Effects of octreotide on morphology of pituitary adenomas in acromegaly.

We studied the effects of the long-acting somatostatin analogue octreotide (SMS 201-995, Sandoz, Basel, Switzerland) on the morphology of pituitary adenomas in acromegaly. Of the 29 adenomas examined by light microscopy, 16 had been treated pre-operatively with octreotide. The treated adenomas were compared with the untreated adenomas. 14 adenomas were also studied by electron microscopy. In 23 cases we performed in-situ-hybridization for GH-mRNA. Under light microscopy, we found a decrease in amyloid deposits and a higher amount of cell necroses and fibroses after treatment, mainly in the tumors with shrinkage. Tumor shrinkage was diagnosed when the maximal diameter of the adenoma decreased for at least 1/3 during octreotide treatment in NMR examination. Immunohistochemical examinations showed that treated adenomas, especially those with tumor shrinkage, possessed more GH immunoreactive cells, and after in-situ-hybridization we found a higher content of GH-mRNA. On the ultrastructural level, rough endoplasmic reticulum appeared to be increased in treated adenomas. The increase of GH-mRNA and of rough endoplasmic reticulum suggests the likelihood of an increased secretory activity due to a rebound effect after short-term pre-operative omission of octreotide. Other findings are discussed.

Epidermal Langerhans cells and prognosis of patients with mycosis fungoides and Sezary syndrome.

Langerhans cells (LC) (CD1a-positive dendritic epidermal cells) have been proposed to favour the pathogenesis of mycosis fungoides (MF) and Sézary syndrome (SS). We therefore examined the influence of LC retrospectively on the survival of 35 patients. Two clinical parameters (age, stage of disease) were additionally evaluated. LC densities were morphometrically assessed on immunohistochemically stained cryostat sections of the respective diagnostic specimen. Death resulting from MF and SS was significantly (p = 0.003) less frequent in patients with CD1a-positive epidermal cell densities higher than 90 cells/mm2 (optimal break point) as compared with patients with lower numbers, independently of the stage of disease. This result suggests that LC have a significant impact on the prognosis of patients with MF and SS, playing an important role in the host defense mechanisms against these lymphomas.

Retroperitoneal sarcoma in a series of 51 adults.

Fifty-one patients with retroperitoneal sarcoma underwent surgery at the University Clinics of Hamburg from 1970 to 1988. Malignant schwannoma, liposarcoma and malignant fibrous histiocytoma were the most common histological types. High grade sarcomas (G3) predominated (42%), while 26% were graded G2 and 33% G1. Complete resection was possible in 59% of cases. Reoperation for local recurrence and debulking in case of not completely resectable disease was common. Regional lymph node metastasis was found in 20% of cases. The peritoneum was the preferred location of metastatic spread. All adjuvant chemotherapies were followed by tumour recurrences. After adjuvant radiotherapy three of six patients remained free of disease. In cases of residual tumour we observed few partial responses on chemo- and radiotherapy, and all patients died because of the disease. The mean survival time was 60 months, the 5- and 10-year survival rates were 35% and 15%, respectively. Factors influencing prognosis in univariate analysis included grade, size, resectability, presence of metastatic spread, histological type, microscopic local growth (infiltrative vs intact pseudocapsule of fibrous tissue) and local recurrence. With multivariate analysis grade, size and lymph node metastasis retained their prognostic significance.

DNA cytophotometry and prognosis in ovarian tumors of borderline malignancy. A clinicomorphologic study of 80 cases.

Surgical specimens of 80 ovarian tumors of borderline malignancy (OTBM) were investigated by scanning DNA cytophotometry. Diploid or euploid DNA histograms were found for 21 tumors, whereas 59 OTBM showed noneuploid or aneuploid DNA patterns. All patients were followed-up after surgery for at least 3 years (mean observation period, 6.7 years). Follow-up showed 11 cases of recurrent disease and 6 deaths. DNA findings and several other morphologic and clinical details (including patient age, histologic type and stage of disease, and extent of therapy) were correlated to the postoperative course. Statistical analyses disclosed that, of these parameters, only DNA content significantly affected prognosis. Recurrences and deaths resulting from tumor exclusively were observed among patients with noneuploid or aneuploid OTBM, whereas none of the diploid or euploid tumors recurred (P less than 0.05). DNA cytophotometry thus might be regarded as an effective complementary means to assess the prognosis of individual OTBM cases.

[Exocrine function of a heterotopically transplanted pancreas segment in humans]. / Die exokrine Funktion eines heterotop transplantierten Pankreassegmentes des Menschen.

