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The expression of tumour promoter gene S100A4, metastasis suppressor gene nm23, oestrogen and progesterone receptors, and tumour grade and size have been investigated for their potential to predict breast cancer progression. The molecular and cellular data have been analysed using artificial neural networks to determine the potential of these markers to predict the presence of metastatic tumour in the regional lymph nodes. This study shows that tumour grade and size are poor predictors. The relative expression of S100A4 and nm23 genes is the single most effective predictor of nodal status. Inclusion of oestrogen- and progesterone-receptor status with tumour grade and size markers improves prediction; however, there may be some overlap between steroid receptors and molecular markers. This study also underscores the power of artificial neural network techniques to predict the potential of primary breast cancers to spread to axillary lymph nodes. This could aid the clinician in determining whether invasive procedures of axially node dissection can be obviated and whether conservative forms of treatment might be appropriate in the management of the patient.

Leukocyte-associated Ig-like receptor-1 (LAIR-1) is a surface molecule that functions as an inhibitory receptor on natural killer cells, T lymphocytes and monocytes. Here, we provide evidence that occupancy of LAIR-1 on human myelomonocytic leukemic cell lines inhibits proliferation and leads to programmed cell death (PCD), evaluated by propidium iodide staining and transmission electron microscopy. Interestingly, PCD elicited via LAIR-1 was not blocked by different caspase inhibitors, at variance with apoptosis induced via CD95/Fas, which was prevented by the caspase-1 and caspase-8 specific inhibitors. In addition, we show that the p65 subunit of the nuclear factor kappaB (NF-kappaB), constitutively expressed in the nucleus of these cell lines, was retained in the cytoplasm upon engagement of LAIR-1. This was evident already 8 h after LAIR-1 occupancy, when apoptosis was not yet detectable by fluorometric or ultrastructural analysis. Moreover, a reduction in inhibitor kappaBalpha phosphorylation was observed after LAIR-1 engagement. As blocking of NF-kappaB activation has been shown to rescue sensitivity to anti-cancer drugs in solid tumors, we suggest that LAIR-1 may represent a possible target for pharmacological approaches aimed to potentiate anti-leukemic therapy.

Background. The possibility of performing transplantation several days after explant seems to be a peculiarity of islet grafts, and the opportunity to cryo-preserve human islets may permit an indefinite period for modulating the recipient immune system. The aim of the present study was the evaluation of in vitro and in vivo functional properties of cryopreserved human islets. Methods. We used six consecutive human islet preparations not suitable for an immediate transplantation in diabetic patients because the limited islet mass separated. The in vitro function of cryo and fresh islets was studied by determination of insulin and glucagon secretion in response to such classical stimuli as glucose (16.7 mM), glucose (16.7 mM) + 3-isobutyl-1-methylxanthine (0.1 mM), arginine (10 mM), and tolbutamide (100 mu M). In vivo isfet function was assessed through intravenous glucose tolerance tests performed at 15, 30, 60, and 90 days after transplantation of 1000 hand-picked fresh or cryopreserved islets in nude mice. Results. Basal secretion of true insulin was significantly higher in cryopreserved islets than in fresh ones. The response of cryopreserved islets to arginine and glucose + isobutyl-l-methylxanthine seemed partially impaired. Proinsulin-like molecule secretion seemed higher in cryopreserved than in fresh islets in response to all secretagogues used, and the difference was statistically significant for arginine. The capacity of human cryopreserved islets to maintain a correct metabolic control in diabetic nude mice was progressively lost in 3 months. Conclusions. These findings showed that cryopreservation affects the function of isolated human islets, maintaining in vivo function for a limited period of time.

