Sclerosing epitheloid fibrosarcoma. A report of two cases.

Sclerosing epitheloid fibrosarcoma is a rare, histologically well-defined member of adult fibrosarcoma group of soft tissue tumors. Its main histological features are nests and cords of rounded tumor cells surrounded by hyalinized collagenous stroma. Epitheloid appearance with marked sclerosis and infiltrating growth pattern, along with occasional immunohistochemical positivity for epithelial markers may be highly suggestive of infiltrating carcinoma. Despite of bland cytological features clinical course is often protracted with a high local recurrence rate and late metastases. In this report, we present histopathological characteristics of two cases of sclerosing epitheloid fibrosarcoma, together with their clinical presentation, follow-up information and differential diagnosis.

Syndrome of inappropriate secretion of antidiuretic hormone due to malignant thymoma.

The authors present the case of a 51-year-old female with a syndrome of inappropriate secretion of antidiuretic hormone (SIADH) due to a malignant thymoma. Laboratory examinations of the patient showed hyponatremia, plasma hypoosmolarity in the presence of concentrated urine and normal urine excretion of sodium. CT revealed a mass lesion in the mediastinum. A biopsy of the mediastinal mass was performed and the diagnosis of thymoma with SIADH was established. This is a rare description of a malignant thymoma associated with SIADH.

Aberration of FHIT gene is associated with increased tumor proliferation and decreased apoptosis-clinical evidence in lung and head and neck carcinomas.

BACKGROUND: Human FHIT (fragile histidine triad) gene is highly conserved gene homologous to a group of genes identified in prokaryotes and eukaryotes. Loss of FHIT function may be important in the development and/or progression of various types of cancer. MATERIALS AND METHODS: We undertook a clinical study to analyze the relation between aberrant function of FHIT gene, tumor cell proliferation, and intensity of apoptosis as well as prognostic output in lung and squamous cell head and neck carcinoma (HNSCC). Status of FHIT gene, expression of p21waf1, intensity of apoptosis, and cell proliferation were analyzed in HNSCC and lung carcinoma tissues by molecular genetic methods, immunohistochemistry, [3H]-thymidine labeling method, and FACScan analysis in frozen and paraffin-embedded tissue sections. RESULTS: The majority of the malignant lung and HNSCC lesions displayed aberrant expression of FHIT gene, followed by low or negative expression of p21waf1, and increased intensity of cell proliferation. Similar results were obtained on synchronous combinations of normal, precancerous, and cancerous head and neck tissues. The observed changes increased with progression of these lesions. We examined tumor and corresponding normal tissue samples for microsatellite markers D3S1300 and D3S4103 to evaluate the loss of heterozygosity (LOH) at the FHIT gene loci. We found high percentage of LOH in both lung tumors and HNSCC (75% for D3S1300 and 79% for D3S4103 in lung cancer, and 87% for D3S1300 and 78% for D3S4103 in HNSCC). The median survival time of the patients suffering from lung cancer without FHIT protein expression was 22.46 months and that of the patients with FHIT expression 36.04 months. FHIT-negative cases tended to correlate with a worse prognosis, but this was not statistically significant. Median survival time of HNSCC patients without FHIT protein expression was 30.86 months and that of the patients with FHIT expression was 64.04 months (p < 0.05). CONCLUSIONS: Our results show a correlation between aberrant FHIT expression, a low rate of apoptosis, and high tumor cell proliferation. Aberrant FHIT gene could be a prognostic marker in lung cancer.

Natural zeolite clinoptilolite: new adjuvant in anticancer therapy.

Natural silicate materials, including zeolite clinoptilolite, have been shown to exhibit diverse biological activities and have been used successfully as a vaccine adjuvant and for the treatment of diarrhea. We report a novel use of finely ground clinoptilolite as a potential adjuvant in anticancer therapy. Clinoptilolite treatment of mice and dogs suffering from a variety of tumor types led to improvement in the overall health status, prolongation of life-span, and decrease in tumors size. Local application of clinoptilolite to skin cancers of dogs effectively reduced tumor formation and growth. In addition, toxicology studies on mice and rats demonstrated that the treatment does not have negative effects. In vitro tissue culture studies showed that finely ground clinoptilolite inhibits protein kinase B (c-Akt), induces expression of p21WAF1/CIP1 and p27KIP1 tumor suppressor proteins, and blocks cell growth in several cancer cell lines. These data indicate that clinoptilolite treatment might affect cancer growth by attenuating survival signals and inducing tumor suppressor genes in treated cells.

