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R M MacKie

Publications and source records attributed to R M MacKie.

At least 19 recordsLinked to original sources
PubMed1999

Genetic and environmental influences in the development of multiple primary melanoma.

OBJECTIVES: To identify risk factors and the prognosis associated with the development of multiple primary melanoma (MPM). DESIGN: Case-comparison studies of subjects with MPM and single primary melanoma. Sequencing of CDKN2A in germline DNA. SETTING: Population-based study of patients with invasive melanoma in Scotland between 1979 and 1996. PATIENTS: For mortality studies, 108 patients with MPM and 216 single melanoma controls matched for age, sex, site, and tumor thickness. For risk factor studies, 48 patients with MPM and 48 single melanoma controls matched as above. For CDKN2A analysis, a sample of 23 subjects with MPM. RESULTS: The development of MPM was found not to be an independent prognostic factor. The risk of MPM was greatest in those with a family history of melanoma, with large numbers of benign nevi, and the presence of clinically or histologically atypical nevi. Germline mutations of CDKN2A were present in 6 of 23 patients with MPM and in 5 cases consisted of the base pair substitution Met53Ile. CONCLUSIONS: The importance of MPM should be addressed in melanoma follow-up protocols. Those patients at greatest risk can be identified by a family history of melanoma and their mole pattern. Germline mutations in CDKN2A occur in both familial and sporadic MPM and further studies are required to determine the value of analysis of this gene in melanoma surveillance. Patients should be informed that the development of MPM does not adversely affect their prognosis.

Disease Susceptibility↗
PubMed1999

Pregnancy and exogenous hormones in patients with cutaneous malignant melanoma.

In this article, recent literature is reviewed with regard to possible hormonal influences on susceptibility to melanoma and prognosis once melanoma is developed. At the present time, there is little data to suggest that melanoma and pregnancy interact as far as prognosis is concerned for patients with stage 1 and stage 2 disease. Recent data have provided further reassurance that oral contraceptives are safe for patients who have had melanoma, and more data is required before a definitive statement can be made regarding hormone replacement therapy for women who have had stage 1 or 2 melanoma adequately treated.

Contraceptives, Oral↗
PubMed1999

Pentoxifylline-induced modulation of melanoma cell growth, adhesion and lymphokine activated killer cell-mediated lysis.

Pentoxifylline (PX) is a phosphodiesterase inhibitor which effectively increases overall cAMP levels within the cell. This study analyses the ability of PX to alter growth, adhesion and lymphokine activated killer (LAK) cell-mediated lysis of the C8161 and Hs294T human melanoma cell lines, and investigates the role of intercellular adhesion molecule-1 (ICAM-1) in the tumour/LAK cell interaction. We have demonstrated that 4 days' pretreatment with PX (100-250 microg/ml) significantly reduces cell numbers in a dose- and time-dependent manner, with cell numbers decreasing by 67.5% in the C8161 cell line and by 65.4% in the Hs294T cell line with 250 microg/ml PX. Adherence of both cell lines to a range of extracellular matrix components is not affected by PX, with the exception of the C8161 cells, where 4 days' pretreatment with 250 microg/ml PX causes a 24.2% reduction in adherence to fibronectin. Four days' pretreatment of the tumour cells with 250 microg/ml PX leads to increased lysis of the C8161 cells and decreased lysis of the Hs294T cells. The addition of blocking ICAM-1 antibody (10 microg/ml) to the C8161 cells at an effector:tumour cell ratio of 40:1 causes a 2.3-fold reduction in lysis of both control and PX-treated cells. Addition of blocking ICAM-1 antibody (5 microg/ml) to Hs294T cells reduces lysis of control cells 1.8-fold. In PX-treated Hs294T cells, 10 microg/ml of blocking ICAM-1 antibody significantly reduces lysis 1.5-fold. The more aggressive C8161 cells produce 5-fold greater levels of soluble ICAM-1 (sICAM-1) than the poorly metastatic Hs294T cells. PX (10-250 microg/ml) causes a dose-dependent increase in sICAM-1 expression in both cell lines, with maximum increases of 4.7-fold and 4.3-fold in the Hs294T and C8161 cell lines, respectively, following 4 days' pretreatment with 250 microg/ml PX. Collectively, these data demonstrate the ability of PX to alter tumour cell growth, adhesion and LAK cell-mediated lysis and also support a role for the involvement of ICAM-1 in the tumour/LAK cell interaction.

