Heterogeneous protooncogene amplification correlates with tumor progression and presence of metastases in gastric cancer patients.

In order to evaluate the relevance of protooncogene alterations in gastric cancer and to specifically relate these alterations to types and stages of the neoplasia, we studied oncogenes of possible interest in gastric tumors with different clinical parameters. Fifty DNAs from primary gastric adenocarcinoma were analyzed, by the Southern blotting technique, for the presence of amplification or rearrangements of seven different protooncogenes: c-myc, c-erbB2, c-Ki-ras, c-Ha-ras, c-N-ras, hst, and c-mos. All the tumors analyzed were histologically classified and staged. Amplification of the following genes was found: c-myc (2 of 50), hst (3 of 50), c-erbB2 (3 of 50), and c-Ki-ras (5 of 50). The simultaneous amplification of hst (3 cases), c-myc (1 of 3), or c-Ki-ras (2 of 3) was observed. Analysis of DNAs from atrophic and metaplastic gastric mucosa (which can be regarded as preneoplastic lesions) of the 10 patients showing gene amplification demonstrated that this was limited to neoplastic cells. Considering protooncogene amplification in general (i.e., involving different genes and occurring to different degrees) and clinical parameters of tumors, we found a statistically significant association between amplification and both tumor progression and presence of metastases. Therefore, at least for the genes analyzed, amplification is a relatively infrequent phenomenon and represents a late event in the temporal development of gastric cancer.

Identification of occult micrometastases in patients with early gastric cancer using anti-cytokeratin monoclonal antibodies.

The presence of occult micrometastases was evaluated in 1488 lymph nodes removed from 139 patients with node-negative early gastric cancer (EGC). Additional multiple levels of the lymph nodes were examined with haematoxylin-eosin staining and keratin immunostaining. Occult nodal micrometastases were detected in 24 patients (17%) in one or more lymph nodes dissected after a gastrectomy. The cases investigated were a small group from a total of 412 EGC patients who underwent surgical treatment in our hospital between 1976 and 1997; the mean follow-up period was 9 years (range 1-22). We found no significant differences between cytokeratin-negative and positive patients regarding the following clinicopathological parameters: age, gender, tumour size and site, macroscopic and microscopic type, depth of invasion and type of infiltration, according to Kodama's classification. The survival rate at 5 years was 88% and 87% for cytokeratin-negative and positive patients, respectively (log-rank = 0.6; ns). Our data suggest that occult micrometastases do not add useful information and immunohistochemical studies to detect them are probably unnecessary.

Early gastric cancer in the province of Forlì: follow-up of 337 patients in a high risk region for gastric cancer.

Long-term clinical outcome was analysed in a series of 337 patients with early gastric cancer (EGC) at a median follow-up of 8 years. Tumours were classified according to the macroscopic and microscopic criteria proposed by the Japanese society of gastroenterological endoscopy (JSGE) and Lauren, respectively. Type of penetration (PEN) was classified according to Kodama. Overall survival rate was 92% at 5 years and 88% at 8 years and was significantly related to depth, type of penetration, lymph node status and tumour size. A significantly lower 5-year survival (p<0.05) was observed for patients with lymph node metastases and PEN A type EGC (55%) or for those with node-positive tumours and submucosal wall penetration (58%) than for the other pathologic subgroups. Therefore, these two subgroups should be considered as advanced gastric cancer patients from the prognostic point of view. Moreover, multivariate analysis by Cox regression model showed the degree of lymph node involvement and Kodama's type PEN A as the only independent prognostic factors.

CEA levels in gastric juice in precancerous conditions and cancer.

First described in 1965 as a specific antigen for cancer of the colon, CEA is now considered to be an antigen associated with many types of malignant neoplasia, although the CEA-Test's role in clinical routine has yet to be clearly defined. In the present study CEA levels in gastric juice were measured in subjects with gastric carcinoma (n = 25) and with benign gastric lesions (n = 171). CEA was significantly (p less than 0.05) higher in patients with gastric carcinoma (GC) than in subjects with benign gastric lesions, other than chronic atrophic gastritis (CAG) associated with intestinal metaplasia (IM). In this latter condition CEA levels were similar to those in patients with GC. These results suggest that the assay of CEA in gastric juice could be included in the diagnostic program for gastric cancer and its precursors with the aim of assessing its utility as risk indicator in the management of precancerous conditions and lesion.