Pancreatic secretion is involved in circadian regulation of the whole organism. This observation was obtained in animals and humans with pancreatic fistulas. We report on three patients in whom the pancreas was removed totally or subtotally because of chronic pancreatitis with severe pain. A segment of the removed gland was transplanted into the thigh in order to preserve endocrine function. The pancreatic duct was drained by a polyethylene tube until pancreatic duct occlusion. Postoperatively juice volume increased within 3 days and remained constant afterwards with 300 ml in 24 hours. Secretin, cholecystokinin and food intake are able to stimulate the transplanted segment in a typical manner. The secretion showed circadian changes. In all patients the pancreatic juice content of protein, amylase, trypsinogen, calcium, and zink decreased till 11 p.m. After 11 p.m. the content of all substances increased and reached maximal values at 6 a.m. Flow rates and therefore output per minute decreased greatly till 6 a.m. The large juice volume of 300 ml in 24 hours is perhaps the consequence of a break down of the feedback mechanism between intraduodenal trypsin activity and CCK-release. The changes during the night may be of pathogenetic relevance. In the early morning pancreatic juice is highly concentrated and the flow rate is very low. High protein concentrations, high calcium concentrations, and reduced flow rates may lead to protein and calcium carbonate precipitates. This mechanism is under discussion in the pathogenesis of chronic pancreatitis.

Prognostic indices for tumor relapse and tumor mortality in follicular thyroid carcinoma.

To establish an objective basis for therapeutic decisions and follow-up programs in patients with follicular thyroid cancer, the authors developed a prognostic scoring system. The prognostic impact of nine clinical, histologic, and therapeutic parameters was quantified retrospectively based on a multivariate analysis covering 149 patients. The relative relapse risk in follicular thyroid cancer (RR) was 6.8-fold increased in the presence of a moderate when compared with a high degree of histologic tumor differentiation. The RR rose with increasing age of the patient at time of tumor diagnosis by a factor of 1.8 per 20 years. The RR was reduced by a factor of 4.3 after the performance of a neck dissection and by a factor of 2.3 after percutaneous radiation therapy of the neck. The relative mortality risk in follicular thyroid cancer (RM) rose in the absence of a tumor capsule by a factor of 10, in the presence of a moderate compared with a high degree of histologic tumor differentiation by a factor of 5.9, in the presence of distant metastases by a factor of 3.2, and with increasing age of the patient at the time of tumor diagnosis by a factor of 2.2 per 20 years. From these data prognostic indices denoting the individual risk for tumor relapse (IRR index) and tumor mortality (IMR index) were calculated. The indices categorize patients into low-risk, medium-risk, or high-risk groups with regard to tumor relapse and tumor-related death. Consequently, the IRR and IMR indices contribute to select patients with follicular thyroid cancer who need an aggressive form of treatment and an intensive follow-up program. The indices may also be used for risk stratification in prospective therapy trials.

[Mycosis fungoides and Sézary syndrome: diagnostic and prognostic relevance of cellular antigen expression]. / Mycosis fungoides und Sézary-Syndrom: diagnostische und prognostische Relevanz der Expression zellulärer Antigene.

Mycosis fungoides and Sézary syndrome (cutaneous T-cell lymphomas [CTCL]) are recognized, especially in the early stages, as being a potentially difficult diagnostic problem when they have to be histologically differentiated from a series of inflammatory disorders (ID). The diagnostic value of immunophenotyping is controversial; almost all studies have been semiquantitative. The prognostic implications of the antigen expression in CTCL are not known. To acquire more insight into these problems, the expression of differentiation-associated and activation/proliferation-associated antigens was examined in cryostat sections from 35 patients with conclusively diagnosed CTCL and 19 patients with ID. Positive cells were calculated as numbers/mm2 tissue section. The results were analysed statistically. Single antigen expressions were not helpful for differentiation between CTCL and ID. High percentages (89%-96%) of patients with CTCL stages I, II, and III and patients with ID could be classified correctly (discriminant analysis) by combined quantitative assessment of the expression of antigens Ki67 and Ki1/CD30 in the dermis and CD25 in the epidermis. In later stages (IVa, IVb) the note of correct classifications was worse because of the decrease in discriminating properties of the respective antigens. The biological role of antigen expressions was analyzed together with the clinical parameters (age, stage of disease). Stage was the parameter with the most significant influence on patient survival. CD1a-positive epidermal cells (Langerhans cells) were the only cell population that was significantly (P = 0.011) associated with survival. Death resulting from CTCL was significantly (P = 0.003) less frequent in patients with epidermal CD1a-positive cell densities higher than 90 cells/mm2 in comparison with patients with lower numbers.(ABSTRACT TRUNCATED AT 250 WORDS)

Epidermal Langerhans' cell densities influence survival in mycosis fungoides and Sézary syndrome.

