Post-operative neutron irradiation.
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Biomedical subjects
Publications and source records attributed to A Courdi.
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To evaluate the utility of bone scans for the follow-up of patients with small breast cancers (T less than or equal to 3 cm), the files for 133 patients whose disease was diagnosed between Jan. 1, 1979 and Dec. 31, 1980 were reviewed. At initial presentation, two of these patients already had bone metastases. During their disease course, 30 patients developed metastases and 16 of them had at least one bone metastasis. In 7 of these 16 cases, the bone metastasis was solitary; in 4 cases bone lesions were symptomatic. A total of 178 bone scans were performed during the follow-up of these 133 patients; 16 of these scans were positive, but only 4 examinations allowed the diagnosis of bone metastasis. Despite the slight prognostic value of initial bone scanning in this series, the technique is of little value unless it is combined with clinical examinations aimed at early detection of disease recurrence or metastasis. Except as part of clinical trial protocols, systematic bone scans appear unnecessary for the staging and follow-up of patients with small breast cancers.
The clonogenicity in soft agar and the labeling index (LI) which represents the percentage of cells in the DNA synthesis phase, were studied in 59 breast cancer patients and these parameters were related to other known clinicopathological features, namely age, histological grading, estrogen and progesterone receptors and the status of axillary lymph nodes. Out of 59 tumors, 49 could be successfully cloned in soft agar and the mean plating efficiency (PE) was 0.1%. Low grade tumors were more frequently encountered in tumors which did not form colonies (P = 0.025). Cloned tumors had a higher mean LI (P = 0.05). A high PE was associated with low estrogen receptors (ER) (P = 0.03). Clonogenicity was not related to patient age, progesterone receptors (PR) or the status of axillary lymph nodes. These results suggest that a successful in vitro cloning and a high PE are associated with unfavorable prognostic factors in breast cancer.
The DNA labelling index (LI), representing the fraction of S-phase cells, was studied in 76 patients operated on for breast cancer from 1975 to 1979. No patient had lymph node involvement following axillary dissection (N-), and no adjuvant medical treatment was given. Patients were classified in one of two groups according to the median LI. Patient distribution by age, tumour size, and receptor status was identical in both groups. A higher frequency of grade 3 tumours was noted in the group with an LI above the median value. The cell proliferation rate was an important discriminative factor for metastatic potential. The probability of survival at 8 years for patients with a high LI was significantly lower than that of patients with low LI (36% versus 100%; p less than 0.001). Relapse-free survival at 8 years was respectively 56% and 83% (p less than 0.02). At 2 years, these values were 75% and 100%, indicating the early occurrence of metastases. By contrast, the LI had no prognostic value concerning loco-regional disease recurrence or survival after the appearance of metastasis. No relationship was found in this study between survival and other prognostic factors, namely tumour size, histological grade, or hormone receptor level. The LI currently appears to be the best prognostic factor for N- breast cancer. High risk patients identified by this method could thus be offered adjuvant medical treatment.
The labeling index (LI), representing the percentage of S-phase cells, was measured in the healthy colorectal mucosa of subjects without a personal or familial history of neoplasm as well as in persons with a positive history, and was compared to the LI in benign or malignant lesions in a total of 128 subjects. In the healthy mucosa, LI was lowest in control subjects; it rose progressively in patients with a personal history of adenoma, patients with non colorectal cancer, and colorectal cancer patients respectively. There was a significant increase in LI from healthy mucosa to adenoma to carcinoma. The pattern of labeling in the crypts was studied in 56 subjects with different familial and personal histories. Limitation of labeling to the deepest part of the crypts was observed in control subjects and to a lesser extent in the healthy mucosa of patients with adenoma. An upward shift of the proliferative zone was observed in patients with a personal or familial history of cancer; adenomatous lesions had an inverse labeling distribution: labeling decreased from the luminal aspect towards the deep segments. High LI values and a shift of the proliferative zone towards the surface of the crypt may identify individuals at high risk for cancer of the colon and rectum.