Squamous cell lung carcinomas: the role of nm23-H1 gene.

This analysis of 32 pairs of human squamous cell lung carcinomas and normal matched control DNA demonstrates that loss of heterozygosity (LOH) is infrequent at the nm23-H1 locus, affecting only 2 of the 18 informative cases. Both LOH cases were in the tumor stage IIIA. One tumor was of poor and the other of moderate histological grade. These and an additional 34 tumor samples were also analyzed immunohistochemically for the presence of nm23-H1 protein. Of the 66 cases tested for the presence of nm23-H1 protein 54 were negative. Eight samples exhibited up to 35% positive cells (with weak immunostaining intensity) and four between 35% and 70% (moderate immunostaining intensity); no sample showed more than 70% positive cells. Noncancerous lung parts contained no nm23-H1 protein. nm23-H1 expression was independent of TNM stage, grade, tumor size, and patient's survival. Two samples with LOH were negative for nm23-H1 protein. We therefore conclude that neither loss of heterozygosity of the nm23-H1 gene nor the intensity of specific protein expression are related to squamous cell lung carcinoma development and progression.

[Bronchopneumonia, obstructive bronchitis and bronchiectasis in children with adenovirus infections]. / Bronhopneumonije, opstruktivni bronhitis i bronhiektazije u djece s adenovirusnim infekcijama.

During the five-year period 56 children were treated in hospital due to respiratory infections caused by adenovirus. Clinical, laboratory and radiographic signs of the illness are presented. The infections manifested as the upper respiratory tract infection in 3 patients (5.4%), obstructive bronchitis in 16 patients (28.6%), bronchopneumonia in 32 patients (57.1%) and bronchiectasis in 5 patients (8.9%). Three children were operated: bilobectomy was performed in two cases, and left-sided pulmonectomy in one case. Histologically, bronchiectasis was found in two cases and bronchiolitis obliterans in one case. In this work we tried to show the gravity, importance and consequences of the adenoviral infection of the respiratory tract in children.

Nucleolar organizer region in transitional cell carcinoma of the bladder.

The silver staining technique that identifies NORs (nucleolar organizer regions) associated proteins was used for examining changes in nucleolar organizer region numbers in transitional cell carcinoma of the bladder. This method reveals NORs as black dots in the cell nuclei, and the number of NORs per cell (NORs/cell) has been taught to be related to cellular activation and to be a possible predictor of clinical outcome. A hundred specimens of transitional cell carcinoma of the bladder divided into four histologic grades (Ash classification) with 25 specimens each, and 25 specimens of normal bladder mucosa were analyzed. It has been demonstrated that the amount of protein synthesized by carcinoma varies according to its histologic grade, i.e. the higher histologic grade, the greater the NORs/cell number for each histologic grade. The characteristic mean NORs/cell SD was determined (GI 4.85 +/- 0.82, GII 5.94 +/- 1.42, GIII 8.54 +/- 1.01 and GIV 8.72 +/- 1.42), among which statistically significant differences were found. For similar histologic grades the characteristic mean NORs/cell +/- SD showed no statistically sex and age related differences. In some cases the mean NORs/cell for the examined carcinoma did not match the characteristic mean NPRs/cell +/- SD for the respective histologic grade.

Loss of heterozygosity of the nm23-H1 gene in human renal cell carcinomas.