To identify prognostic subgroups among non-functioning (nonsyndromic) pancreatic endocrine tumours, a series of 61 tumours were analysed systematically for macroscopic, histopathological and immunohistochemical variables potentially predictive of malignancy. High-grade nuclear atypia, elevated mitotic rate and multifocal necrosis allowed us to separate 5 poorly differentiated carcinomas from 56 well differentiated tumours. Among the latter, 29 well-differentiated carcinomas showing gross local invasion or metastases were identified. Vascular or perineural microinvasion, Ki67 proliferative index2%, mitotic rateor = 2, sizeor = 4 cm, capsular penetration, nuclear atypia, lack of progesterone receptors and presence of calcitonin were among the variables correlated with malignancy. The first two were the most sensitive and specific. Their presence or absence was used in the 27 tumours lacking evidence of malignancy at the time of surgery to separate 11 cases with increased risk of malignancy (in 2 of which metastases developed during follow-up) from 16 cases with limited risk. The resulting four prognostic groups of non-functioning pancreatic endocrine tumours (limited- and increased-risk tumours, well-differentiated carcinomas and poorly differentiated carcinomas) showed distinct survival curves, which were significantly affected by vascular microinvasion, Ki67 proliferative index and metastases.

A case of Primary Malignant Lymphoma of the Spleen (PMLS) with exclusive red pulp involvement is described and discussed. Although the unusual topographic presentation the authors emphasize the physiologic arrangement of lymphoid cell in splenic red pulp cords that can give origin to the neoplasia. They moreover discuss problems of differential diagnosis with Malignant Histiocytosis (MH), Hairy Cell Leukemia (HCL) and Myeloid Process, both by morphology and immunohistochemistry.

We studied K-ras and p53 gene mutations in a panel of 57 primary pancreatic cancers including ductal and nonductal tumors. DNAs were obtained from formalin-fixed, paraffin-embedded material. Target sequences were amplified by polymerase chain reaction and analyzed by denaturing gradient gel electrophoresis and sequencing. Both K-ras and p53 genes were frequently mutated in ductal cancers (25 of 35, 71.4%; 18 of 35, 51.4%, respectively). K-ras mutations were confined to the second position of codon 12 where base transitions and transversions were equally observed. p53 changes were mainly missense mutations. Transitions and transversions were found equally with a prevalence of G:C--A:T changes among transitions. No gene alterations were present in the 6 exocrine nonductal tumors and (with one exception) in the 12 endocrine tumors analyzed. Our results indicate that mutated K-ras and p53 genes can cooperate in the establishment of ductal pancreatic cancers, whereas other genetic events have to be present in nonductal tumors. Moreover, K-ras alterations may represent an early event in ductal tumorigenesis, as suggested both by the high gene mutation frequency and by the presence of mutations in low-grade tumors. On the contrary, p53 gene changes seem to represent an event required for the malignancy progression of ductal tumors from lower to higher grades.

We describe five cases of extragonadal germ cell tumor (EGCT) diagnosed by the electron microscope (EM) on cytological material. The clinical diagnosis was incorrect in all cases and EGCT was suspected in two cases; cytological diagnosis by light microscopy confirmed the presence of malignant tumor cells, but did not identify the cytotype/s correctly except in one case. Ultrasonography, laparoscopy. and autopsy (in case 3) excluded a primitive germ cell tumor (GCT). Histology confirmed the EM diagnosis in all cases. EM, even of scanty or necrotic cytological material, is particularly useful for mediastinal and retroperitoneal masses. In case of EGCT, EM can identify the different cytotypes and the different ultrastructural subcellular cytotypes and demonstrates a close relation between seminomatous and nonseminomatous GCT, which could influence their classification and prognosis. © 1992 Wiley-Liss, Inc.

The ultrastructural localization of chromogranin A (Chr A) was studied in eleven neoplasias of the diffuse neuroendocrine system (3 pancreatic islet-cell tumours, 1 medullary carcinoma of the thyroid, 1 large bowel and 1 small bowel carcinoid tumours, 2 carcinoid tumours of the lung, 1 adenoma of the parathyroid gland, 2 pheochromocytomas of the adrenal gland). On account of the great influence of the technical treatment of the samples on the immunolocalization of Chr A, the effect of the following variables was studied in a case of pheochromocytoma: fixation in glutaraldehyde versus paraformaldehyde, postfixation in osmium tetroxide versus omission, embedding in epoxy resin versus acrylic resin. The method of choice for the better preservation of the antigenic character of the tissue was found to be fixation in 4% paraformaldehyde, omission of osmium postfixation and embedding in LRWhite acrylic resin; by this procedure we were able to find Chr A in the neurosecretory granules of all the studied cases, using three commercially available antibodies directed against Chr A. These findings further confirm that Chr A is a reliable marker for the study of neuroendocrine neoplasias by electron microscopy.