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The effect of polyamine depletion on the radiosensitivity of a human tumor cell line was investigated. CAL 18 A cells, derived from a breast carcinoma, were incubated with alpha-difluoromethylornithine (DFMO)--a specific and irreversible inhibitor of ornithine decarboxylase (ODC)--at a 1 mM or 10-mM concentration for either 1 hr or 24 hr and irradiated thereafter. Survival curves of exponentially growing cells revealed a moderate but significant enhancement of radiosensitivity as compared to untreated irradiated cells. Maximum radiosensitization was observed at a concentration of 10 mM after 1 hr incubation. Plateau-phase cells were used to study the effect of polyamine inhibition on repair of radiation-induced potentially lethal damage (PLD). DFMO enhanced the radiation response and significantly inhibited PLD repair in these cells. Measurement of ODC indicated that this enzyme was markedly inactivated upon brief incubation of CAL 18 A cells with DFMO, reflecting a depletion of polyamine synthesis. These results extend findings that have demonstrated enhancement of drug-induced cytotoxicity, and raise the possibility of clinical use of this substance for potentiation of radiation response.
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In vitro culture of a human breast cancer biopsy fragment gave rise to two permanent cell lines, CAL 18 A and CAL 18 B, which were differentiated by both morphological and ultrastructural analysis. The karyotypic and growth properties of these two cell lines also differed, providing further evidence of cell heterogeneity within a given tumor. Both cell lines lost their hormone receptors in vitro. CAL 18 A cells grew in agar and were tumorigenic after inoculation into nude mice; neither of these properties was observed in CAL 18 B cells. The chemosensitivity of 12 antineoplastic drugs was assessed by a short-term assay, using inhibition of tritiated thymidine incorporation by the cells after contact with the drugs as the end point. Only a few drugs were active at moderate concentrations. The overall responses of both cell lines were similar. The cell survival curves, established by the colony method following a single dose of radiation, were also very similar, despite the greater heterogeneity of CAL 18 B cells. The two cell lines appear to be interrelated, since CAL 18 B cells were occasionally observed to emerge from CAL 18 A clones, suggesting that malignant cell redifferentiation may occur spontaneously in vitro.
The mean inactivation dose (D) is calculated for published in vitro survival curves obtained from cell lines of both normal and neoplastic human tissues. Cells belonging to different histological categories (melanomas, carcinomas, etc.) are shown to be characterized by distinct values of D which are related to the clinical radiosensitivity of tumors from these categories. Compared to other ways of representing in vitro radiosensitivity, e.g., by the multitarget parameters D0 and n, the parameter D has several specific advantages: (i) D is representative for the whole cell population rather than for a fraction of it; (ii) it minimizes the fluctuations of the survival curves of a given cell line investigated by different authors; (iii) there is low variability of D within each histological category; (iv) significant differences in radiosensitivity between the categories emerge when using D. D appears to be a useful concept for specifying intrinsic radiosensitivity of human cell lines.
Three human melanoma cell lines were derived from tumor specimens and established in culture. CAL 1 originated from a bone marrow metastasis and CAL 4 and CAL 7 were derived from solid tumor fragments. CAL 1 and CAL 7 were cloned before establishment. Ultrastructural and chromosome analysis were carried out along with the response to nine chemotherapeutic agents at various concentrations. Survival curves after irradiation were also plotted. The uncloned cell line, CAL 4, displayed some differences from the other two cell lines as regards ploidy and response to chemotherapy. Greater spread of chromosome numbers were observed with this cell line, which contained both hypoploid and a hyperploid modal numbers. All three cell lines showed a relatively high extrapolation number after irradiation, suggesting that inherent cellular properties may be partly responsible for the clinical radioresistance of malignant melanomas.
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Metastatic axillary lymph nodes following the injection of EMT6 tumour cells were observed in athymic nude mice, more often in female animals, and had a rapid growth rate. These metastases did not develop in syngeneic hosts. The latency of their appearance was inversely related to the number of injected cells.
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