Cell Adhesion↗
PubMed1998

Immediate or delayed dissection of regional nodes in patients with melanoma of the trunk: a randomised trial. WHO Melanoma Programme.

BACKGROUND: The use of elective regional node dissection in patients with cutaneous melanoma without any clinical evidence of metastatic spread is still debated. Our aim was to evaluate the efficacy of immediate node dissection in patients with melanoma of the trunk and without clinical evidence of regional node and distant metastases. METHODS: An international multicentre randomised trial was carried out by the WHO Melanoma Programme from 1982 to 1989. The trial included only patients with a trunk melanoma 1.5 mm or more in thickness. After wide excision of primary melanoma, patients were randomised to either immediate regional node dissection or a regional node dissection delayed until appearance of regional-node metastases. FINDINGS: Of the 252 patients entered, 240 (95%) were eligible and evaluable for analysis. 122 of these were randomised to immediate node dissection. 5-year survival observed in patients who had delayed node dissection was 51.3% (95% CI 41.7-60.1) compared with 61.7% (52.0-70.1) of patients who had immediate node dissection (p=0.09). 5-year survival rate in patients with occult regional node metastases was 48.2% (28.0-65.8) and 26.6% (13.4-41.8, p=0.04) in patients in whom the regional node dissection was delayed until the time of appearance of regional node metastases. Multivariate analysis showed that routine use of immediate node dissection had no impact on survival (hazard ratio 0.72, 95% CI 0.5-1.02), whilst the status of regional nodes affected survival significantly (p=0.007). The patients with regional nodes that became clinically and histologically positive during follow-up had the poorest prognosis. INTERPRETATION: Node dissection offers increased survival in patients with node metastases only. Sentinel node biopsy may become a tool to identify patients with occult node metastases, who could then undergo node dissection.

Elective Surgical Procedures↗
PubMed1998

Incidence, risk factors and prevention of melanoma.

The incidence of cutaneous malignant melanoma steadily increased between 1940 and 1990 in both sexes. However, this increase appears to have peaked in females in Scotland. Excessive exposure to ultraviolet radiation among Caucasians is the main etiologic factor implicated in the incidence of melanoma. Mortality due to melanoma also increased between 1940 and 1990, but the rate of increase is less than that of the incidence of melanoma. This may be due to earlier diagnosis and treatment of melanoma as a result of public education campaigns. Independent risk factors for developing melanoma include the presence of benign melanocytic naevi (moles), the development of lentigines or freckles, three or more dysplastic naevi and a history of three or more severe sunburns that resulted in peeling or blistering. Approximately 2% of melanoma patients have a family history of the disease and research into potential melanoma susceptibility genes is ongoing. Primary prevention campaigns, initiated mainly in Australia, are aimed at encouraging sensible sun exposure. Secondary prevention campaigns are directed at preventing death from melanoma by encouraging early diagnosis and treatment. Additional prospective studies are needed to determine if the incidence of melanoma has peaked and whether the recent trends observed in females will also occur in males.

Humans↗
PubMed1998

Sunbeds in current use in Scotland: a survey of their output and patterns of use.

Spectral irradiances of 100 commercially available sunbeds in current use have been measured. Ultraviolet (UV) A and UVB doses from sunbed use have been calculated and compared with doses likely to be received from solar radiation. The majority of sunbeds use UVA fluorescent tubes for irradiating the body and filtered metal halide lamps, which have a higher proportion of UVA1, for the face. The average minimum erythemal dose per session is 0.80, but irradiances for particular models varied by a factor of two to three primarily because of decline in lamp output with age. The UVA dose from a session on a sunbed is similar to that which might be received from 20 to 30 min sunbathing at a Mediterranean resort or 1 h on a sunny day in Glasgow, while UVB doses are 20-25% of this level. Responses from 200 current users of the sunbeds indicate that 38% had skin types 1 and 2, that 17% had more than 100 annual sunbed sessions and that 35% rarely or never used the goggles provided.

Adult↗
PubMed1998

Extrafacial lentigo maligna melanoma: analysis of 71 cases and comparison with lentigo maligna melanoma of the head and neck.

