Biomedical subjects
Publications and source records attributed to E Paul.
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In 22 patients isolated extremity perfusion with cis-platinum for treatment of malignant melanoma was performed; 18 had local metastastic disease (M. D. Anderson stages II and III A, B, AB) and four were stage I. A further five patients were submitted to isolated DTIC perfusion. DTIC-perfused tumors showed regression rates of 30%-80%, followed by recurrences within 4 months. After cis-platinum perfusion stage-III AB cases tended to show tumor recurrence within 4 months, while to date stage-III A and stage-II cases have reached disease-free survival times of 17 and 20 months respectively. While in DTIC perfusion the tissue temperature may range between 40 degrees and 41 degrees C, in cis-platinum perfusions 40 degrees C should not be exceeded; otherwise neural damage will occur.
The effect of isolated cytostatic perfusion was determined in in-transit metastases from malignant melanomas at various times after therapy. Fluorescence-microscopically positive tumor cells (formalin-induced fluorescence) were regarded as viable and possibly capable of dividing. Most of the metastases examined showed fluorescent cells even after perfusion, and these were often found at characteristic sites within the metastases. Under the electron microscope, the cell damage was seen mainly in the nucleus, but also in the organelles of the cytoplasm. The source of cell damage might be multifactorial, and the cytostatic effect could not be clearly separated from the effect of hyperthermia or hypoxia.
To assess the effect of the new, selective, reversible MAO A inhibitor, CGP 11305 A (4-(5-methoxy-7-bromo-benzofuranyl-2-)piperidine HCl), on MAO A and B activity in man, the daily excretion of total normetanephrine (NMN), metanephrine (MN), 3-methoxytyramine (3-MT) and beta-phenylethylamine (PEA) was measured in the urine of healthy volunteers treated with weekly increasing doses from 40 to 150 mg/d. A similar study was carried out with tranylcypromine in weekly increasing doses from 10 to 25 mg/d. Both compounds increased the excretion of NMN; with CGP 11305 A, a plateau was obtained at 50 mg/d, and tranylcypromine 20 mg was more effective than 10 mg, and was also more active than the highest dose of CGP 11305 A. Increases in MN and 3-MT produced by the latter compound were comparable to that in NMN, whereas tranylcypromine had a biphasic effect on MN excretion, and caused only a small increase in 3-MT excretion. CGP 11305 A up to 150 mg/d did not alter total tyramine excretion, whereas tranylcypromine at 20 mg caused a definite increase. Tranylcypromine led to 4-6 fold increases in PEA output at 20 and 25 mg/d, but not at 10 mg. No such effect could be demonstrated for CGP 11305 A up to 150 mg/d. These results suggest that in man MAO A was inhibited by CGP 11305 A in daily dose of 40 mg or more, whereas it did not affect MAO B at up to 150 mg.(ABSTRACT TRUNCATED AT 250 WORDS)
The regeneration of nevus cells after shave biopsy was investigated by means of fluorescence-histochemical and electron microscopic methods. A prerequisite for the regeneration of pigmented nevi seems to be the retention of their deepest part. It appears that the remaining nevus cells primarily induce proliferation of pigment-producing dendritic cells in the epidermis. These dendritic cells form nest-like conglomerations at the dermal-epidermal junction, which eventually separate from the epidermis during a process called "dropping off". The fluorescence-histochemical and electron-microscopic results lead to the conclusion that under these circumstances melanocytes are transformed into nevus cells.
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In a randomized trial of adjuvant chemotherapy, immunotherapy, or immunochemotherapy, 761 evaluable patients with pathological Stage II cutaneous melanoma anywhere on the body or with pathological Stage I melanoma of the trunk (Clark's level 3 to 5) were studied by the World Health Organization International Melanoma Group. Wide local excision and excisional regional lymphadenectomy alone were performed in 185 patients and the results were compared with those of surgery plus chemotherapy with dacarbazine (in 192 patients), surgery plus immunotherapy with bacille Calmette-Guérin vaccine (in 203), and surgery plus chemotherapy combined with immunotherapy (in 181). The rates of disease-free survival and overall survival at 36 months were 30.4 +/- 8.3 per cent (mean +/- S.E.) and 41.6 +/- 10.0 per cent, respectively, after surgical treatment alone; 37.2 +/- 7.9 per cent and 46.5 +/- 8.3 per cent after surgery plus chemotherapy; 34.8 +/- 7.9 per cent and 48.7 +/- 8.7 per cent after surgery plus immunotherapy; and 33.6 +/- 7.9 per cent and 50.0 +/- 8.8 per cent after surgery plus a combination of chemotherapy and immunotherapy. None of the differences between groups was significant, and thus no effect of adjuvant therapy could be demonstrated in this study.