Because Langerhans' cells (LC) (CD1a-positive epidermal cells) have been discussed to be involved in the pathogenesis of mycosis fungoides and Sézary syndrome, the authors examined the influence of densities of Langerhans' cells and, concurrently, of other phenotypes retrospectively on survival of 35 patients. Cell densities were assessed on cryostat sections (alkaline phosphatase antialkaline phosphatase-technique) of the respective diagnostic biopsy specimens. Additionally, two clinical parameters (age, stage of disease) were evaluated. CD1a-positive epidermal cells were demonstrated to be the only cell population being significantly associated (P = 0.011) with survival. Death resulting from mycosis fungoides and Sézary syndrome was significantly (P = 0.003) less frequent in patients with epidermal CD1a-positive cell densities higher than 90 cells/mm2 (optimal break point) as compared with patients with lower numbers. These results suggest that Langerhans' cells have a significant impact on prognosis of patients with mycosis fungoides and Sézary syndrome. They play an important role in the host defense mechanisms against these lymphomas rather than to favor their progression as proposed recently.

Role of transmitral blood flow velocity by Doppler echocardiography in the evaluation of coronary artery disease.

To determine the relation between presence and severity of coronary artery disease and diastolic filling abnormalities by Doppler echocardiography, recordings of transmitral inflow velocity were made at rest in 90 patients with coronary artery disease and 28 normals. At the time of the Doppler examination, 81 patients with coronary artery disease (90%) and 10 normals (36%) were treated with antianginal medications. No difference was found in the ratio between early (E) and late (A) diastolic filling velocity (E/A ratio) when comparing patients with greater than 70% obstruction of at least one coronary artery to age-matched normals, regardless of the presence or absence of wall motion abnormalities. The E/A ratio was 1.3 +/- 0.46 in coronary patients with normal wall motion, 1.2 +/- 0.47 in coronary patients with abnormal wall motion, and 1.3 +/- 0.53 in both samples of age-matched normals. Multivariate analysis of the relation between E/A ratio and other variables showed that heart rate (F = 24.46, p less than 0.00001) and age (F = 19.51, p less than 0.00001) were significant independent determinants of the E/A ratio, while the presence or severity of coronary artery disease, the presence of hypertension, the magnitude of wall motion abnormalities, and end-diastolic dimension by echocardiography were not. These data suggest that transmitral inflow velocity recordings by Doppler have limited value for the recognition of coronary artery disease, since the E/A ratio is profoundly influenced by other factors, such as heart rate and age.

[Changes in pure human pancreatic juice in chronic pancreatitis]. / Veränderungen im reinen menschlichen Pankreassaft bei chronischer Pankreatitis.

Investigations of pancreatic juice revealed new insights into the pathogenesis of chronic pancreatitis (cP). But many results are contradictory. In this paper pure human pancreatic juice from patients with cP (n = 14) was compared with results obtained from normal subjects (n = 22). The pancreatic juice was obtained endoscopically recording the absorption (280 nm) simultaneously. By means of this special technique 4 fractions could be exactly distinguished: 1. wash-out-period, 2. phase of secretin action, 3. phase of pancreozymin (CCK) action, and 4. post-CCK-phase. Total protein, trypsinogen, zinc sodium, and potassium were determined. In fraction 1 (wash-out-period) mean values of protein, trypsinogen and zinc are lower in patients with cP compared with control subjects. In case of zinc the difference is statistically significant. In fraction 2 (secretin-phase) no differences could be detected between cP and control subjects. In contrast in fraction 3 (CCK-phase) mean values of protein and trypsinogen are lower in control subjects than in patients with cP. But the standard deviations are so high that all differences are not statistically significant. The results indicate that under fasting conditions the pancreatic juice content of protein, trypsinogen and zinc is lower in patients with cP. But patients with cP can be stimulated much better with CCK than control subjects. Till now such a different behaviour during wash-out-period and CCK-stimulation is not reported in the literature.

Radioprotection of minipig salivary glands by orciprenaline-carbachol. An ultrastructural and semiquantitative light microscopic study.

