Effects of anti-erbB-2 (HER-2/neu) recombinant oncotoxin AR209 on human non-small cell lung carcinoma grown orthotopically in athymic nude mice.

The recombinant oncotoxin AR209 [e23(Fv)PE38KDEL; formerly OLX-209] was developed to treat neoplasia that expresses the c-erbB-2 (HER-2/neu) protein product p185(erbB-2). The AR209 compound contains a single-chain antibody domain specific for p185(erbB-2), coupled with a portion of the Pseudomonas exotoxin. The drug has been shown to be effective in inhibiting cells that overexpress erbB-2 due to gene amplification and in cells that do not contain amplified erbB-2 but express slightly higher levels of the protein than normal cells do. To test the efficacy of AR209 on human lung tumors, athymic nude mice were inoculated intrathoracically with a cell line derived from a poorly differentiated lung adenocarcinoma. This cell line, termed 201T, expresses moderately elevated levels of p185(erbB-2) 7.6-fold over normal bronchial epithelium. Mice treated with i.v. injections of AR209 for 5 weeks after orthotopic tumor implantation had smaller tumors and in 20% of cases showed no evidence of disease. The data from this study indicate that AR209 may be an effective treatment for patients with non-small cell lung cancers that express p185(erbB-2).

DNA ploidy pattern and tumor suppressor gene p53 expression in gallbladder carcinoma.

The relationship between p53 gene expression and DNA content in advanced gallbladder carcinoma was studied. Fifty-three cases of advanced gallbladder carcinoma (45 primary tumors and 8 metastases) were analyzed, p53 protein expression was determined by immunohistochemistry, DNA content was measured by cytophotometric techniques. Study subjects included 45 (85%) female and 8 male patients, with an overall mean age of 58.6 years. Positive staining for p53 protein was observed in 27 (51%) cases. In subserosal tumors, the expression was significantly less than that in tumors that reached the serosa (P = 0.01). Twenty-nine (55%) cases were diploid and 24 were aneuploid. Sixty-seven % of primary tumors were diploid, whereas 87% of metastases showed an aneuploid DNA content. Both diploid and aneuploid tumors were positive for the p53 protein in the same proportion, and p53 was also expressed equally in both primary and secondary tumors. In advanced gallbladder carcinoma, the expression of the p53 gene was earlier than the accumulation of abnormal quantities of chromosomal DNA in the tumor cells. The determination of these events as markers in preneoplastic lesions is warranted in gallbladder carcinogenesis.

Mutagenicity of blue rayon extracts of human bile in the Ames test.

The mutagenicity of human bile was examined in the Ames Salmonella/microsome assay. Bile samples were obtained from the gallbladders resected from patients with cholelithiasis, choledocholithiasis, gallbladder cancer, extrahepatic bile duct cancer and other diseases. For extraction of mutagenic components, the bile samples were treated with blue rayon and the adsorbed materials were assayed with Salmonella typhimurium TA98 in the presence of S9 mix. Twenty-four bile samples were tested and positive mutagenic activity was found in 14 samples. A 200-microliter bile equivalent material gave 6.3 times as many revertant colonies as the solvent control. With several samples that had undergone two cycles of blue rayon extraction, clear dose-response relationships in mutagenicity were demonstrated.

Comparison of mutagenic activity of bile between Chilean and Japanese female patients having cholelithiasis.

The mutagenic activity of bile was compared between Chilean and Japanese female patients having cholelithiasis by the Ames assay using Salmonella typhimurium tester strain TA98 in the presence of S9 mix with blue rayon adsorption technique. A reason for conducting the present investigation is that Chile and Japan have the highest mortality rates for the gallbladder cancer (GBC) in the world. Of 24 bile samples collected in Chile, 20 (83.3%) samples showed mutagenicity. In the case of Japanese bile, 21 (80.8%) of 26 and 5 (19.2%) of 26 cases were mutagenic in samples from high- and low-risk areas for GBC, respectively. Therefore, both the Chilean and the Japanese samples collected in high-risk areas showed higher mutagenic rates than the Japanese ones in a low-risk area, with a statistical significance (p < 0.001), chi-square test). The average number of revertant colonies were 128 +/- 92 (mean +/- SD), 62 +/- 14 and 66 +/- 13, respectively, when the blue rayon extracts of 200 microliters bile were applied to the Ames test. Thus, Chilean bile had a tendency to show a higher mutagenic activity than Japanese.