One might expect a positive correlation between the number of CSF lymphocytes and the relative amount of CSF IgG, especially in cases of local synthesis of IgG within the CNS. However, previous attempts at correlating the number of CSF lymphocytes with IgG levels have yielded varying results. Since it is known that the estimation of CSF IgG levels can vary according to the method of immunoglobulin determination used, we decided to perform the analyses by three separate methods: (1) the commonly used, immunoprecipitation technique of radial immunodiffusion; (2) physico-chemical separation on the basis of hydrated size/charge using alkaline electrophoresis through the molecular sieving effects of polyacrylamide gels, followed by densitometry of the gamma region of Coomassie Blue-stained proteins; (3) separation into constituent Ig heavy chains and light chains on the basis of unfolded chain lengths by molecular sieving using sodium dodecyl sulphate (SDS), followed by densitometry of heavy chains of immunoglobulins having been labelled with the fluorescent dye dansyl chloride. Our results show a correlation of white count with the latter two techniques but not the former. Possible reasons for discrepancies in the literature are discussed with regard to the peculiar physical properties of the selected CSF IgG molecules.
We measured free and total 5-S-cysteinyldopa excretion in 24-h urine specimens from nine patients with malignant melanoma and forty-five controls, and found that the levels of 5-S-cysteinyldopa excretion (measured by a fluorometric method) were greatly increased in the melanoma patients. The conjugates were hydrolysed by enzymatic treatment with beta-glucuronidase/arylsulphatase, and we found that the percentage of conjugated 5-S-cysteinyldopa was higher in urines with a low content of free 5-S-cysteinyldopa than in those with a higher concentration.
In a total of 1,828 determinations, urinary excretion of 5-S-Cysteinyldopa was studied over a period of three years in 384 patients treated for melanoma or with metastases of malignant melanoma. By serial investigations the excretion of 5-S-Cysteinyldopa was compared to the course of the disease. In the case of small and circumscribed metastases which could be eliminated by surgical treatment, the excretion of 5-S-Cysteinyldopa remained normal. When the disease became generalized, an increase of the urinary excretion of 5-S-Cysteinyldopa prior to the clinical manifestation of the metastases was observed in only four out of 26 cases. In the remaining cases, the increase of 5-S-Cysteinyldopa coincided with the manifestation of metastases, or the excretion of the substance became pathological when the metastases were already conspicuous. In five patients, the urinary excretion of 5-S-Cysteinyldopa remained normal inspite of widespread disease. Therefore, its diagnostic value seems to be similar to that of the "common" laboratory investigations the results of which are only pathological when the disease has already become generalized. Our investigations demonstrate that serial investigations of the urinary excretion of 5-S-Cysteinyldopa only rarely indicate melanoma metastases prior to their clinical manifestation. In cases of early metastasing melanoma, all common laboratory investigations are of limited value. BSR and GGT levels which become pathological very early in the course of the disease are so sensitive that slightly pathological levels may be ambiguous. In these cases, however, pathological levels of 5-S-Cysteinyldopa most probably will indicate a widespread disease.
Ten patients with varying degrees of hypothroid myopathy were studied clinically and by serial percutaneous needle muscle biopsies before and during treatment with L-thyroxine. The biochemical evidence of hypothyroidism was related to the severity of the myopathic and signs before treatment. The severity of myopathic symptoms before and during treatment correlated with the biochemical evidence of hypothyrodism, a type II fibre atrophy and increased central nuclear counts. Likewise, the clinical evidence of a myopathy before and during treatment was correlated with both a type II fibre atrophy and loss and increased central nuclear counts but was not related to the biochemical parameters of hypothyroidism, except the level of thyroid stimulating hormone. In the muscle, before and during treatment, of the two most severely affected patients, intracellular glycogen inclusions were seen in scattered muscle fibres. On light microscopy and on electronmicroscopy, numerous mitochondria were seen responding to L-thyroxine with accumulations of subsarcolemmal honey-combing. Vesicular abnormalities, an electron dense matrix or occasional crystalline deposits were seen in muscle mitochondria from less severely azffected patients. Severely myopathic muscle contained excessive glycogen, membrane bound glycogen and excess lipid in a mainly perinuclear distribution. Occasional myelin and membranous bodies were seen and satellite cells during the recovery phase. A group of patients with hypothyroid myopathy who are likely to have a delayed recovery of full muscle strength on L-thyroxine may be recognised by the presence of severe proximal muscle weakness and characteristic changes on histochemical and electronmicroscopic examination of muscle. The spectrum of histochemical and electronmicroscopic abnormalities of muscle revealed with increasing degree of hypothyrodism, suggests that a generally reversible acquired glycogen storage and mictochondrial disorder is an important feature in the pathogenesis of this condition.