We report a retrospective analysis of extrafacial lentigo maligna melanoma (LMM), and a comparison with patients with LMM of the head and neck. Seventy-one patients (22 men, 49 women) with extrafacial LMM were identified from the Scottish Melanoma Group database for January 1979-March 1996. Their mean age (63 years) was significantly less than that of 335 patients with head and neck LMM (mean 72 years, P < 0.001), with a significantly greater difference among women than men. Extrafacial sites comprised 17.5% of LMMs. There was a marked body site distribution difference between the sexes (P = 0. 001): 68% of extrafacial LMMs in men were on the trunk while 80% in women were on the limbs, particularly the lower leg. Extrafacial LMMs were thinner at presentation than head and neck LMMs (P < 0.05) in both sexes, but this was not simply explained by the younger age of these patients as there was no significant correlation between age and tumour thickness at either extrafacial or at head and neck sites. Although the female lower leg is a site of chronic solar exposure in older women, the other extrafacial sites are habitually covered in the temperate Scottish climate. The significantly younger age group of patients with LMM at extrafacial compared with head and neck sites therefore suggests that the relationship between LMM and sunlight is not simply related to cumulative solar exposure. The demonstration that head and neck LMMs were thicker at presentation compared with extrafacial sites, despite being at a more routinely visible part of the body, suggests that there are still opportunities for targeted pigmented lesion public education.

Age Factors↗
PubMed1998

CDKN2A germline mutations in U.K. patients with familial melanoma and multiple primary melanomas.

We report six of 16 U.K. melanoma families and two of 17 patients with multiple primary melanomas and a negative family history who have between them four different functionally damaging mutations of the CDKN2A (p16) gene: an Arg 24 Pro substitution in exon 1 in one family, a stop codon at codon 44 of exon 1 in one family, and a Met 53 Ile substitution in exon 2 in four families. One multiple primary melanoma patient also has the Met 53 Ile mutation and a second has a G-T substitution at the IVS2 + 1 splice donor site. Our data together with other recent publications from France and the U.S.A. indicate that screening melanoma kindreds with only two affected family members for CDKN2A mutations is justified.

Adolescent↗
PubMed1997

Cutaneous malignant melanoma in Scotland: incidence, survival, and mortality, 1979-94. The Scottish Melanoma Group.

OBJECTIVE: To determine the changing incidence of and mortality from cutaneous malignant melanoma in Scotland from 1979 to 1994. DESIGN: Detailed registration of clinical and pathological features, surgical and other treatment, and follow up of all cases of cutaneous malignant melanoma diagnosed from 1979 to 1994 and registered with specialist database for Scotland. SETTING: Scotland. SUBJECTS: 6288 patients with invasive primary cutaneous malignant melanoma diagnosed between 1 January 1979 and 31 December 1994. RESULTS: The annual age standardised incidence of cutaneous malignant melanoma rose significantly from 3.5 to 7.8 per 100,000 per year in men and from 6.8 to 12.3 per 100,000 per year in women (P < 0.001 for both). World standardised rates increased from 2.7 to 6.0 per 100,000 per year in men and 4.6 to 8.50 per 100,000 in women. The incidence of melanoma continued to increase significantly in men of all ages during the study, but the rate stabilised in women after 1986. Mortality from cutaneous malignant melanoma was 1.3 per million per annum in men in 1979, rising to 2.3 per million per annum in 1994 (P < 0.01); it was 2.4 per million per annum in women in 1979, falling to 1.9 per million per annum in 1994 (P = 0.09). The underlying mortality trends showed a continuing rise for men but a downward trend for women that was not significant (P = 0.09). In men, melanoma free survival was 69% at 5 years and 61% at 10 years; in women the corresponding rates were 82% and 75%. Younger patients had higher survival rates, which were not entirely explained by thinner tumours. Over the 15 year period, survival rates improved by 12% overall, only partly owing to thinner tumours. CONCLUSIONS: In Scotland the incidence of melanoma in women has stabilised, while mortality associated with melanoma in women shows a downward trend.

Adolescent↗
PubMed1997

Cerebral metastases of cutaneous melanoma.

Cerebral metastases of cutaneous melanoma carry a very poor prognosis. We report our experience of 31 patients who presented with cerebral metastasis of cutaneous melanoma in a 5-year period between mid-1991 and mid-1996. Cerebral metastases were diagnosed on computerized tomography (CT) scan after patients became symptomatic. The overall median survival in our series was 4 months. Seventeen patients (55%) received treatment with radiotherapy and dexamethasone with resolution of their symptoms, although median survival remained at 4 months. Six patients (19%) had surgery followed by whole brain radiotherapy, with median survival of 5 months. The remaining eight patients received dexamethasone alone. Data from patients surviving less than 2 months and over 6 months suggest that the poor prognostic factors are the presence of more than one cerebral metastasis and additional extracranial metastases.

