[Subjective grading of Barrett's neoplasia by pathologists: correlation with objective histomorphometric variables]. / Subjektive Graduierung von Barrett-Neoplasien durch den Pathologen: Korrelation mit objektiven histomorphometrischen Variablen.

Even though pathologists are trained to recognize the same histological features for the diagnosis and grading of different histological images, not all pathologists are influenced to a similar level of intensity by the same morphological characteristics of the tissue when scoring Barrett's dysplasia/neoplasia. The variables which most pathologists have intuitively chosen to use for scoring of the severity of Barrett's changes are mainly those related to the general tissue architecture, such as nuclear crowding, orientation and stratification. Interestingly, nuclear size is not used by most pathologists but nuclear pleomorphism and symmetry does influence a significant number of pathologists. Maybe the most difficult variables for the human eye to recognize are variables of chromatin texture (such as margination or heterogeneity), the predictive importance of which has been demonstrated in a previously published work. Textural variables may therefore remain the subject of a computerized analysis. Nevertheless, the fact that a few pathologists do actually correlate with nuclear texture in scoring, argues in favor of making further attempts to train pathologists to also rely on texture, similar to cytologists, when scoring Barrett's dysplasia.

Sensitivity to thermochemotherapy of AKR lymphoma and B16 melanoma variants of malignancy.

Drug resistance, which so often accompanies tumor progression, has been shown to be related to changes in membrane properties which may result in decreased drug accumulation in the tumor cell. A correlation between sensitivity to thermochemotherapy and degree of malignancy was found in the AKR lymphoma system. Hyperthermia increased adriamycin (ADR) uptake and concomitantly its cytotoxicity to AKR lymphoma cells. Moreover, these effects were more pronounced on a variant of high malignancy (HM) than on a low malignancy (LM) one. Fluorescent microscopy, as well as cytofluorometry, indicated that lymphoma cells treated by ADR at 43 degrees C were more permeable to the cytotoxic agent than those exposed to the chemotherapeutic substance at 37 degrees C. Cytofluorometry indicated the presence of a minor cell subpopulation with low ADR uptake in the HM variant, not found in the LM one. Fluorocytometry also showed that the temperature-dependent increased ADR uptake was more marked in the HM than in the LM variant, explaining the differential effect of thermochemotherapy on the two lymphoma variants. However, correlation between degree of malignancy and sensitivity to thermochemotherapy is not a general feature. In contrast to the results obtained in the AKR lymphoma system, in the B16 melanoma the low malignancy variant, F1, was more markedly affected by the combined treatment than the F10 variant. The increased cytotoxic effect of ADR by supranormal temperatures in the F1 variant was shown to be due to an augmented drug uptake. The results suggest that drug resistance in late stages of tumor progression can be overcome by an agent acting on the cell membrane. However, the data also indicate the necessity of assaying cancer treatment modalities, including those designed to circumvent drug resistance, on various tumor system models.

A model for cancer treatment in advanced compared to early cancer.

Loss of sensitivity to drugs following tumor progression constitutes the main reason for failure of treatment in advanced cancer. In view of the dynamic nature of neoplasms, models of tumor progression should be used for the testing of drugs. In the present study, two variants of malignancy of AKR lymphoma were used as a model of tumor progression to test various treatment modalities. The two variants, TAU-39 (of low-malignancy) and TAU-38 (of high-malignancy) differed in the pattern of local tumor growth as well as in the rate of metastatic spread and mice killing capacity. The efficiency of chemotherapy, immunotherapy and hyperthermia on the two variants was compared. The low-malignancy tumor was more sensitive to adriamycin than the high-malignancy one. Administration of levan-activated macrophages at the tumor site inhibited the growth of TAU-39. However, growth of the high-malignancy variant was stimulated by macrophages. Hyperthermic treatment was, in contrast to the other treatments, more effective against the high - than against the low-malignancy tumor. Models of tumor progression used in tests for antitumoral drugs may help in the discovery of treatment modalities effective also for advanced stages of cancer.

Effect of hyperthermia on AKR lymphoma variants differing in degree of malignancy.

The effect of hyperthermic treatment on AKR lymphoma cells of varying malignancy was investigated. Tumor cells were pretreated at 37 or 43 degrees C and then injected to mice. The effect on the highly malignant variant, TAU-38, was compared to that on the low-malignancy variant, TAU-39, following both subcutaneous (s.c.) and intravenous (i.v.) inoculation. Hyperthermia showed no effect on the TAU-39 variant following s.c. inoculation on the primary tumors or mice survival, but the TAU-38 variant exhibited a significant delay of tumor appearance following treatment, namely, decreased tumor size and increased life span. Following i.v. inoculation, in both variants, hyperthermia caused a significant decrease in metastatic spread and an increased life span. We conclude that hyperthermia, in addition to exerting a greater effect on the high-malignancy variant, acts at the late phases of metastasis. Hyperthermia might therefore have a place in the management of cancer in its advanced disseminated phase.