Preoperative chemoradiotherapy in the treatment of gallbladder cancer.

Gallbladder cancer is generally associated with a poor prognosis, with local recurrence being the main pattern of failure. In an attempt to improve on the present status of management, we evaluated a prospective Phase II study involving preoperative 5-fluorouracil and radiation. Among 27 eligible patients with a potentially resectable gallbladder cancer detected after cholecystectomy, 18 were treated with preoperative radiation (4500 cGy; 180 cGy/fraction, 5 days/week) concurrent with a continuous infusion of 5-fluorouracil (350 mg/m2/day, days 1-5 and 21-25). Toxicity included leukopenia (8 patients) and thrombocytopenia (7 patients). Delay in surgery due to hematological toxicity was seen in 6 patients. Of the 18 patients, 15 underwent a reoperation. Resection was performed in 13 (86%). Pathologic findings after reoperation revealed residual tumor in both liver and lymph nodes in 3 patients. At a median follow-up of 24 months, 7 patients are alive. Among the patients who died after curative resection, local recurrence was demonstrated in only 1. This is the first report concerning preoperative chemoradiation in gallbladder cancer. To assess its effect on survival, a prospective randomized trial will be necessary.

Peritoneal pseudomyxoma in a child with a gallbladder Peutz-Jeghers-like hamartomatous polyp: a case report.

A 2-year, 6-month-old boy with peritoneal pseudomyxoma had a hamartomatous Peutz-Jeghers-like polyp in the gallbladder. The morphological pattern of the polyp was very characteristic of what is usually considered an hamartomatous polyp. The patient presently reported has no clinical characteristics of Peutz-Jeghers syndrome. The peritoneal pseudomyxoma creates differential diagnostic problems with well-differentiated mucinous adenocarcinoma.

Gallbladder cancer in a high risk area: morphological features and spread patterns.

BACKGROUND/AIMS: Gallbladder carcinoma is one of the most frequent malignant tumors in Chile. The aim of this paper is to show our experiences in gallbladder carcinoma. METHODOLOGY: Six-hundred-sixty-nine cases of gallbladder carcinoma were included in this prospective study; 557 females (83.5%) and 112 males (16.5%). In 466 cases (70%), diagnosis was carried out in the cholecystectomy sample, 45 cases were partial cholecystectomies and 158 cases were metastases of gallbladder carcinoma. RESULTS: Ninety-eight per cent of the cases were adenocarcinomas, and in 85% of the cases gallstones were observed. Thirty-seven per cent of the primary tumors were macroscopically inapparent. One-hundred-thirty-one cases (29%) were early carcinomas and 323 cases (71%) were advanced carcinomas. A relationship between differentiation grade and infiltration level (p=0.0001) was observed. Lymph-node metastasis was found in 18.5%, 4.5% and 3.3% in the first, second and third lymph-node barriers respectively. Muscular tumors presented no lymph-node metastasis, while in serosal tumors lymph node metastasis reached 62% (p=0.04). Hepatic tumor infiltration was observed in 11%, 19% and 38% of muscular, subserosal and serosal tumors. CONCLUSIONS: The high frequency of inapparent carcinomas, gallstones and inflammatory changes of the vesicular wall are elements that make the pre-operative diagnosis of gallbladder carcinoma difficult. Differentiation grade and infiltration level are the most reliable prognostic factors in gallbladder carcinoma. Lymph-node metastasis or liver tumor infiltration are infrequent in early gallbladder carcinoma.

Pilonidal disease: 25 cases treated by the Dufourmentel technique.