Parotid and submandibular glands of miniature pigs were exposed to 36 Gy X-irradiation given as 6 x 6 Gy in 3 weeks. Half of the animals received orciprenaline and carbachol before each dose. The effects were analysed 6 months later by light and electron microscopy. Ultrastructural examination showed less change in the pretreated glands. Semi-quantitative light microscopic data confirmed the significance of the differences. Acinar cells of both glands were significantly more numerous (P less than 0.01) and the cells were better preserved (P less than 0.01) in the pretreated group. The effect was more pronounced in the parotid gland, which appeared almost normal. Intercalated ducts of the parotid glands (P less than 0.01) and striated ducts of the submandibular glands (P less than 0.05) showed less change in pretreated animals. The findings confirm the radioprotective effect of pharmacologically induced degranulation of acinar cells. The biological effects of the radiation schedule (cumulative radiation effect value 18.76) as well as the dosage of orciprenaline and carbachol are within the normal range of medical treatment. Similar results may be expected from future studies in man.

[Radioimmunotherapy of solitary liver metastases using intratumor instillation of 131I-labeled monoclonal antibodies--initial results of a clinical study]. / Radioimmunbehandlung solitärer Lebermetastasen mittels intratumoraler Instillation 131J-markierter monoklonaler Antikörper--Erste Ergebnisse einer klinischen Studie.

Solitary liver metastases (carcinoembryogenic antigen positive) in two patients suffering from colon carcinoma were multifocally injected with 131I-labelled monoclonal antibodies (131I-MAb) against the carcinoembryogenic antigen (CEA). The 131I activity in the metastases decreased biexponentially. The 131I serum concentration declined triexponentially in patient 1 and monoexponentially in patient 2. The radiation dose to the whole tumor volume amounted to 358 Sv and 762 Sv, respectively; the whole-body radiation dose was 87.5 mSv for patient 1 and 39.0 mSv for patient 2. Complications did not occur. Before treatment there had been a volume doubling time of the metastases of 1.5 and 0.9 months, respectively; this contrasts with a constant tumor volume after treatment as observed over the follow-up period of 3.5 and 2 months, respectively. The CEA serum concentration decreased after 131I-MAb instillation within 1.5 and 2.5 months to 66% and 58%, respectively, when compared with values immediately before treatment. On the basis of these results the intratumoral application of 131I-MAb appears in selected cases to be a suitable method of slowing down growth of liver metastases from gastrointestinal tumors.

Dendritic/Langerhans cells and prognosis in patients with papillary thyroid carcinomas. Immunocytochemical study of 106 thyroid neoplasms correlated to follow-up data.

Paraffin sections of 106 primary thyroid carcinomas were the subject of an immunocytochemical study to determine the density of infiltrates of S-100 protein-positive dendritic/Langerhans cells (LC), lysozyme-positive histiocytes, and LCA-positive lymphocytes. Evidence of dense infiltrates of LCs was found only in the majority of papillary thyroid carcinomas (PCs). The determination of the quantity of LCs proved to be a highly effective means of assessing the prognosis of these tumors. Irrespective of other morphologic and clinical features, no single instance of death resulting from cancer occurred among 23 PCs with dense LC infiltrates (including 6 tumors of stage pT4), while 9 of 53 (17%) of the remaining patients ultimately died from thyroid cancer. On the other hand, the degree of histiocytic and lymphocytic infiltrations was not associated with a distinct biologic behavior neither among PC nor among the remaining thyroid carcinomas. These findings suggest that LCs may play an important role in the immunologic defense mechanisms of the host against the tumor only in the papillary type of thyroid cancer.

Leu-M1 immunoreactivity and prognosis in medullary carcinomas of the thyroid gland.

Leu-M1 antigen is a monocyte/granulocyte-related marker known to be consistently expressed in the Reed-Sternberg cells of patients with Hodgkin's disease and to be present in tumour cells of a variety of non-haematopoietic neoplasms, most of them adenocarcinomas. The biological significance of this aberrant reaction has not yet been clarified. Recently, however, we have demonstrated that marked epithelial Leu-M1 immunoreactivity significantly correlated with an unfavourable clinical course in papillary carcinomas of the thyroid gland. The findings of the present study obtained from surgical specimens of 39 tumours suggest that Leu-M1 immunostaining also provides significant prognostic information in patients with medullary carcinoma (MC) of this organ. Irrespective of other morphological and clinical features, local recurrences occurred 2.9 times (P less than 0.005) and death resulting from tumour occurred 4.3 times (P less than 0.03) more frequently among MCs with marked Leu-M1 positivity (greater than 15% tumour cells positively stained) in comparison to tumours with only slight or absent immunoreactivity. A significantly higher recurrence rate of intense Leu-M1-positive MCs was even evident when comparing only tumours of stage pT1-3N0M0 (P less than 0.005). Our findings infer that Leu-M1 immunostaining might be of clinical relevance to the selection of different aggressive adjuvant therapeutic procedures to be used in MCs with high or low malignant potential.

