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Biomedical subjects

U Ringborg

Publications and source records attributed to U Ringborg.

At least 37 records · Page 2Linked to original sources
PubMed1999

Metastatic patterns, clinical outcome, and malignant phenotype in malignant cutaneous melanoma.

The objective of this population-based study was to assess metastatic pathways and outcomes vs. selected clinical and histopathologic features of the primary tumor in patients with recurrent cutaneous malignant melanoma. At a median follow-up time of 11 years, 569/2493 patients with recurrence were identified. We demonstrated a 5-year survival rate of 82% and 30% among those with a primary local or regional recurrence, respectively. Patients with primary distant skin, distant lymph node, or pulmonary metastases had a significantly better survival compared with those with CNS, bone, visceral, liver, or multiple sites of first distant metastases. The metastatic pathways were similar with regard to histogenetic type, primary tumor thickness, Clark's level of invasion, and primary tumor ulceration. Different histogenetic types, as assessed by light microscopy, imply different risks of recurrence. However, once the recurrence is manifest, the metastatic pathways are uniform, as well as prognosis, and survival.

Adult↗
PubMed1999

Epidemiological characteristics of cutaneous malignant melanoma of the head and neck--a population-based study.

Since cutaneous malignant melanoma (CMM) and melanoma in situ (MIS) of the head and neck have only partially been differentiated from CMM of other anatomic sites, these lesions are classified in detail in this study. Data from 756 patients derived from the population-based register of the Stockholm-Gotland area were analyzed and the findings showed that the incidence of CMM was 3.4 times higher in the face compared to the skin outside the head-neck area and that lentigo maligna melanoma was 74 times and nodular melanoma 2.3 times more common in the face. Mean age at diagnosis was significantly higher for patients with CMM of the head and neck irrespective of histogenetic type. Tumor site within the head and neck related to age at diagnosis. CMM of the head and neck differs from CMM of other locations. Epidemiological data are in agreement with the hypothesis that UV radiation (chronic or intermittent) may give rise to melanomas with various phenotypic traits.

Adolescent↗
PubMed1998

Screening of germline mutations in the CDK4, CDKN2C and TP53 genes in familial melanoma: a clinic-based population study.

Germline mutations within the CDKN2A gene, coding for the cyclin-dependent kinase inhibitor p16, have been detected by screening in 8% of Swedish families with an inheritance of cutaneous melanoma (FMM) and dysplastic nevus syndrome (DNS). Contrastingly, the closely related gene CDKN2B had no disease-related mutations in these families. A majority of Swedish families with hereditary melanoma predisposition thus lack germline mutations in these cell cycle G1 checkpoint-regulating genes. Additional genes with the potential to contribute to increased melanoma risk may code for related components of the cell cycle-regulating machinery. The gene for cyclin-dependent kinase 4, CDK4, has been found in mutated form in the germline from individuals belonging to 2 melanoma kindreds in the United States. The CDKN2C gene coding for the cyclin-dependent kinase inhibitor p18 is localized on 1p32, a region frequently involved in chromosomal changes in melanomas and other tumors. The TP53 suppressor gene, involved in cell cycle regulation and maintenance of genetic stability, is found mutated in the germline of patients with hereditary Li-Fraumeni syndrome, leading to early onset of several human cancers, including melanoma. The present investigation reports the results of screening the 100 Swedish melanoma families for germline mutations in the CDK4, CDKN2C and TP53 genes. No disease-related mutations were detected in the coding regions. A direct contribution of these genes to the hereditary risk for melanoma in members of Swedish melanoma kindreds therefore appears unlikely.

Base Sequence↗
PubMed1998

Dacarbazine-vindesine versus dacarbazine-vindesine-cisplatin in disseminated malignant melanoma. A randomised phase III trial.

In a multicentre phase III study of disseminated malignant melanoma performed in Sweden and Norway, 326 patients were randomised to receive treatment with the combination dacarbazine [DTIC] (D) and vindesine (V) with or without the addition of cisplatin (P). D was given intravenously (i.v.) at a dose of 250 mg/m2 days 1-5 every 4 weeks and V was given i.v. at a dose of 3.0 mg/m2 day 1 weekly. P was given i.v. at a dose of 100 mg/m2 day 1 every 4 weeks. There was no statistically significant difference in overall survival between the treatment arms (P = 0.22). Increased toxicity was observed in the treatment arm containing P of which leucopenia, alopecia and nausea/vomiting were the most pronounced. The median time to progression was significantly longer in patients treated with DVP (4.2 versus 2.2 months, P = 0.007). In conclusion, adding P to DV did not change overall survival but did significantly increase toxicity.