Twenty-five patients with pilonidal disease were treated by the Dufourmentel technique between 1984 and 1989. In this series, 18 patients (72 percent) were women and 7 (28 percent) were men (mean age, 24 years); hospital stay averaged 4 days. There were no recurrences and no reports of surgical wound infection. Diagnosis was confirmed histologically in all cases.

[The sea blue histiocyte syndrome: a case report]. / Sindrome del histiocito azul marino: caso clínico.

A young pregnant woman presented with splenomegaly and a hemorrhagic syndrome. A persistent alteration of several coagulation tests was demonstrated. Large foamy pigmented macrophages were shown by bone marrow aspiration. The histopathologic findings are consistent with the sea blue histiocyte syndrome, a benign type of lipid storage disease.

[Malignant histiocytosis in children]. / Histiocitosis maligna en el niño.

A case of malignant histiocytosis in a two year old boy is reported. His main clinical features were fever, lymphadenopathy, hepatomegaly and splenomegaly. Lymph node biopsy showed a sinusoidal type of lymph node infiltration, histiocytes of malignant aspect and erythrophagocytosis. Liver infiltration with tumoral cells was demonstrated by needle biopsy. The clinical evolution was rapidly progressive and after six months of chemotherapy he died of intercurrent respiratory infection.

[Regeneration of gastric mucosa after endoscopic biopsy]. / Regeneración de la mucosa gástrica después de biopsia endoscópica.

Eleven gastric mucosal defects produced by endoscopic biopsy in non-tumoral areas were histologically studied in gastrectomy specimens. The biopsies had been performed from one up to seven days before the operation. The base of each defect was formed by submucosa infiltrated by erythrocytes, fibrin and neutrophils, which were later replaced by small blood vessels, fibroblasts and collagen fibrils. The mucosa of the margins bowed down towards the base of the defect. This marginal mucosa showed dedifferentiation of the glandular epithelial cells, increased mitotic index and some cystic glandular structures lined by basophilic cells. The defect was progressively covered by a layer of flattened or cuboidal cells in which no mitoses were observed; their cytoplasm contained mucosubstances similar to those of the superficial epithelium of the remaining mucosa, either foveolar- or intestinal metaplastic-type. From this layer, simple gland-like invaginations to the underlying connective tissue were observed. The findings are consistent with the regenerative events described in experimental gastric ulcers in animals. The method employed may be useful to study specific aspects on the regeneration of the human gastric mucosa.

[Helicobacter pylori and chronic gastritis: relationship between infection and inflammatory activity in a high risk population for gastric cancer]. / Helicobacter pylori y gastritis crónica: relación entre infección y actividad inflamatoria en población de alto riesgo de cáncer gástrico.

BACKGROUND: Helicobacter pylori has been involved in gastric epithelial cell damage and gastric gland loss or atrophy. AIMS: To evaluate role of Helicobacter pylori infection in acute and chronic changes of chronic gastritis in a high gastric cancer-risk population. MATERIAL AND METHODS: 200 patients with chronic gastritis were selected from pathological files of Temuco Hospital. A complete histopathological protocol was fulfilled considering the presence of infection by Helicobacter pylori-like-organism (HLO), acute and chronic inflammatory infiltrate, epithelial cell damage and epithelial cell regeneration. RESULTS: 82% of patients showed infection by HLO. Moreover, this infection reached a frequency of 92.7% in gastric ulcer patients and 94.4% in duodenal ulcer patients. A statistically significant positive correlation was found between HLO infection and polymorphonuclear infiltrate, lymphocytic infiltrate, mucus depletion and epithelial regenerative activity. There was not a statistical correlation between HLO infection and atrophy. Finally, 90% of patients with multifocal atrophic gastritis and 100% of patients with diffuse antral gastritis had HLO infection. CONCLUSIONS: HLO gastric infection frequently caused acute inflammatory changes in gastric mucosa with chronic gastritis. Sometimes these changes were severe, with marked polymorphonuclear migration throughout epithelium and severe epithelial cell damage. Recovery of these changes could be considered as a goal in Helicobacter pylori eradication therapy decision.