This study evaluates the potential contribution of the nm23-H1 gene to malignant transformation in patients with renal cell carcinoma. Using specific oligonucleotide primers for the nm23-H1 microsatellite repetitive sequence, gene instability was followed by polymerase chain reaction/loss of heterozygosity assay on 54 tumor specimens and the corresponding normal tissue samples. We also determined, immunohistochemically, the relative concentration and localization of the nm23-H1 protein product. From 77.7% informative cases, DNA from 6 tumors exhibited loss of heterozygosity, regardless of the tumor stage (TNM). Out of 39 samples analyzed, 30 were negative for Nm23-H1 protein, while the others were only slightly positive. No correlation with tumor stage was found. Normal renal tissue was also negative for this protein. Our results provide the evidence for loss of heterozygosity, followed by means of microsatellite tandem-repeat polymorphism, at the nm23-H1 locus in renal cell carcinoma. However, since no correlation was found between the tumor stage or metastatic potential on the one hand, and allelic loss and specific protein expression on the other, it seems that nm23-H1 does not play a key role in the invasiveness of this tumor type.

Concomitant point mutation of tumor suppressor gene p53 and oncogene c-N-ras in malignant neuroendocrine pancreatic tumor.

Activation by point mutation of ras family genes as well as point mutations of the p53 tumor suppressor gene are found in many tumors. Here we describe a rare case of malignant neuroendocrine pancreatic tumor with multiple metastases in different organs showing strong positivity for synaptophysin, glucagon-like peptide 1, pan-cytokeratin, moderate positivity for chromogranin, Phe-5 and calcitonin and weak positivity for vasointestinal peptide. We found a point mutation at codon 61 of the c-N-ras oncogene, and point mutations in the p53 tumor suppressor gene in the primary tumor as well as in its metastases in liver. The mutation in the c-N-ras gene was a cytosine to adenine transversion, resulting in the amino-acid lysine. Allele specific hybridization showed that the mutation involved one of two c-N-ras alleles as the oligonucleotide for the normal codon also hybridized to amplified tumor DNA. Concomitant mutation of the p53 tumor suppressor gene at codons 248 and 249 was found. The mutation in codon 248 was a cytosine to guanine transversion resulting in the amino-acid glycine. The mutation in codon 249 was a third base, G- > T, transversion leading to a change from arginine to serine. This is the first time that concomitant point mutations in c-N-ras and p53 have been found in a neuroendocrine pancreatic tumor. Based upon these and our previous results, we concluded that these genetic changes may play a role in the development of this particular pancreatic tumor.

Molecular genetics of malignant insulinoma.

Malignant insulinoma is an rare form of cancer with poor prognosis and a reported 5-year survival of 35%. Relatively little is known about the etiology of this disease or of the oncogenes and tumor suppressor genes that participate in its genesis and progression. To address this issue, several protooncogenes, including K-ras, N-ras, erbB-2, erbB-3,c-myc, c-fos, c-jun were examined. Also analyzed was the expression of the growth factors TGF-alpha, EGF, and insulin as well as the EGF receptor (EGF-R), p53 and the putative anti-metastasis gene nm23-H1. These were examined in malignant insulinomas, benign insulinomas, pancreatic B cell hyperplasias and in normal endocrine pancreas. Normal endocrine pancreas showed moderate immunoreaction for c-myc and a strong reaction for insulin. All other parameters were negative. Benign pancreatic B cell hyperplasias were slightly or moderately positive for N-ras and TGF-alpha, and were weakly positive for EGF-R. They were strongly positive for c-myc and insulin. In malignant insulinomas there was strong immunoreaction for c-myc, TGF-alpha, N-ras, K-ras and p53. Insulin reaction was moderate or strong. Molecular genetic studies have been performed for the presence of activating point mutations in codon 12 of the c-K-ras oncogene. Mutations were detected using primer-mediated, mutant-enriched, polymerase chain reaction-restriction fragment length polymorphism analysis and were further characterized by allele-specific oligonucleotide hybridization. Four out of six patients with malignant insulinoma and two out of eight patients with benign insulinoma harbored K-ras point mutations at codon 12. All patients with mutated K-ras oncogene also had elevated levels of p53 protein as well as c-myc and TGF-alpha. In one extremely malignant case we found concomitant mutation at codon 12 of K-ras and codon 61 of the N-ras gene. Our data are consistent with the idea that malignant progression is accompanied by the progressive accumulation of multiple genetic lesions and suggest that activation of myc, TGF-alpha and ras genes may be early events in the development of insulinoma.

Proliferating cell nuclear antigen (PCNA) as a prognostic factor for colorectal cancer.