Adolescent↗
PubMed1998

N-ras mutations are common in melanomas from sun-exposed skin of humans but rare in mucosal membranes or unexposed skin.

Ras mutations, preferentially in codon 61 of the N-ras oncogene, are common in human cutaneous melanomas. In this study, we questioned the association between ras mutations in primary melanomas and sun exposure. DNA was extracted from formalin-fixed primary melanomas: 28 at chronically sun-exposed head and neck areas, 18 at sites subject to intermittent sun exposure, and 28 from unexposed mucosal membranes (vulva/vagina, anus/ rectum, palate). Mutations of both exons of H-, K-, and N-ras genes were examined by polymerase chain reaction/single-strand conformation polymorphism and by direct nucleotide sequencing of the polymerase chain reaction amplified exons. Thirty-two per cent of the head and neck melanomas and 11% of the melanomas from intermittently sun-exposed skin had N-ras codon 61 mutations; comparatively only 7% of the tumors from the unexposed areas had such mutations. One vulvar melanoma had an N-ras codon 12 mutation. No H-ras or K-ras mutations were detected in any sample. The frequency of N-ras exon 2 mutations in melanomas of typically sunbathed skin was compared for the first time with that in melanomas of areas completely protected from sun exposure. The significantly higher frequency (p = 0.04, chi square exact test) of these N-ras mutations on the head and neck demonstrates their UV-light induction in a subset of melanomas explaining one of the molecular effects of UV light in human skin.

Base Sequence↗
PubMed1998

Central nervous system metastases of cutaneous malignant melanoma--a population-based study.

The objectives of this population-based study were to assess putative prognostic factors for central nervous system (CNS) metastases among patients with cutaneous malignant melanoma, to assess the cumulative risk of CNS metastases in different subsets of patients with recurrent disease, and to describe patient outcome. At a median follow-up of 11 years, 201/2516 patients with melanoma had developed CNS metastases, corresponding to a cumulative risk at 5 years of 7%. In 41 of these 201 patients the CNS metastases were recorded as the first site of recurrence. In a Cox's multivariate model, primary tumor thickness and ulceration in stage I patients were independent risk factors. The cumulative rates of incidence of CNS metastases 5 years after local or regional recurrence as first event were 5 and 42%, respectively. These results may help to form an individually based risk assessment, which might be of value for melanoma patients in certain occupations.

Adult↗
PubMed1998

Alcohol and risk of cancer.

A large number of cohort and case-control studies have contributed to increased knowledge regarding alcoholic beverages and risk of malignant diseases. A clear association pointing at a causal relationship has been found for cancer of the oral cavity, pharynx, larynx, esophagus, and liver. A suggestive association has been found for cancer of the large bowel and breast. An association is considered unlikely for cancer of the stomach, pancreas, lung, urinary bladder, prostate, ovary, and for malignant melanoma. Studies have also been conducted regarding endometrial cancer, kidney cancer, leukemia, and lymphoma. No associations have been demonstrated, but the number of studies is too small for conclusions.

Alcohol Drinking↗
PubMed1998

Nodular histogenetic type -- the most significant factor for thick melanoma: implications for prevention.

Tumour thickness is the most important prognostic factor in malignant melanoma. To reduce the melanoma-related mortality, factors related to the presentation of thick melanoma have to be identified. Three samples of melanoma patients (n=694) were studied for this purpose. Histogenetic type was the only factor which differentiated between 'thin' (< or = 0.8 mm) and 'thick' (> 2.0 mm) lesions. During a 10-year period only 3% of the nodular lesions were 'thin' at diagnosis. Differences in knowledge about melanoma or the location of the lesion (either 'easy' or 'difficult' for the patient to observe) did not explain differences in tumour thickness. The most common tumour site irrespective of histogenetic type and gender was 'back of the trunk'. 'Increase in diameter' and 'bleeding' were the symptoms most frequently reported by patients with 'thick' melanoma. 'Thick' lesions were diagnosed in older age groups and in men to a greater extent. Considering these results, melanoma prevention should also be targeted to older age groups and attention should be paid to symptoms such as 'increase in diameter' even in the absence of other characteristic symptoms of melanoma. An increased proportion of nodular melanoma diagnosed as 'thin' lesions can be interpreted as a step forward in secondary prevention.

Adult↗
PubMed1997

Outcomes of patients with local recurrence of cutaneous malignant melanoma: a population-based study.