[Gastric cancer and tumor growth regulation. Study of cell proliferation markers and protein complex p53/p21WAF1/CIP1/mdm-2]. / Cáncer gástrico y regulación del crecimiento tumoral. Estudio de marcadores de proliferación celular y del complejo proteínas p53/p21WAF1/CIP1/mdm-2.

BACKGROUND: p53/p21WAF1/CIP1 and mdm-2 proteins play an important role in cell cycle regulation. The study of the pathogenesis of gastric cancer is important to understand how these tumors progress during their natural history. AIM: To study the relationship between the immunohistochemical expression of p53/p21WAF1/CIP1 and mdm-2 and cell proliferation in gastric cancer. MATERIAL AND METHODS: Fifty one gastrectomy specimens with gastric cancer were studied using immunohistochemistry for p53/p21WAF1/CIP1 and mdm-2. Cell proliferation was determined by immunolabelling with PCNA and Ki67 antigens. Mitosis figures were counted in 10 high power microscopic fields. RESULTS: Patients from whom gastric cancer specimens were obtained had a mean age of 59.3 years. Ki67 and mitosis counting showed the highest correlation index with proliferation indexes studied. No correlation was found between the expression of protein complex p53/p21WAF1/CIP1 and mdm-2 and morphological characteristics of gastric tumors. Mdm-2 protein overexpression was the only marker that showed an independent correlation with cell proliferation. Moreover, mdm-2 positive tumors showed the highest proliferation indexes when p53 was not immunohistochemically over-expressed, as determined by PCNA labelling index. CONCLUSIONS: In gastric cancer, a direct correlation between mdm-2 overexpression and cell proliferation was observed. Moreover, the fact that mdm-2 positive tumors showed the highest cell proliferation when p53 was not overexpressed, entitles us to hypothesize that mdm-2 overexpression could play a major role in gastric carcinogenesis.

[Carcinoma hepatocellular. Description of verified clinical characteristics in a region of Southern Chile]. / Hepatocarcinoma. Descripción de características clínicas verificadas en una Región del sur de Chile.

BACKGROUND: Hepatocellular carcinoma is the most frequent primary tumor of the liver. It is associated to chronic liver diseases and has a high prevalence in some regions of Africa and Asia. AIM: To describe the clinical characteristics of patients with hepatocellular carcinoma, admitted to two hospitals of the IX region of southern Chile. MATERIAL AND METHODS: Prospective study of 29 consecutive patients admitted to two hospitals in Temuco, Chile. Clinical features, laboratory values and viral markers were analyzed. RESULTS: Eighteen patients were male and ages ranged from 29 to 75 years old. The most frequent presenting symptom was abdominal pain in 21 patients. Seven subjects had a history of alcoholism. Serum bilirubin values ranged from 0.1 to 15.8 mg/dl, alkaline phosphatases ranged from 171 to 3476 U/l, ASAT from 24 to 5400 U/l and alpha feto protein from 1.4 to 350 ng/ml. Two patients had a positive hepatitis B surface antigen and all had negative hepatitis C virus antibodies. Mean tumoral diameter was 9.6 cm and the most common presentation was nodular. Mean survival after the diagnosis was 6.3 months. CONCLUSIONS: These patients with hepatocellular carcinoma have a low frequency of positive viral markers and tumors of large sizes on presentation.

[Proliferating cell nuclear antigen (PCNA) in patients with malabsorption syndrome: comparative study with morphometric parameters]. / Antígeno nuclear de proliferación celular (PC10) en pacientes con síndrome de malabsorción: estudio comparativo con parámetros morfométricos.

The study of small bowel mucosa is routine in the study of patients with malabsorption. We report 16 children aged from 8 months to 6 years old (2 with giardiasis, 8 with primary malnutrition and 5 with celiac disease) in whom a morphometric and PCNA immunostaining was performed in the small intestinal biopsy. Positivity for PCNA was found in the lower portion of the crypts reaching 156 microns of heigh in patients with giardiasis, 103 microns in primary malnutrition and 182 microns in celiac disease (p < 0.01 compared to primary malnutrition). A negative and significant correlation was found between the degree of architectural disorder (expressed the mucosal index) and the proliferative portion of the crypts (expressed as the percentage of PCNA(+) crypts. We propose these methods as complements to the small bowel mucosa histopathological study in the diagnosis of celiac disease, to assess the degree of architectural disorder and the proliferative activity.