A fatal case of poisoning with cantharidin.

A case of fatal poisoning due to voluntary ingestion of cantharides powder for aphrodisiac purposes is reported. Clinical history, autopsy and analytical findings are described. Blood and urine samples collected during the 30 h of survival, as well as the cantharides product, were analyzed by gas chromatography-mass spectrometry. On the basis of the percentage of the active principle measured in the powder, an ingested dose of 26-45 mg of cantharidin could be estimated.

Centred radio-frequency hyperthermia in solid tumours.

After some notions on the mechanisms of action of radio-waves on solid tumours, the treatise illustrates the results achieved in the first 125 cases of malignant tumours treated with this method, its results are definitely encouraging, even in cases apparently with no hope. It also describes briefly the histologic modifications induced by this therapeutic method on neoplastic masses and discusses the criteria of the directions of thermotherapy, alone or combined, which is obviously the fifth weapon against tumours.

Gastric cancer: histopathologic patterns according to Lauren's classification in a high-risk area and distribution by residence.

A total of 1061 advanced gastric cancers with histologic confirmation, diagnosed from 1973 to 1982 at the Morgagni-Pierantoni Hospital (Forlì) were reclassified according to Lauren, and histologic types were related to the source of the histologic specimen, sex, age at diagnosis, place of birth and residence. This large case series showed a high percentage of intestinal type cancers, consistent with the high risk for gastric cancer which characterizes the area under study. Intestinal type carcinomas tend to be represented more in the older age groups, in males and in subjects born in the Forlì province and resident in hilly and mountainous areas. The distribution over time of biopsy specimens in this case series showed an increased use of gastroscopy for diagnosis in the population under study.

Hepatic injury associated with amineptine therapy.

Cases are reported of two patients in whom acute hepatitis and cholestatic jaundice were induced by a tricyclic antidepressant, amineptine. A 29-year old woman received amineptine for 10 days before the onset of acute hepatitis. Slight jaundice and pruritus were preceded by fever, nausea and anorexia. The case is documented by a rapid return to normality of the liver function tests after amineptine was discontinued. We also report the case of a 55-year old woman to whom amineptine was administered for 4 weeks: she was admitted to our Department due to a 14-day history of pruritus and painless jaundice. Histological examination, in this case showed marked cholestasis without inflammatory infiltration. After suspending the treatment, it took 3 weeks for the liver function tests to return to normal. These observations, and the features of the cases published in the literature, suggest that amineptine can produce a wide spectrum of liver injuries, in different patients, taking the form of hepatocellular necrosis, cholestasis or a combination of both.

[Value of the in situ hybridization technique in the diagnosis of human papilloma virus infections of the uterine cervix. Correlations between the human papilloma virus type and the morphological features]. / Valore della tecnica di ibridizzazione in situ nella diagnosi delle infezioni da papilloma virus umano della cervice uterina. Correlazioni fra i tipi di papilloma virus umano ed aspetti morfologici.

Clinico-pathologic, epidemiologic and molecular analytic studies have shown that: i) the squamous cancer of the uterine cervix derives from intraepithelial lesions with different degrees of atypia; ii) human papillomavirus (HPV) can play a fundamental role in the progression of these lesions. We have examined 219 uterine cervix biopsies by means of the in situ hybridization technique (ISH) using biotinylated probes for 6/11, 16/18 and 31/35/51 HPV strains. The histologic lesions were as follows: 104 (49.7%) focal koilocytotic lesions 26 (11.8%) low grade intraepithelial lesions (SIL) 45 (20.5%) high grade intraepithelial lesions (SIL) 18 (8.2%) condylomata acuminata 21 (9.8%) invasive cancers. The percentage of the positivity found in the whole material examined is 14.1%. In particular, none of the 109 cases of focal koilocytotic lesions was positive, whereas the 28.1% of the remaining 110 biopsies turned out to contain HPV. We hypothesize that our small percentage of positivity in preinvasive and invasive lesions of the uterine cervix can be due to the fact that the HPV is not the only cancerogenic factor involved, although the possibility of a low sensitivity of the technique cannot completely be excluded.

Chronic lymphocytic leukaemias and non-Hodgkin's lymphomas by histological type in farming-animal breeding workers: a population case-control study based on a priori exposure matrices.