BACKGROUND: The definition of local recurrence of cutaneous malignant melanoma varies. The outcomes of patients with a local recurrence reported in the literature also vary, but the appearance of a local recurrence has generally been considered a negative prognostic sign. Few studies have been population-based thus far. METHODS: During the period 1976-1997, 3706 patients with cutaneous malignant melanoma (including 575 patients with melanoma in situ) were registered in a population-based regional cancer registry. Local recurrence was defined as a recurrence within the scar or transplant with no signs of regional or distant spread of the disease. Prognostic factors were investigated using univariate and multivariate analytic techniques. The prognostic importance of a local recurrence in terms of survival was analyzed using the Cox proportional hazards regression model, with local recurrence as a time-dependent covariate. RESULTS: Local recurrence as a first event was rare (occurring in 48 of 3706 patients, or 1.3%). Twenty-eight percent (11 of 39) of the patients with local recurrence of invasive primary melanoma developed distant metastases and subsequently died. Only ulceration had prognostic significance in univariate analysis. A Cox analysis, with melanoma death as the endpoint and local recurrence as a time-dependent covariate, demonstrated a relative risk of 1.3 associated with local recurrence; however, this was not statistically significant (confidence interval, 0.7-2.3). CONCLUSIONS: In this population-based study, local recurrence was a rare event. The outcomes after diagnosis were relatively favorable. The results did not indicate a major detrimental effect on survival from the local recurrence per se.

Adolescent↗
PubMed1997

Screening of germline mutations in the CDKN2A and CDKN2B genes in Swedish families with hereditary cutaneous melanoma.

BACKGROUND: Approximately 10% of human cutaneous melanomas occur in families in which several members are affected. The familial predisposition to this disease is often associated with dysplastic nevus syndrome, a condition in which afflicted family members have multiple dysplastic nevi (atypical moles). The chromosome region 9p21 and markers on chromosomes 1p and 6p have been linked to melanoma susceptibility. The tumor suppressor genes CDKN2A and CDKN2B have been mapped to the 9p21 region, and genetic analyses have revealed the presence of germline CDKN2A alterations in melanoma families. The reported frequencies of such alterations, however, vary among these families. PURPOSE: The present investigation was carried out to determine the frequencies of CDKN2A and CDKN2B germline gene mutations among members in a population-based cohort of Swedish melanoma families (i.e., melanoma kindreds). METHODS: DNA was prepared from blood samples obtained from 181 individuals belonging to 100 melanoma kindreds. The polymerase chain reaction (PCR) technique, followed by single-strand conformation polymorphism (SSCP) and nucleotide sequence analyses, were used to identify the types and frequencies of mutations in exons 1, 1beta, 2, and 3 of the CDKN2A gene and in exons 1 and 2 of the CDKN2B gene. RESULTS: CDKN2A gene aberrations were independently identified by both SSCP and nucleotide-sequence analyses. Nucleotide-sequence analysis identified a single point mutation leading to a substitution of leucine for proline in codon 48 of exon 1 in a family with a history of melanoma and several other cancers. A second abnormality, leading to an insertion of an extra arginine residue at codon number 113 of exon 2, was seen in four separate families. The CDKN2A exon-3 coding region had the wild-type sequence in all samples. No germline mutations were found in the alternative exon 1beta of the CDKN2A gene or in exons 1 and 2 of the CDKN2B gene. CONCLUSIONS: The present investigation demonstrates that CDKN2A germline gene mutations were observed in 7.8% of the 64 Swedish melanoma kindreds that each included at least two first-degree relatives with melanoma and dysplastic nevus syndrome. No CDKN2A exon 1beta or CDKN2B mutations were identified. The critical genes responsible for the inheritance of a susceptibility to develop melanoma among family members in this population have yet to be identified.

Carrier Proteins↗
PubMed1997

Neoadjuvant chemotherapy with cisplatin and 5-fluorouracil in advanced squamous cell carcinoma of the head and neck: a randomized phase III study.