[Gallbladder cancer in the IX Region of Chile. Impact of the anatomopathological study of 474 cases]. / Cáncer de vesícula biliar en la IX región de Chile. Impacto del estudio anatomopatológico en 474 casos.

We studied prospectively 474 cases (83% female with a female:male ratio of 5:1) of gallbladder carcinoma diagnosed in a period of 7 years. Twenty two percent of patients were younger than 50 years old. Ninety percent of tumors were adenocarcinomas. In 1987, 45% of cases were diagnosed in metastases compared to 1993, when only 10% of tumors were diagnosed in such histological material. Thirty four percent of tumors were not macroscopically identified; all these inapparent tumors were advanced in 1987, whereas 53% were incipient in 1993. Moreover, inapparent tumors had a significantly lower degree of gallbladder wall infiltration and higher degree of differentiation. Well differentiated tumors had a lesser degree of wall infiltration. It is concluded that the careful histopathological study of gallbladder cancer has allowed a thorough knowledge of the natural history and clinical presentation of gallbladder carcinoma.

[Nucleolar organizer regions in uterine cervical cancer and its precursor epithelial lesions]. / Regiones del organizador nucleolar en cancer de cuello uterino y sus lesiones epiteliales precursoras.

The number of nucleolar organizer regions was assessed in 115 histological samples of uterine cervical carcinoma or precursor epithelial lesions. Normal endocervical or exocervical epithelial tissues were used as controls. Nucleolar organizer regions were stained with colloidal silver in formalin fixed histological samples and quantified in 100 cells, according to Crocker's method. The mean number of nucleolar organizer regions were 13.7 in infiltrative carcinoma, 9.15 in carcinoma in situ, 9.3 in severe dysplasia, 8.4 in moderate dysplasia, 7.5 in mild dysplasia, 6.4 in condylomas and 3.2 and 2.9 in normal exocervical and endocervical epithelia respectively. There were significant differences in the number of nucleolar organizer regions between normal and abnormal tissues and between the different lesions except between moderate and mild dysplasia and between carcinoma in situ and moderate and severe dysplasia. The highest number of nucleolar organizer lesions was always observed in the basal strata of both normal and abnormal tissues. It is concluded that nucleolar organizer regions are a good index of cellular proliferation in uterine epidermoid cervical carcinoma and its precursor lesions, and have a diagnostic value in infiltrative carcinoma.

[Lithiasis of gallbladder in the IX region. Study of the autopsies in a zone with a high proportion of Mapuche population]. / Litiasis de la vesicula biliar en la IX region. Estudio de autopsias en una zona con alta proporcion de poblacion mapuche.

The frequency of gallbladder stones in he IXth Region of Chile with a large indigenous population, was studied in forensic necropsies from 1980 to 1989. Among 2,505 autopsies, 85% were males and 15% females. At least 1 "mapuche" surname occurred in 27% of cases. Stones were found in 34% of females and 12.7% of males. No differences were found between "mapuche" and non mapuche cases. Cholecystectomy had been performed in 2.3% of males and 9.1% of males. These results do not differ from those reported from other regions in Chile.

[Gastric cancer in the IX Region of Chile: an analysis of 233 cases]. / Cáncer gástrico en la IX Región de Chile: análisis de 233 casos.

Gastric cancer is the leading cause of mortality from malignancy in Chile. Different reports indicate a high incidence of well differentiated forms of this tumor. Among 233 endoscopically diagnosed lesions in patients from the Ninth Region of Chile, we found a high incidence of poorly differentiated tumors and a relatively high incidence of signet-ring cell carcinoma. The incidence of inoperable lesions was high.