PCNA (proliferating cell nuclear antigen) is a cell cycle related protein that is maximally elevated in late G1 and S-phase of proliferating cells. 114 biopsy specimens of colorectal cancer were immunolabeled with PC 10 which specifically recognizes PCNA; Dukes' staging and histological grading were estimated for each case. All patients were followed-up for at least 60 months or to death. All data were analysed by the computer program NCSS (Number Cruncher Statistical System). According to the results, PCNA-index may be considered an independent prognostic factor for colorectal cancer; it may also be helpful in supporting the therapeutic strategies based only on Dukes' stage.

[Pulmonary arteriovenous fistula in an adolescent]. / Plucna arterijsko-venska fistula u adolescenta.

We report the case of a patient, a 19-year-old young man, with a rare malformation of the pulmonary blood vessels--a complex arteriovenous (A-V) fistula. The disease was characterized by typical signs of the right-to-left shunt: cyanosis, clubbed fingers and exertional dyspnea. Hypoxemia and polyglobulia were present in the blood examination findings and functional tests showed significantly reduced diffusion lung capacity and progressive dyspnea, while ergometry revealed cyanosis. The physical examination, ECG and ultrasound of the heart were normal as well as aortography. The final diagnosis was made by pulmonary angiography which showed a complex A-V malformation of several feeding arteries and profuse initial multiple venous drainage. Following a successful surgical procedure the diagnosis was also confirmed histopathologically-diffuse teleangiectatic A-V fistula of the lower lobe of the left lung. Following surgery cyanosis, dyspnea, hypoxemia and polyglobulia disappeared and the young man has been well for the following two years.

[Mediastinal and pulmonary hemangiopericytoma]. / Hemangiopericitom medijastinuma i pluca.

Two cases of hemangiopericytomas, localized in the mediastinum and lung were described. In the former case the tumour was operated 19 years ago and later three relapses of the disease occurred. Today the patient is well without signs of the tumour. In the second case there was no relapse 6 years after the operation. The biological behaviour of hemangiopericytomas cannot be predicted on the basis of the clinical and morphological signs.

Frozen section analysis of breast biopsy specimens.

The authors compared the diagnoses from intraoperative frozen section consultation with the final diagnosis using permanent tissue sections from 179 breast biopsy specimens. Of these, there were 175 correct diagnoses (97.8%), two diagnoses were incorrect (1.1%) and two were inconclusive (1.1%). The distribution of the correct diagnoses within each particular group of breast diseases proves that in the invasive tumor group the diagnosis on FS was correct for 101 patients (98.1%) and incorrect for two patients (1.9%). In the fibrocystic breast disease group, diagnoses correlated for 42 patients (97.7%), whereas the problem in diagnosing the extent of epithelial proliferation appeared for only one patient (2.3%) and was categorized as an inconclusive diagnosis. Of 4 incorrect and inconclusive diagnoses, two occurred as a result of sampling nonrepresentative tissue specimens and two as a result of diagnostic misinterpretation. This study has shown that for the determination of the histological type of carcinoma, FS is not of significant morphological value since correct diagnoses were made for only 60% of the patients.

[Sclerosing hemangioma of the lung]. / Sklerozirajuci hemangiom pluca.

The sclerosing hemangioma of the lung is a rare benign tumor. Its histogenesis has not been explained yet. Following the electron-microscopic and immunohistochemical researches, the opinions have been still unhomogeneous. Therefore, it is concluded that is a tumor of epithelial, endothelial, mesenchymal and even mesothelial origin. This study deals with this tumor. Its immunohistochemical analysis points at its epithelial character.

[Spontaneous bacterial peritonitis in patients with decompensated liver cirrhosis and "tense" ascites]. / Spontani bakterijski peritonitis u bolesnika s dekompenziranom cirozom jetre i "napetim" ascitesom.