Administration, Oral↗
PubMed1997

Effect of retinoic acid on melanoma cell-derived factor stimulation of fibroblast glycosaminoglycan synthesis.

The hyaluronan-rich matrix that surrounds many tumours and facilitates tumour cell growth and invasion is thought to be predominantly synthesized by normal stromal cells stimulated by tumour cell-derived factors. This study examines the possibility that the production of tumour cell-derived factors that stimulate fibroblast glycosaminoglycan (GAG) synthesis may be blocked by exposure to differentiation-inducing agents such as retinoic acid. We have demonstrated that Hs294T, C8161 and A375 human melanoma cell lines release factors into their medium that stimulate normal fibroblast GAG synthesis. Exposure of these melanoma cells to retinoic acid failed to mediate any significant reduction in growth over a 7-day period. Retinoic acid failed to block the tumour cell production of GAG-stimulating activities and even enhanced the activities produced by the C8161 cell line, particularly at low retinoic acid concentrations (48% stimulation at 10(-9) M retinoic acid; P < 0.02). Addition of retinoic acid directly to fibroblast cultures exposed to fibroblast-conditioned medium resulted in an inhibition of GAG synthesis with a 33% inhibition observed at 10(-5) M. Addition of retinoic acid to fibroblast cultures exposed to the tumour cell-conditioned medium failed to inhibit the stimulation of GAG synthesis. Other differentiation-inducing agents, such as hexamethylene-bis-acetamide and butyrate, also failed to block the production of tumour cell-derived GAG-stimulating activities. These results demonstrate that retinoic acid and other differentiation-inducing agents fail to inhibit melanoma cell production of fibroblast GAG synthesis-stimulating factors or their action upon fibroblasts.

Acetamides↗
PubMed1997

Secondary prevention of cutaneous malignant melanoma.

The incidence of cutaneous malignant melanoma continues to increase in most parts of the world. Survival rates for melanoma patients show a striking difference between those diagnosed with thin primary tumours, and those whose tumours are only 2 mm thicker at the time of excision. This fact together with the poor response rates to current non-surgical therapies makes a clear case for earlier diagnosis and prompt surgical treatment of primary cutaneous malignant melanoma. Campaigns aimed at both early diagnosis (secondary prevention) and also at primary prevention of cutaneous malignant melanoma are discussed and methods of their evaluation considered.

Europe↗
PubMed1996

Incidence and thickness of primary tumours and survival of patients with cutaneous malignant melanoma in relation to socioeconomic status.

OBJECTIVE: To study incidence of and survival from cutaneous malignant melanoma in relation to socioeconomic status. DESIGN: Application of Carstairs deprivation score to all malignant melanoma patients diagnosed in a geographically defined area over a 15 year period. SETTING: West of Scotland (area population 2,716,900). SUBJECTS: 3142 patients first diagnosed with malignant melanoma in the period 1979-93. INTERVENTIONS: Surgical excision of primary malignant melanoma with additional treatment as appropriate and follow up until December 1994. MAIN OUTCOME MEASURES: Malignant melanoma incidence, primary tumour thickness and five year survival by socioeconomic status. RESULTS: From 1979 to 1993, the age standardised incidence rate for cutaneous malignant melanoma was 9.1/100,000 for the most affluent men and 2.4/100,000 for the least affluent men and 16.1/100,000 and 5.0/100,000 respectively for most and least affluent women (P < 0.001 for trend in both). The incidence increased steadily over time in both sexes in all socioeconomic groups. Good prognosis tumours ( < 1.5 mm thick) were most common in the most affluent men and women, and over the study period the proportion of such tumours increased most in the intermediate affluence group (both sexes) and in the least affluent women. Five year disease free survival from melanoma for the sexes combined was 81% for most affluent, 77% for intermediate, and 73% for least affluent groups. Even after adjustment for known prognostic factors of tumour thickness, ulceration, age, and body site of primary melanoma, the more affluent the group, the better the survival. CONCLUSION: Although the incidence of cutaneous malignant melanoma is higher among more affluent people, the prognosis is better in this group than for less affluent individuals. Early diagnosis campaigns should be targeted particularly to less affluent men and primary prevention campaigns should emphasise the greater risk in more affluent women.

Female↗
PubMed1996

A single centre's 10 year experience with isolated limb perfusion in the treatment of recurrent malignant melanoma of the limb.

