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Biomedical subjects

U Ringborg

Publications and source records attributed to U Ringborg.

At least 73 records · Page 4Linked to original sources
PubMed1994

Prognostic factors in thin cutaneous malignant melanoma.

BACKGROUND: Thin melanomas can metastasize and be lethal. The predictive importance of tumor thickness in thin melanomas and the specific features identifying the patients at risk have not been investigated fully. METHODS: Prognostic factors were analyzed in 585 patients with clinical Stage I invasive cutaneous malignant melanoma with a thickness of less than or equal to 0.8 mm. The patients were included in a population-based cancer registry in Stockholm county during 1976-1987. They constituted about 64% of all patients with thin melanomas who were diagnosed in the region during the study period. Information was available on age, sex, anatomic site of the tumor, histologic type of melanoma, level of invasion, tumor thickness, and tumor regression. In a Cox regression analysis, the prognostic importance of each factor was studied. By a case-control technique with individual matching for the identified independent predictors of recurrence, the additional prognostic information given by type and grade of inflammatory response, presence of vertical growth phase, mitotic rate/mm2, and histologic ulceration of the tumor was assessed. RESULTS: After a median follow-up time of 50 months, recurrent disease developed in 26 patients (4%). There was no difference in recurrence rate between patients treated with narrow (1-2 cm) or wide (5 cm) excision. Anatomic site, tumor thickness, level of invasion, and tumor regression were found to be independent prognostic factors in the multivariate analysis. In the case-control study, only grade of inflammatory reaction added significant prognostic information. No subgroup could be identified that was without risk of recurrent disease. CONCLUSIONS: Thin melanomas do not seem to constitute a separate form of melanoma, but compose one end of a continuous spectrum of biologic behavior.

Adolescent↗
PubMed1994

Cell cycle dependent sensitivity of human melanoma cells to melphalan is correlated with the activity and cellular concentration of glutathione transferases.

Glutathione transferases (GSTs) are enzymes involved in the resistance of tumor cells to bifunctional alkylating cytostatic drugs. We investigated the melphalan sensitivity together with activity and cellular concentration of GST isoenzymes of human melanoma cell line RPMI 8322 in different phases of the cell cycle. By centrifugal elutriation three cell fractions containing different proportions of cells in the G1 phase were isolated. Melphalan sensitivity was estimated by the colony formation assay. The cell fraction with the largest proportion of G1 cells was more sensitive to the drug than the fractions enriched in S and G2 cells. The GST activity of the cell fractions was measured with 1-chloro-2,4-dinitrobenzene (CDNB) as substrate and the concentrations of GST P1-1, GST M1-1 and GST A1-1 were quantitated by use of isoenzyme-specific ELISA. The results show that there were less GST activity and lower GST P1-1 and A1-1 concentrations in the G1 cell enriched fraction, demonstrating a cell cycle dependence of GST expression. Thus, the cell fraction most sensitive to melphalan had the highest proportion of G1 cells and displayed the lowest GST activity, suggesting that the cell cycle dependent sensitivity to melphalan may at least partially depend on the expression of GSTs.

Cell Cycle↗
PubMed1994

Melanoma metastases from patients with hereditary cutaneous malignant melanoma contain a high frequency of N-ras activating mutations.

Mutations in N-ras exon 2 codon 61 were studied in formalin-fixed human melanoma metastases. DNA fragments including codon 61 were amplified by polymerase chain reaction (PCR) and mutational analysis was performed by oligonucleotide hybridization (ODN), allele specific PCR and PCR combined with single strand conformation polymorphism analysis (SSCP). Thirty metastases from 25 patients with 'spontaneous' cutaneous melanoma were compared with 35 metastases from 17 patients with 'hereditary' cutaneous melanoma. The frequency of mutations as measured by PCR/ODN was significantly higher in patients with hereditary melanoma (mutations in 24% versus 59%, p < 0.05). The most frequent mutations were C/A transversions to lysine (AAA). The occurrence of lysine mutations was, in addition, studied by allele specific polymerase chain reaction. Again, the mutation frequency was significantly higher in metastases from patients with hereditary melanoma. PCR/SSCP finally enabled the isolation of lysine mutant alleles and nucleotide sequence analysis which confirmed the presence of the mutated codon 61. The relatively higher frequency of N-ras mutations in tumours from patients with hereditary melanoma may be related to the hypermutability described in hereditary melanoma and dysplastic naevus syndrome. The results support an involvement of N-ras mutations in the molecular pathogenesis of melanoma.