BACKGROUND AND PURPOSE: In 1986 a prospective, randomized, multi-centre trial for evaluation of neoadjuvant chemotherapy with cisplatin and 5-fluorouracil in the treatment of advanced squamous cell carcinoma of the head and neck was initiated. As survival in this group of patients is poor the purpose was to find a possible survival benefit of the chemotherapy in addition to radiotherapy compared to radiotherapy only. METHODS: Four-hundred sixty-one patients from Denmark, Norway and Sweden with tumors in oral cavity, oropharynx, hypopharynx and larynx were randomized to receive either standard treatment (radiotherapy or radiotherapy followed by surgery) or neoadjuvant chemotherapy followed by standard treatment. Chemotherapy included three courses of cisplatin 100 mg/m2 i.v. infusion on day 1 followed by 5-fluorouracil 1000 mg/m2 per day continuous i.v. infusion for 120 hours. Radiotherapy 64-70 Gy in 2 Gy per fraction, 5 times/week, was given to patients in both treatment arms. RESULTS: Response rate was 71% for patients randomized to chemotherapy-radiotherapy and 66% for patients randomized to standard treatment (not statistically significant). Residual tumors were excised if possible. After surgery 62% of the patients randomized to chemotherapy-radiotherapy and 60% of the patients in the standard treatment group were clinically tumor free. CONCLUSIONS: No statistically significant benefit in survival was observed for patients treated with neoadjuvant chemotherapy followed by radiotherapy. Nor was there any impact of chemotherapy on the number of patients achieving loco-regional tumor control after primary treatment.

Adult↗
PubMed1997

Immunohistochemical examination of the expression of O6-methylguanine-DNA methyltransferase in human melanoma metastases.

In tumour cell lines, an inverse relationship has been shown between susceptibility to the cytotoxic effects of the O6-alkylating agents and the expression of the DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT). One of the most effective single agents in chemotherapy of metastatic melanoma is the O6-alkylating drug, dacarbazine. We therefore examined the distribution of MGMT in 37 skin and lymph node melanoma metastases using rabbit antihuman MGMT antiserum. MGMT expression was undetectable in tumours from 2 out of 34 patients and low in 4 further patients. When present, staining was mainly nuclear and showed a marked variation both among tumour cells within the same metastases, between separate metastases in the same patient and between tumours in different patients. MGMT expression determined by immunohistochemistry showed a relation to MGMT activity measurements, but was not related to the number of proliferating cells, as identified by staining with MIB-1 antibody. Tumour cells with moderate to strong immunostaining with MGMT antiserum were significantly more abundant in metastases excised after dacarbazine-based chemotherapy (n = 8) than in those excised before treatment (n = 29).

Adult↗
PubMed1997

Role of O6-methylguanine-DNA methyltransferase, glutathione transferase M3-3 and glutathione in resistance to carmustine in a human non-small cell lung cancer cell line.

O6-methylguanine-DNA methyltransferase (MGMT), glutathione transferase (GST) M3-3 and glutathione (GSH) have all been implicated in the resistance of cells to the cytostatic drug carmustine. U1810, a human non-small cell lung cancer cell line, expresses all of these putative resistance factors. The U1810 cells show a 4.4-fold lower sensitivity to carmustine compared with the U1690 cell line, a human small cell lung cancer cell line lacking detectable levels of both MGMT and GST M3-3. We investigated the effect of the MGMT inhibitor O6-benzylguanine, the GST inhibitor ethacrynic acid and the GSH synthesis inhibitor D,L-buthionine-S,R-sulfoximine (BSO) on the cytotoxicity of carmustine to U1810 cells. No potentiation to carmustine was observed after treatment with ethacrynic acid, while a 2-fold potentiation was found after exposure to O6-benzylguanine. Depletion of GSH with BSO showed a similar sensitising effect as that obtained with O6-benzylguanine. Thus, MGMT and GSH are the predominant resistance factors to carmustine in the U1810 cell line, whereas it is unclear whether GST M3-3 plays any role.

Antineoplastic Agents, Alkylating↗
PubMed1996

Predictors of late mortality in cutaneous malignant melanoma--a population-based study in Sweden.

We determined risk factors for late deaths from cutaneous malignant melanoma (CMM) based on clinical characteristics at diagnosis, initial surgical treatment, histopathologic features of the primary tumor and type of eventual recurrences during follow-up. We examined deaths from CMM 8 or more completed years after the initial diagnosis in a case-control study nested in a nationwide cohort comprising all 8,838 patients with CMM diagnosed in Sweden during 1960-1978 with complete follow-up through 1986. There were 285 case patients and 285 control patients, individually matched by sex, age and follow-up time. Conditional logistic regression was used to obtain odds ratios (OR) as estimates of the relative risk. The risk of late mortality increased stepwise, almost 19-fold, with increasing tumor thickness from < or = 0.75 to > or = 7.00 mm. Besides the thickest tumors (> or = 7.00 mm), those of intermediate thickness (1.50-2.49 mm) had the highest risk (OR 8.5). After adjustment for tumor thickness, non-radical primary surgical treatment increased the risk of late mortality almost 3-fold while prophylactic lymph node dissection entailed a significantly reduced risk of late mortality (OR 0.5); the histopathologic features increasing level of invasion and vertical growth phase also remained significantly associated with a poor outcome. In a multivariate model, non-radical primary surgical treatment, prophylactic lymph node dissection, vertical growth phase, level of invasion and lymphocyte reaction were independent predictors of late mortality.