The correlation between age and CSF protein in 38 patients with pathologically proven motor neurone disease was the reverse of that described for normal subjects by Tibbling et al in 1977. Eight had CSF protein ranging from 0.75 g/1 to 1.52 g/L. These patients were younger, but other clinical and gross and light microscopy pathological features were not significantly different from those with lower CSF protein. Transudation from serum may be only one of the mechanisms underlying this elevation in CSF protein.
The physical conditions of challenge were investigated in a climatic chamber on 8 patients with cholinergic urticaria and 10 patients with generalized cold urticaria. The cholinergic urticaria was induced by passive or active (physical exercise) heating and psychological stimulation; the generalized cold urticaria was induced by general cooling at rest and during physical effort. The ambient temperature was varied, and the mean body temperature was recorded continuously at different measuring points. The experiments revealed that in both types of urticaria the physical trigger mechanism seems to be strictly related to thermoregulatory processes; the crucial point is neither the actual temperature of the skin surface, the average skin temperature, nor even the "core" temperature, but a rise or fall in the weighted average body temperature. In cholinergic urticaria it was not relevant whether skin lesions were provoked by passive heating of the body at rest (sauna-like conditions) or by active heating at low ambient temperature. A basically different challenge mechanism must be assumed therefore in the generalized type of heat and cold urticaria, in contrast to their localized contact types.
With fluorescence-histochemical methods (FIF method) pigment-producing cells were investigated in benign and malignant skin lesions. Here, pigment cells appear predominantly dendritic, whilst they are separated from each other by keratinocytes, cells of hair follicles, or cells of sebaceous glands. In lentigo maligna melanoma, superficial spreading melanoma as well as in nodular melanoma and some metastases of these melanomas, the tumour cells can show a dendritic pattern under special environmental situations. It is, therefore, assumed that the shape of tumour cells in melanomas is more closely dependent on their particular environment and other modifying factors than on a different histogenesis.
Series of "private" photographs taken of patients over many years can greatly aid in following the course of development of malignant melanomas. In one case of superficial spreading melanoma, the pigmented lesion displayed spread around the entire circumference, maintaining its round shape throughout its course. The other tumors enlarged by focused spreading at various points along the border, changing in shape over several years of development. The temporary appearacne of two closely adjacent pigmented lesions frequently occurred during the early development of malignant melanomas, followed by fusion after progressive spread. Lentigo maligna melanoma showed the greatest continuous alteration of shape. Different tumor types observed over similar periods of time showed different dynamics of growth with reference to shape (horizontal spreading growth) and depth to invasion (vertical growth).
Concerning the often discussed carcinogenic risk of psoriasis treatment with 0.005% S-mustard-vaseline (so-called Russian Ointment) -- especially by inhalation -- 19 patients were treated with a radioactive labeled S-mustard-ointment and examined. The patients' whole bodies were inuncted for 1--2 days with about 50 g of radioactive S-mustard vaseline (U14C, 3 muCi/g). Afterwards the radioactivity was determined in the patients' expired air, blood, urine, and in their surrounding air. In three patients punch biopsy material from normal and psoriatic skin was assayed for radioactivity after combustion. In the skin, radioactivity distinctly decreased from the epidermis (13.1 pCi/mg) to the subcutis (0.77 pCi/mg) without significant differences between normal skin and psoriatic lesions as confirmed by autoradiography. In all samples of air, body fluids and tissue, definitive amounts of radioactivity were found, which, however, were far below the US-American MAK-values. Between skin surface and shirt, the values varied from 1.5 to 13.7 nCi/20 l air, at a distance of 2 meters by 0.3 nCi/100 l air, in the breath by 0.5 nCi/20 l. The radioactivity decreased to 1/10 of the maximum values after 1--2 hours. In blood the activity was at the limit of detection and was parallelled by the activity of the urine. Generally, 1--7% of the radioactivity applied to the skin was eliminated with the urine within one week. Thus, the carcinogenic risk may be very low in the external S-mustard therapy of psoriasis and other skin diseases.
Forty papillomatous nevi, mainly with junctional nests, were partially removed surgically in such a way that a small margin was left intact on one side and the deep nevus cells were retained on the flor of the wound. After healing of the wound, a small layer of scar tissue separated the regenerated epidermis from the deep nevus cells, which were left in the dermis. After very differing intervals, as early as 30 days after the partial surgical removal, typical alterations could be observed in the epidermis above the cicatrical tissue. Most frequently, there was a hyperpigmentation with an increase in the number of basal fluorescing dendritic cells, which could also be found along the uppermost parts of epidermal appendages. Moreover, nest-like conglomerations of pigment-producing cells appeared in the form of junctional nevus cell nests. About 2-3 month after the partial surgical removal "Abtropfung" was visible, indicating a regeneration of the nevus. Fluorescence-histochemical and enzyme-histochemical results revealed that marked alterations can be found not only in the newly formed epidermis above the scar, which morphologically show minor alterations.
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