Alleles↗
PubMed1994

Elective lymph node dissection in stage I cutaneous malignant melanoma of the head and neck. A report from the Swedish Melanoma Study Group.

The effect of elective lymph node dissection in patients with cutaneous malignant melanoma of the head and neck was investigated in a retrospective study. Of 517 patients in clinical stage I, 84 underwent elective dissection of the ipsilateral neck lymph nodes. In six of these patients, lymph node metastases were demonstrated at histopathological examination. There was a slight reduction in the incidence of recurrent disease in the regional lymph nodes in the group of patients who had undergone elective lymph node dissection, but this difference was not statistically significant. No significant differences were seen between the two groups regarding overall survival of disease-related survival.

Aged↗
PubMed1993

Contribution of glutathione transferase M3-3 to 1,3-bis(2-chloroethyl)-1-nitrosourea resistance in a human non-small cell lung cancer cell line.

The glutathione transferase (GST) isoenzyme profile was determined in two human tumor cell lines, U1690 derived from a small cell lung cancer and U1810 derived from a non-small cell lung cancer. U1810 cells are 3.2-fold more resistant to 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) than are U1690 cells, a finding ascribable in part to the expression of O6-alkylguanine-DNA alkyltransferase activity in the U1810 cells. GST P1-1 and GST A1-1 were determined quantitatively by enzyme-linked immunoassay and were found to be 1.3- and 15-fold higher in the cytosol fraction of U1690 cells as compared to U1810 cells, respectively. The higher BCNU resistance in U1810 cells can, therefore, not be correlated with the expression of these isoenzymes. However, sodium dodecyl sulfate/polyacrylamide gel electrophoresis in combination with immunoblot analysis demonstrated a class Mu GST, which was identified as GST M3-3 on the basis of electrophoretic mobility and cross-reaction with anti-rat GST 3-3 antibodies. This isoenzyme was detectable in U1810 cells but not in U1690 cells. Studies with purified human GST A1-1, GST M1-1, GST M3-3, and GST P1-1 demonstrated that GST M3-3, but not the other isoenzymes, catalyzed the denitrosation of BCNU. Such inactivation of BCNU has previously been demonstrated with rat class Mu GSTs (M. T. Smith et al., Cancer Res., 49: 2621-2625, 1989) but not with any human GST. These findings suggest that GST M3-3 contributes to BCNU resistance in the U1810 cells.

Carcinoma, Non-Small-Cell Lung↗
PubMed1993

Malignant melanoma of the vulva and vagina. Trends in incidence, age distribution, and long-term survival among 245 consecutive cases in Sweden 1960-1984.

BACKGROUND: Malignant melanomas of the vulva and vagina are rare tumors located in areas of the body not exposed to ultraviolet radiation. Investigations comprising large consecutive population-based series of patients with these diseases have not been published previously, to the knowledge of the authors. METHODS: Trends in incidence, age distribution, and prognosis were investigated among 219 consecutive cases of malignant melanoma of the vulva and 26 cases in the vagina, reported to the Swedish National Cancer Registry and representing virtually all primary tumors of that kind in Sweden during a 25-year period, 1960-1984. RESULTS: On average, 75% of the patients with vulvar melanoma and 73% with vaginal melanoma were older than 60 years of age. The mean age increased slightly but not significantly during the period. The age-standardized incidence of vulvar melanoma decreased from 0.27 to 0.14 per 100,000 Swedish women, or by 3% per year. The observed 5-year survival rate of patients with vulvar melanoma was 35%, and the relative survival rate was 47%. The observed and relative survival rates at 10 years were 23% and 44%, respectively. Observed and relative survival rates among patients with vaginal melanoma after 5 years were 13% and 18%, respectively. CONCLUSIONS: Accordingly, there was a decreasing incidence of vulvar and vaginal melanoma over the observed 25 years. This is in contrast to the trends in incidence for cutaneous melanomas in Sweden, which, during the same time period, increased almost 6% per year.

Adolescent↗
PubMed1993

Cutaneous malignant melanoma of the head and neck. Analysis of treatment results and prognostic factors in 581 patients: a report from the Swedish Melanoma Study Group.