Adult↗
PubMed1996

Resection margins of 2 versus 5 cm for cutaneous malignant melanoma with a tumor thickness of 0.8 to 2.0 mm: randomized study by the Swedish Melanoma Study Group.

BACKGROUND: The traditional surgical treatment for primary malignant melanoma has often been a wide excision with a margin of about 5 cm. Since the risk of local recurrences is dependent on tumor thickness, thin tumors (<1 mm) have routinely been excised with a narrow margin. For thick tumors, the optimal resection margin is controversial, and can be determined only by prospective, randomized trials. METHODS: The Swedish Melanoma Study Group performed a prospective, randomized multicenter study to evaluate an excision margin of 2 versus 5 cm for patients with cutaneous malignant melanoma with tumor thickness > 0.8 and < or = 2.0 mm. The trial includes 769 patients. Patients with melanomas of the skin of the head, neck, hands, feet, or vulva were not included in the trial. In the event of an excision biopsy for diagnosis, radical surgery was completed within 6 weeks. The median follow-up time was 5.8 years for estimation of survival and 4.0 years for diagnosis of recurrent disease. RESULTS: No significant differences have been observed between the treatment groups regarding local or regional recurrences or survival. CONCLUSIONS: We recommend an excision with a margin of 2 cm for cutaneous malignant melanoma with a tumor thickness > 0.8 and < or = 2.0 mm.

Biopsy↗
PubMed1996

Comparison of induction chemotherapy before radiotherapy with radiotherapy only in patients with locally advanced squamous cell carcinoma of the lung. The Swedish Lung Cancer Study Group.

The aim of this randomised trial was to investigate the effect of induction chemotherapy before radiotherapy on survival in 302 patients with non-resectable squamous cell carcinoma of the lung. Radiotherapy, 56 Gy to the chest, was given to 154 patients and combined treatment, with chemotherapy preceding the radiotherapy, to 148 patients. Chemotherapy consisted of three courses of cisplatin (120 mg/m2) and etoposide (100 mg/m2 i.v. for 3 days) administered every fourth week. Median survival was 10.5 months in the radiotherapy arm and 11 months in the combined treatment arm. The 2-year survival rate was 17% in the radiotherapy arm and 21% in the combined treatment arm. Addition of chemotherapy seemed to significantly improve survival, according to the Cox multivariate analysis (P = 0.04), but as only a trend according to life-table analysis (P = 0.11). Chemotherapy also accomplished a trend towards improved local control (P = 0.08) and towards decreased metastatic disease (P = 0.10). 2 patients in the combined treatment arm, but none in the radiotherapy arm, died from toxicity. The conclusion was that the value of the chemotherapy used in this study was very modest, but the results strongly support further research for more efficient drugs and combinations.

Aged↗
PubMed1996

Second primary cancers in patients with cutaneous malignant melanoma: a population-based study in Sweden.

To quantify the risk of second primary cancers among patients with cutaneous malignant melanoma, we studied 20,354 patients in the Swedish Cancer Register during 1958-88. A second primary cancer was reported in 1605 patients, compared with an expected number of 1109.5 [standardised incidence ratio (SIR) = 1.45, 95% confidence interval (CI) = 1.38-1.52]. The highest risk was found among patients younger than 60 years. The greatest risk was seen during the first year after diagnosis (SIR = 1.91, CI = 1.69-2.14), but even after long-term follow-up--15 years or more--the risk was still significantly elevated (SIR = 1.56, CI = 1.35-1.79). The strongest association was found for a second primary malignant melanoma (men, SIR = 10.0, CI = 8.26-12.00; women, SIR = 8.66, CI = 7.22-10.30) and non-melanoma skin cancer (men, SIR = 3.58, CI = 2.85-4.44; women, SIR = 2.41, CI = 1.71-3.29). The risk of second cancers associated with tissues of neuroectodermal origin was increased, especially tumours of the nervous system (men, SIR = 1.73, CI = 1.10-2.60; women, SIR = 2.03, CI = 1.45-2.78). The SIR of second cancers involving the immune system was also increased. An excess risk of endometrial cancer was seen (SIR = 1.41, CI = 1.03-1.88), but no significant associations existed for cancers of the breast, ovary, testis or other endocrine glands. Among tumours of the digestive tract, only colon cancer in men had a significantly increased SIR (1.33, CI = 1.00-1.74).

Age Factors↗