ultrasound findings in calcifying arteriosclerosis: in vitro validation using "soft" roentgen images].

AIM: The aim of this study was to validate the detection of calcified arteriosclerotic plaques with intravascular ultrasound (IVUS). METHOD: 181 arteries were examined by 20/30 MHz IVUS. The ultrasound cross-sections were compared to the corresponding radiologic (30 kV) and histologic cross-sections. RESULTS: Calcified lesions were imaged as bright echos with shadowing. In 13 cases of 161 calcified lesions were too small to detect by IVUS. In 5 ultrasonic sections the diagnosis "calcified lesion" could not be verified neither by radiology nor by histology. The sensitivity was 91.6%, the specificity was 94.7% and the accuracy was 93.0%. CONCLUSIONS: Because of the acoustic properties of calcium, calcified lesions can be detected accurately by IVUS. IVUS can generate new insights into the effect of plaque composition on the response to catheter therapies.

Aged↗