BACKGROUND: Results of surgical treatment of cutaneous malignant melanoma (CMM) have been highly variable, probably because of patient selection. Therefore, a study of representative patients with this disease was performed. METHODS: In a defined area of Sweden, 581 patients were analyzed. Clinical records and histopathologic findings were reviewed. The minimum follow-up time was 7 years. Prognostic factors were evaluated by the Cox proportional hazards model. RESULTS: Evaluation of sex distribution, age, and anatomic site of the primary tumor showed that the patients were representative of all Swedish patients with CMM of the head and neck. The mean patient age at diagnosis was 64 years for both sexes. Fifty-three percent of the patients were women. Female patients had more tumors of the face than did male patients, whereas male patients were overrepresented among patients with tumors of the auricle-external ear canal and scalp-neck area. Localization to the face was observed in 68%, which is an overrepresentation of three to four times when skin surface is taken into consideration. Twenty-four percent of the patients had lentigo maligna melanoma. Only 33% of the patients had superficial spreading melanoma. In univariate analyses, sex, anatomic site of the primary tumor, histogenetic type, Clark level of invasion, and tumor thickness had prognostic power. In a multivariate analysis, tumor thickness, anatomic site of the primary tumor, and sex of the patient were independent prognostic factors. CONCLUSIONS: In representative patients with CMM of the head and neck, tumor thickness, anatomic site of the primary tumor, and sex of the patients were independent prognostic factors.

Age Factors↗
PubMed1993

Psychological reactions in public melanoma screening.

Participants in public screening for malignant melanoma (n = 190) completed a questionnaire containing items regarding cognitive and emotional responses to skin examination on two occasions, before screening and 7 months later. The results suggest subjective susceptibility to melanoma in participants in public screening, especially in women. No increase in psychosomatic problems, anxiety or depressive symptoms or signs of "false security" were seen as an effect of the screening, neither in the total sample nor in those who at the screening were recommended further medical procedures.

Aged↗
PubMed1992

Psychological effects of participation in a prevention programme for individuals with increased risk for malignant melanoma.

The Swedish Melanoma Study Group runs a programme aimed at prevention and early detection of premalignant and malignant melanoma in families with two or more members having malignant melanoma. Psychological consequences of participation in this programme were studied. A questionnaire containing items concerning cognitive and emotional responses to the programme was completed by 115 consecutive individuals at their first visit to the clinic. The same questionnaire was administered by mail 7 months later. The levels of psychological and psychosomatic problems were relatively low at both points of assessment. No negative psychological effects were found, neither in the group with dysplastic naevus syndrome (DNS) with increased risk for malignant melanoma, nor in the group without dysplastic naevi. Only one variable, "emotional responses to the visit" differentiated between the groups, with higher scores in the group without DNS. A majority of the individuals expressed positive attitudes to the clinic.

Adult↗
PubMed1991

Sensitization of human melanoma cells to the cytotoxic effect of melphalan by the glutathione transferase inhibitor ethacrynic acid.

Glutathione transferases are enzymes implied in the resistance of tumor cells to bifunctional alkylating cytostatic drugs. We have investigated the effect of the glutathione transferase inhibitor by ethacrynic acid on the cytotoxicity of melphalan to a human melanoma cell line (RPMI 8322) with a high level of glutathione transferase activity. Using 1-chloro-2,4-dinitrobenzene as substrate, ethacrynic acid was shown to inhibit the activity of purified human glutathione transferases, with 50% inhibition values of 1, 10, and 15 microM for transferase mu (class mu), transferase epsilon (class alpha) and transferase pi (class pi), respectively, all of which occur in RPMI 8322 cells. Ethacrynic acid at a concentration of 20 microM, which by itself was noncytotoxic, increased the cytotoxicity of melphalan to RPMI 8322 human melanoma cells approximately 2-fold. The induction of DNA interstrand cross-links by 40 microM melphalan was increased 1.4-fold by 30 microM ethacrynic acid. These results indicate that a potentiation of the cytotoxic effect of bifunctional alkylating agents can be achieved by inhibition of glutathione transferase and that the enhanced cytotoxicity may be caused at least in part by increased formation of drug-DNA adducts.

Cell Survival↗
PubMed1991

Early detection and prevention of cutaneous malignant melanoma: emphasis on Swedish activities.

The incidence of cutaneous malignant melanoma has increased more than the incidence of any other malignant tumour disease in Sweden the last three decades. Parallel to the almost 6% annual increase in incidence there has been a 3% annual increase in mortality. The knowledge of significant risk factors for melanoma (intermittent sun exposure and phenotypic traits related to skin pigmentation and propensity for dysplastic nevi) as well as the relationship between thin tumours and a good prognosis has been used to develop strategies for primary and secondary prevention. In this paper the Swedish programs for education of physicians, nurses and the general population are presented. A nationwide program for the identification and follow-up of individuals with dysplastic nevus syndrome has been initiated. The effects of the programs are followed by population-based melanoma registries.