Increased thyrotropin binding in hyperfunctioning thyroid nodules.

The object of this study was to investigate TSH receptors in hyperfunctioning thyroid nodules (HFN). In HFN, obtained from seven patients, 125-I-TSH binding as determined by equilibrium binding analysis on particulate membrane preparations, was found to be significantly increased as compared with normal thyroid tissues (five patients; P less than 0.001). Scatchard analysis of TSH-binding revealed two kinds of binding sites for both normal thyroid tissue and HFN, and displayed significantly increased association constants of high- and low-affinity binding sites in HFN (Ka = 11.75 +/- 6.8 10(9) M-1, P less than 0.001 and Ka = 2.1 +/- 1.0 10(7) M-1, P less than 0.025; x +/- SEM) as compared with normal thyroid tissue (Ka = 0.25 +/- 0.06 10(9) M-1, Ka = 0.14 +/- 0.03 10(7) M-1; x +/- SEM). The capacity of the high-affinity binding sites in HFN was found to be decreased (1.8 +/- 1.1 pmol/mg protein, x +/- SEM) in comparison with normal thyroid tissue (4.26 +/- 1.27 pmol/mg protein; x +/- SEM). TSH-receptor autoradiography applied to cryostatic tissue sections confirmed increased TSH binding of the follicular epithelium in HFN. These data suggest that an increased affinity of TSH-receptor sites in HFN in iodine deficient areas may be an important event in thyroid autonomy.

[Morphology and prognosis of follicular thyroid cancer--a clinico-pathologic and DNA cytometric study of 95 tumors]. / Morphologie und Prognose des folliculären Schilddrüsencarcinoms--Eine klinisch-pathologische und DNS-cytometrische Untersuchung an 95 Tumoren.

A retrospective study of 95 follicular thyroid carcinomas was conducted to evaluate the prognostic value of different morphological and clinical features. The biological behaviour of these tumours was primarily influenced by presence or absence of a capsule type of confinement: the frequency of lethal outcome among widely invasive carcinomas was six times higher than among encapsulated neoplasms. Furthermore, dismal prognosis could be demonstrated for tumours occurring in older patients (with a sharp break in the prognosis at the age of 52 years) and for those lesions which displayed oxyphilic metaplasia. The same effect was shown for presence of lymph node metastasis, tumour invasion of the cervical soft tissue and, for the case of encapsulated carcinomas, distant haematogenous spread. Conversely, the degree of differentiation and the patients' sex proved to have no significant influence on prognosis. In 22 carcinomas, cytophotometric and flow-cytometric determinations of DNA values were performed. These procedures revealed to have only limited diagnostic value, since for the majority of the tumours, benignancy or malignancy could not be judged from the DNA histograms. However, DNA measurements proved to contribute valuable information for the prognosis in individual cases of widely invasive follicular carcinomas. The discussion focuses on the diagnostic, therapeutic and prognostic relevance of these findings and on their impact on subclassification of follicular thyroid carcinomas.

Prognostic significance of Leu-M1 immunostaining in papillary carcinomas of the thyroid gland.

Leu-M1 antigen is a monocyte/granulocyte-related marker known to be consistently expressed in the Reed-Sternberg cells of patients with Hodgkin's disease. Recently, however, the presence of Leu-M1 has also been noted in tumour cells of a variety of non-haematopoietic neoplasms, most of them adenocarcinomas. The biological significance of this aberrant reaction has not been clarified. We have been able to demonstrate marked epithelial Leu-M1 immunoreactivity (greater than 15% tumour cells positively stained) in 24 out of 76 (32%) papillary carcinomas of the thyroid gland (PC). This phenomenon was more frequently observed among PCs at an advanced stage of disease (pT4 vs. pT1-3 and M1 vs M0 p less than 0.05). The degree of epithelial Leu-M1 positivity was also shown to be significantly correlated to the clinical course of PC. Irrespective of other morphological and clinical features, death resulting from cancer occurred 17 times more frequently among PCs with marked Leu-M1 positivity (8/24) when compared with tumours with only slight or absent immunoreactivity (1/52) (p less than 0.00005). These findings suggest that Leu-M1 immunostaining provides significant prognostic information for patients with papillary carcinoma of the thyroid gland.