In the study 52 patients with decompensated liver cirrhosis and "tense" ascites were included. According to the clinical picture, ascites cultures and the number of polymorphonuclears in cmm of the ascitic fluid, all patients were selected in one of the following groups: 1. group of patients with sterile ascites (28), 2. group of patients with spontaneous peritonitis (16), and 3. group of patients with bacterascites (8). The results have shown that the incidence of spontaneous peritonitis is much higher in the group of "tense" ascites patients than in the group of all patients with ascites, the ratio being 30.7% compared to 6% in all cirrhotic patients with ascites. Spontaneous bacterial peritonitis correlates with increased polymorphonuclears in the ascitic fluid (p less than 0.05), decreased pH values (p less than 0.0), and increased amounts of total proteins in the ascitic fluid (p less than 0.05). The lethality rate in the group of spontaneous peritonitis and sterile ascites was 43.7% and 7.1% respectively. Early diagnosis and, of course, adequate therapy are the main points in spontaneous bacterial peritonitis.

[Heart rupture in myocardial infarction]. / Ruptura srca kod infarkta miokarda.

During the period 1972-1986. 8.589 adult patients died at the Dr. Josip Kajfes General Hospital in Zagreb. Post mortem examinations were performed in 4.459 patients and 496 cases discovered, which were in keeping with so-called ischaemic heart disease (IHD). Acute myocardial infarction (AMI) was found in 322 patients and rupture of the heart (HR) in 64 patients. According to our results IHD and AMI occurred more frequently in persons over 60 years of age, but women were affected on the average some 6 years later than men in all three groups of test subjects. The anterior wall of the left ventricle was the most common site of both AMI and HR. Heart rupture occurred on the average some 3 days after an attack of AMI (average 3.46 days) but this was seen in women a whole day later than in men. The results obtained showed moreover that the mortality rate in patients who died from IHD and AMI over the analysed 15-year period registered a decline, while the mortality rate of patients who died of HR in the same period remained more or less unchanged.

The influence of dopamine agonists and antagonists on indomethacin lesions in stomach and small intestine in rats.

Dopamine agents (saline in control groups) were coadministered with indomethacin by either single or repeated application. The ulcerogenic effect (erosions and/or ulcers) of repeated given indomethacin on gastric mucosa differed clearly from that on intestinal mucosa. The effect on intestinal mucosa was markedly greater than after a single dose. The effects of dopamine agents appeared to be more consistent. Domperidone and haloperidol, given as single or repeated doses, strongly aggravated both the gastric and intestinal lesions. Bromocriptine and amantadine had a protective effect. The adverse effects of both dopamine antagonists (increased after repeated administration) were strongly inhibited by the simultaneous administration of either bromocriptine or amantadine. The involvement of the dopamine system (central or peripheral) in the mechanisms that maintain gastric (probably related to cytoprotection also) and intestinal mucosa integrity is therefore suggested.

The influence of dopamine receptor agonists and an antagonist on acute pancreatitis in rats.

The influence of the dopamine receptor-stimulating agent, bromocriptine, the dopamine-releasing drug, amantadine, and the dopamine antagonist, domperidone, on acute pancreatitis was studied in rats. Acute pancreatitis was induced by ligation of the bile duct at its point of entry into the duodenum. Each drug was applied intraperitoneally 1 h before induction of acute pancreatitis and all the surviving animals were killed 24 h thereafter. The control, saline-pretreated animals exhibited the mortality rate, macroscopical and histological changes, as well as increase of serum amylase levels that were consistent with acute pancreatitis. Domperidone induced a large increase in serum amylase which was significantly reduced by the simultaneous administration of bromocriptine. However, both bromocriptine and amantadine, when given separately did not prevent the increase of serum amylase levels to the control levels. Statistical analysis showed that the difference between the mortality rate in the control and treated groups did not reach the level of significance probably due to the rather limited number of animals used. On the other hand, application of bromocriptine as well as amantadine successfully reduced the onset of acute pancreatitis whereas domperidone, a rather specific peripheral dopamine receptor blocker, had the opposite effect. Both bromocriptine and amantadine significantly reduced the mortality rate from acute pancreatitis in domperidone-pretreated rats. Since the aggravating effect of domperidone was successfully reduced by simultaneous application of bromocriptine, we think that these effects are mediated by peripheral dopamine receptors. However, the mechanisms whereby dopamine receptor-stimulating and dopamine-releasing drugs produce their beneficial effects remain to be elucidated.