Humans↗
PubMed1991

Comparative study of two human melanoma cell lines with different sensitivities to mustine and cisplatin.

The cytotoxic effects of the bifunctional DNA-reactive drugs cisplatin, mustine and melphalan were studied in two human melanoma cell lines, RPMI 8322 and A 375. A 375 cells were 3.0 times more sensitive to cisplatin and 1.5 times more sensitive to mustine than RPMI 8322 cells. In contrast, A 375 cells were less sensitive to melphalan than RPMI 8322 cells. The increased sensitivity of A 375 cells was parallelled by an increased induction of DNA interstrand crosslinks following exposure to cisplatin and mustine. After cisplatin exposure A 375 cells also showed higher levels of platinum-DNA intrastrand adducts than RPMI 8322 cells. The increased effect of cisplatin in A 375 cells was not due to an increased drug accumulation in these cells. The higher sensitivity of A 375 cells to cisplatin may be related to lower intranuclear levels of glutathione, compared to RPMI 8322 cell nuclei, while the sensitivity to mustine may depend on lower overall levels of glutathione than in RPMI 8322 cells.

Cell Line↗
PubMed1991

Carmustine-induced toxicity, DNA crosslinking and O6-methylguanine-DNA methyltransferase activity in two human lung cancer cell lines.

O6-methylguanine-DNA methyltransferase (O6-MT) probably plays an important role in the repair of chloroethylnitrosourea-induced DNA damage. O6-MT was studied as a possible drug resistance factor in two human lung cancer cell lines, one small cell lung cancer (U1690) and one non-small cell lung cancer (U1810), with different sensitivities to carmustine. The U1810 cell line was 3.4-fold more resistant to carmustine than U1690 cells, although the two cell lines were equally sensitive to mustine, melphalan and cisplatin. A 23-fold higher level of DNA interstrand crosslinks was observed following exposure of U1690 cells to carmustine compared with U1810 cells. The O6-MT activity of U1810 cells was 11 times higher than that of U1690 cells. The O6-MT activity in the U1810 cells showed a dose-dependent decrease after exposure to carmustine. These results show a correlation between increased O6-MT activity, decreased drug induced DNA interstrand crosslinking and cellular resistance to carmustine.

Carcinoma, Non-Small-Cell Lung↗
PubMed1991

Induction and time course of DNA single-strand breaks in lymphocytes from patients treated with dacarbazine.

Dacarbazine (DTIC) is an antitumor agent, used for the treatment of metastatic melanoma. It is metabolized to an alkylating agent which reacts with DNA. A fast and simple method was developed in order to measure drug-induced DNA damage in lymphocytes isolated from frozen blood samples of treated patients. The level of DNA damage was determined as single-strand breaks (SSB) by means of the alkaline elution technique using the fluorochrome Hoechst 33258. DTIC induced SSBs in lymphocytes. Most of the DNA damage was repaired after 20 h but after subsequent daily treatments there was an accumulation of SSB. The method described here can be used for monitoring DNA damage in lymphocytes of persons exposed to genotoxic compounds.

DNA Damage↗
PubMed1991

Regional hyperthermic perfusion with melphalan after surgery for recurrent malignant melanoma of the extremities. Swedish Melanoma Study Group.

A prospective randomized trial testing regional hyperthermic perfusion with melphalan has been conducted. Sixty-nine patients with recurrent malignant melanoma of the extremities were randomly allocated to surgery (36 patients) or surgery plus regional perfusion (33 patients). Prognostic variables concerning primary tumor as well as the recurrent disease were evenly distributed in the groups, excluding any bias in the randomization. Median tumor-free survival after randomization was 17 months in the perfusion group and 10 months in the control group. There were 15 locoregional recurrences in the perfusion group and 24 in the control group. The tumor-free survival curve was significantly (P = .044) better for the perfusion group than for the control group. Median survival time after randomization was 57 months in the perfusion group and 35 months in the control group. This difference was not significant. One patient died within 1 month after perfusion of pulmonary embolism. Regional hyperthermic perfusion after surgery of recurrent malignant melanoma should only be recommended in prospective and controlled trials, until its value has been proven in several randomized studies.

Adult↗