OBJECTIVES: A population based case-control study was conducted in a highly agricultural area in Italy to investigate the association between chronic lymphocytic leukaemias (CLLs) and non-Hodgkin's lymphomas (NHLs), and subtypes, and exposure to pesticides in farming-animal breeding workers. METHODS: 187 cases of CLLs and NHLs and 977 population controls were interviewed on medical, residential, family, and occupational history. Detailed information was collected about cultivated crops and animals bred from subjects who worked in farming and animal breeding. Information on crop diseases and pesticides used (and their quantity and duration) was also obtained. A priori job-exposure matrices were applied when a crop disease was reported, estimating the most probable pesticide and, when possible, an estimate of the cumulative dose. Odds ratios (ORs) were calculated by unconditional logistic analysis with adjustment for relevant confounders in farmers who bred animals and in farmers alone, for the main crops, types of animals, and pesticides categories. First recall and then the matrices were used for defining exposure, as it affected CLLs and NHLs and then separately on CLLs and low grade NHLs. Finally, the dose-response was investigated for those pesticides which had shown some association. RESULTS: No variable under study was associated with work in farming alone. In farming and animal breeding, no crop or animal showed an association with CLLs and NHLs when adjusted by exposure during childhood to farming and animal breeding (an indicator of life in a farming and animal breeding environment before the age of 13, which behaved as an independent risk variable). A non-significant association was found with stannates, arsenates, phosphates, and dichloro-diphenyl-trichloroethane (DDT) based on recall, and for stannates, arsenates, and DDT after the application of the matrices. When CLLs together with low grade NHLs were considered, the association with insecticides in general, carbamates, and phosphates became significant according to personal recall (ORs and 95% confidence intervals (95% CIs) 2.46, 1.07-5.63; 3.08, 1.05-9.00; 2.97, 1.28-6.91, respectively). The application of the matrices also showed a risk of borderline significance for stannates and dithiocarbamates. A significant dose-response effect was found for phosphates (for logarithmic unit increase, OR 1.17, 95% CI 1.00-1.57); a strong trend for stannates and carbamates did not reach significance. CONCLUSION: The association of CLLs and NHLs with work in farming-animal breeding is partially explained by exposure to pesticides-namely insecticides (carbamates, phosphates, and DDT) and stannates-possibly related to their use in animal breeding. The association is limited to cases of CLL and low grade NHL. The independent effect of the variable exposure during childhood suggests that early exposures, including possible contact with animals, may play a part in the pathogenic process of these neoplasms.

[Peripheral T-cell lymphoma associated with hemophagocytic syndrome: a recently identified entity. Clinico-pathologic and immunohistochemical study of 2 cases]. / Linfoma a cellule T periferiche con associata sindrome emofagocitica: un'entità di recente identificazione. Studio clinico-patologico ed immunoistochimico di due casi.

The authors report on two examples of peripheral T-cell lymphoma associated with hemophagocytic syndrome. The latter represents a recently described entity, which is characterized by pancytopenia, hepatosplenomegaly, fever and rapid downhill clinical course. Microscopic examination of different tissue samples shows bone-marrow, liver and spleen infiltration by small-medium sized lymphoid elements, which display peripheral T-cell phenotype and are associated with an exuberant hyperplasia of hemophagocytosing, benign-looking histiocytes. The clinical and pathological findings, along with the main differential diagnoses, are discussed.

[Epidermoid cyst of the spleen. Presentation of a case]. / Cisti epidermoidale della milza. Presentazione di un caso.

Cystic lesions of the spleen are unusual. They are classified essentially as: parasitic or nonparasitic, based on their etiology, and true or pseudo based on the presence or absence of lining epithelium. The pathogenesis of true cysts is unknown and numerous hypotheses are given by different Authors. After a short review of the literature, the Authors describe the clinical and pathological data of a case of epithelial (epidermoid) splenic cyst occurs in a 12-year-old woman. The Authors put forward some personal observations on pathogenesis, still doubtful, by means of histochemical and immunohistochemical study.

Isolated metastasis to the gallbladder of a malignant melanoma of the skin. Report of a case.

A case of single, polypoid metastatic malignant melanoma of the gallbladder is described. The differential diagnosis with primary malignant melanoma and undifferentiated carcinoma is discussed.

Cell kinetics and prognosis in gastric cancer.