The aim of this study was to assess whether isolated limb perfusion can be performed safely and whether it offers improved disease-free survival for patients with limb malignant melanoma. Between August 1983 and July 1993, 103 patients (78 female, 25 male) with recurrent limb melanoma were treated by isolated limb perfusion (ILP) in Glasgow, U.K. The mean age of the patients was 62 years; 95 had leg recurrence, 8 had arm recurrence. The mean time from original diagnosis to ILP was 48 months (range 1-290). 102 iliac, 5 femoral, 7 popliteal and 8 axillary perfusions were performed. All patients had stage II (local recurrence within 3 cm of primary site) or stage III (regional metastases; tissues excluding nodes, nodes or combination) disease according to the MD Anderson Cancer Centre Staging System. At a mean follow-up of 30.7 months, 68 patients had died of recurrent disease (mean time to death 22.5 months). The 2 and 5 year survival of the group was 50 and 26%, respectively and disease-free survival was 23 and 12%, respectively. At first perfusion, 76% of patients showed complete response and 23% showed partial response. With repeat perfusion, 47% showed complete response and 53% had partial response. In conclusion, ILP is safe and has an acceptable morbidity. It achieves highly satisfactory local disease control but long-term survival is the exception.

Adult↗
PubMed1996

A comparison of dosimetric methods in isolated limb perfusion with melphalan for malignant melanoma of the lower extremity.

The three dosimetric schedules currently used in isolated limb perfusion with melphalan for malignant melanoma of the lower limb were compared in a series of 51 patients. The doses prescribed by each of the three methods (based on total body weight (TBW), limb tissue volume (LTV) and total blood volume in the perfusion circuit (TBV)) were calculated for all patients and were then compared using Wilcoxon's signed-rank test. This revealed that the method based on TBV consistently prescribed much lower doses of drug than either of the other two methods. Pharmacokinetic profiles of melphalan obtained by HPLC analysis of blood samples during the procedure also showed that the method did not reliably predict the concentration of melphalan achieved in the perfused limb. The dosimetric schedule based on LTV prescribed slightly higher doses than that based on TBW. However, the technique is more difficult to practise due to the problems of measuring the limb volume by immersion. We conclude that the dosimetric schedule based on TBW is the most appropriate by virtue of its simplicity, the high doses of melphalan which it prescribes, and the well-controlled toxicity which it produces.

Antineoplastic Agents, Alkylating↗
PubMed1996

Comparison between lentigo maligna melanoma and other histogenetic types of malignant melanoma of the head and neck. Scottish Melanoma Group.

A study of 953 invasive cutaneous malignant melanomas of the head and neck was performed to determine differences between lentigo maligna melanoma and other histogenetic types with regard to patients and sites affected; prognosis was analysed in 595 of these cases. The cases studied comprised all head and neck melanomas registered with the Scottish Melanoma Group between 1979 and 1992, apart from the 3% of cases that were unclassifiable or rare histogenetic types. The histogenetic types of melanoma were 498 (52%) lentigo maligna melanoma (LMM), 237 (25%) superficial spreading melanoma (SSM) and 218 (23%) nodular melanoma (NM). All types increased in incidence throughout the study period. Patients with LMM (mean age 73 years) and NM (mean 68 years) were significantly older than those with SSM (mean 57 years). There were significant anatomical subsite differences related to sex of patients and histogenetic type of melanoma; melanomas on the face were more frequent in females and 90% of LMM occurred at this site, whereas melanomas on the scalp, neck and ears were more frequent in men. Kaplan-Meier estimates of the probability of survival were produced for the 595 of these 953 patients with 5 year follow-up details. In this group of patients the prognostic significance of tumour thickness, Clark level of invasion, ulceration, histogenetic type of melanoma and number of mitoses were studied using stepwise variable selection of procedures. Each of these possible prognostic factors attained individual significance but the tumour thickness was the dominant risk factor in the proportional hazards analysis. When patients were divided into four sex/ulceration subgroups (male/ulcerated, female/ulcerated, male/non-ulcerated, female/non-ulcerated) and analysed by proportional hazards analysis, no variable other than the tumour thickness had any further prognostic effect. Histogenetic type did not remain an independent prognostic variable at this stage. Despite sex and subsite differences, the prognosis for invasive lentigo maligna melanoma does not differ from that for other histogenetic types after controlling for tumour thickness.

Adolescent↗