Correlation between malignancy level of AKR lymphoma variants and sensitivity to hyperthermia.

The tumor progression process has been found to be accompanied by various cell membrane modifications. This cell organelle may therefore be considered as a target for drugs directed against tumor cells of advanced cancer. Hyperthermia acts on tumor cells largely, although not only, via an effect on the cell membrane. In the present study, the in vitro effect of hyperthermia on the tumorigenicity of cells derived from two AKR lymphoma variants of malignancy, TAU-39 of low (LM) and TAU-38 of high-malignancy (HM), was compared. The cells of the HM variant were markedly more sensitive to hyperthermic treatment than those of the LM one. Pretreatment of cells at 41 degrees C or 43 degrees C resulted in a more marked delay in tumor appearance in mice injected with the HM than in those inoculated with the LM variant. Moreover, in mice inoculated with cells pretreated at 45 degrees C, long term survivors were found only in those inoculated with the HM variant. These results corroborate our previous data regarding the effect of hyperthermia on metastatic and primary tumor cells of AKR lymphoma as well as the F1 and F10 variants of B16 melanoma.

Effect of hyperthermia and thermochemotherapy on primary and metastatic tumour cells of AKR lymphoma.

The cure of metastatic disease constitutes a serious problem. Recent findings showed cell membrane differences between slightly and highly metastasizing tumour cells, suggesting that since this cell organelle determines the metastatic phenotype, it might serve as a target for future drugs programmed against advanced cancer. The cell membrane has also been shown to be involved in the evolution of drug resistance which often accompanies tumour progression. In the present study, the effect of hyperthermia--an antitumoral treatment modality partly exerting its effect on the cell membrane--on primary and metastatic AKR lymphoma cells was compared. The effect of hyperthermia in conjunction with adriamycin (ADR) on the two cell types was also tested. Hyperthermic treatment, alone and in combination with ADR, was more effective in reducing the tumorigenicity of cells derived from metastatic tumours than of the primary tumour cells. Fluorescent microscopy and cytofluorometry showed that the increased effect of ADR by hyperthermia was due to an increased drug uptake at the supranormal temperature.

Differential metastatic capacity of three AKR lymphoma variants.

The comprehension of tumour progression has advanced due to the use of various models, the most rewarding being probably the study of malignancy variants derived from the same tumour. In the present study the biological behaviours of three AKR lymphoma variants were compared. The three variants, TAU-33, TAU-38 and TAU-39, differed markedly in biological behaviour. The TAU-39 variant formed very large 'primary tumours', TAU-33 produced local growths of intermediate size, and TAU-38 formed small s.c. tumours. However, the metastatic potentials of the variants were inversely related to their ability to produce local tumours. According to various parameters (spread to organs, cachexia and mice mortality rate), the variant of highest metastatic potential was TAU-38, the one of intermediate ability TAU-33 and the TAU-39 had the least aggressive behaviour. A lack of difference in invasive capacity as well as a similar ranking of malignancy by both s.c. and i.v. inoculation indicate a differential behaviour in late metastasis phase. Tumour progression models may contribute to a better understanding of this threatening process and to testing of new treatment modalities suitable for cancer at different stages.

Differential sensitivity to hyperthermia of the F1 and F10 B16 melanoma variants.

The currently available antitumoral therapeutic modalities are most often inefficient against metastatic disease. The metastatic phenotype has been shown to be largely determined by cell membrane properties. The cell membrane could therefore be considered as a possible target for antimetastatic drugs. In the present study we examined the effect of hyperthermia (the antitumoral effect of which is based, at least partly, on an action on the cell membrane) on the F1 and F10 variants of B16 melanoma. Cells of the more malignant variant, F10, were found to be markedly more sensitive to hyperthermic treatment than those of the less malignant one, F1. One hour in-vitro treatment by supranormal temperatures (ranging from 40 to 46 degrees C) resulted in a differential effect with regard to both proliferating capacity of the cells in vitro and tumorigenic ability following inoculation to mice. Our present results in the B16 melanoma corroborate data obtained by us in another tumour system, the AKR lymphoma. Study of the effect of membrane-acting agents on tumour variants differing in degree of malignancy might result in the finding of antitumoral agents efficient against advanced cancer.