METHODS: The potential proliferative activity of primary gastric cancer was determined using the in vitro tritiated thymidine labeling index (LI) technique. RESULTS: The proliferative rate had a wide range (0.1-28.4%) with a median value of 9.3%. The cell kinetics of the primary tumor were not related to clinicopathologic features, such as the patient's age and sex or the tumor's histologic type and stage. The contribution of cell kinetics to prognosis was investigated in a series of 28 patients (median follow-up, 34 months). The 3-year survival rate was 50% for patients with slowly proliferating tumors compared with only 13% for those with rapidly proliferating tumors. Moreover, in patients with high-LI tumors, the risk of death was more than sixfold greater than for those with low-LI tumors. CONCLUSIONS: These data suggest that cell kinetic studies might be an important discriminant to predict prognosis in gastric cancer.

Cell kinetics and hormonal features in relation to pathological stage in breast cancer.

Proliferative activity (expressed as 3H-thymidine labeling index, 3H-TdR LI) was evaluated on a series of 281 primary tumors recruited in two years in 6 different institutions from central Italy. 3H-TdR LI proved to be low in intraductal, or well and moderately differentiated, or hormone receptor positive tumors. Conversely, no relation was observed between 3H-TdR LI and menopause, tumor size, or lymph node involvement. An inverse relation was observed between 3H-TdR LI and hormone receptor content. Specific patterns of 3H-TdR LI value and ER content association were observed as a function of menopause, lymph nodal status, and degree of lymph nodal involvement.

Reproducibility of histologic classification of gastric cancer.

A panel review of histologic specimens was carried out as part of a multi-centre case-control study of gastric cancer (GC) and diet. Comparisons of diagnoses of 100 GCs by six pathologists revealed agreement in histologic classification for about 70-80% of the cancers. Concordance was somewhat higher when using the Lauren rather than the Ming or World Health Organization classification systems. Histologic types from reading biopsy tissue agreed with those derived from surgical specimens for 65-75% of the 100 tumours. Intra-observer agreement in histologic classification, assessed by repeat readings up to 3 years apart by one pathologist, was 95%. The findings indicate that, although overall concordance was good, it is important to standardise diagnoses in multi-centre epidemiologic studies of GC by histologic type.

An efficient method for culturing human breast carcinoma to evaluate antiblastic drug activity in vitro: experience on 136 primary cancers and on 116 recurrences.

The feasibility of techniques developed for isolating and culturing human mammary epithelial cells of malignant origin was confirmed in 136 primary breast cancers, 116 hypodermal metastases, and 8 metastatic lymph nodes. In 115 (84%) primary breast cancers and in 81 (70%) hypodermal recurrences we observed a good in vitro cellular proliferation. These proliferating cells, at the second passage, were used for a clonal assay suitable for quantitating drug sensitivity. With this clonal assay median cloning efficiencies of 14% and 6% were obtained respectively in primaries and in skin recurrences. We examined the in vitro response to different drugs and confirmed the test's ability to detect heterogeneity in response to same drugs (doxorubicin, 4'-epidoxorubicin, vinblastine, cis platinum, and idarubicinol) among the different breast carcinoma cultures as well as heterogeneity among subpopulations within a single carcinoma.

Cell proliferation as a predictor of response to chemotherapy in metastatic breast cancer: a prospective study.

Many biologic prognostic markers are available for patients with breast cancer, and considerable interest has been devoted to confirm preliminary evidence of their role as indicators of treatment response. It remains to be assessed whether such markers are predictors of response only to first-line or also to successive therapies. Proliferative activity, defined by the 3H-thymidine labeling index (TLI), was determined on the primary lesion from 76 patients at time of first diagnosis. At relapse, patients underwent chemotherapy as absolute (48 cases) or relative (28 cases) first-line treatment, and their clinical response was analyzed in relation to the TLI of the primary lesion. The objective clinical response was significantly higher for rapidly (47%; CL, 33-61%) than for slowly proliferating tumors (15%; CL, 1-29%). These findings held true also when adjusted for metastatic site, previous treatment, chemotherapy regimen administered, and hormone receptor status. However, the direct relation between cell proliferation and benefit from chemotherapy held true only when such a treatment was used as an absolute first-line approach. Cell proliferation of primary lesions represents a consistent indicator of response to chemotherapy over time. Previously administered regimens, at least hormone therapy, could alter the proliferation-related chemosensitivity profile of individual tumors.