Treatment of frostbite with iloprost

familial breast

important

exists. This panel of families is map the putative BRCA3 gene.

cancer

resource to

an

We thank Dr M R Stratton for helpful discussion and Dr D Ford for assistance with statistical analysis.

Hagay Sobol,

Daniel

Birnbaum, François Eisinger

Department of Oncology Genetics and INSERM U119, Institut Paoli-Calmettes, 13273 Marseille, France

1

Wooster R, Neuhausen SL, cancer

Mangion J, et al. Localization of a breast susceptibility gene, BRCA2, to chromosome 13q12-13. Science

1994; 265: 2088-90. 2

3

4

Sobol H, Mazoyer S, Narod SA, et al. Genetic heterogeneity of earlyonset familial breast cancer. Hum Genet 1992; 89: 381-83. Mazoyer S, Lalle P, Narod SA, et al. Linkage analysis of 19 French breast cancer families, with five chromosome 17q markers. Am J Hum Genet 1993; 52: 754-60. Easton DF, Bishop DT, Ford D, et al. Genetic linkage analysis in familial breast and ovarian cancer: results from 214 families. Am J Hum Genet 1993; 52: 678-701.

SIR-Maxwell and colleagues (July 16, p 193) reported that ingestion of red wine was associated with increased antioxidant activity in human serum by use of an enhanced chemiluminescence assay.’ They also showed that serum antioxidant values rose during the 4 h after red wine intake. Frankel and colleagues2 reported the inhibition of oxidation of human low-density lipoproteins (LDL) by phenolic substances in red wine in vitro. Serafini et aP also showed that the consumption of polyphenol-rich beverages such as red wine and tea was associated with an increase in plasma antioxidant potential. Antioxidant substances inhibit LDL oxidation, thus reducing the development of atherosclerosis, thought to be provoked by atherogenic modified LDL.4 However, it is important to distinguish between the antioxidant properties of red wine compared with other beverages and foods, a consideration that formed the basis of the protocol in our study. 10 male volunteers (33-37 years old) drank vodka (40% ethanol) (wash-out period) and then red wine (Chateau

Lagrange, 1989) (experimental period), corresponding to a dose of 0-8 g/kg ethanol per day for 14 days. All subjects received a standard diet (supplied by Taihei Co, Tokyo) to control their caloric and nutritional intakes, and they abstained from drinking tea, coffee, and other such substances to minimise the intake of phenolic substances other than those derived from red wine throughout

U

Day Figure: LDL oxidation in volunteers Values

1152

are means

(SE). *paired

f test.

We thank Uehara Memorial Foundation and Aging and Health, and the Ministry of Health and Welfare of Japan for funding part of this work.

K Kondo, A Matsumoto, H T Amachi, H Itakura

Inhibition of oxidation of low-density lipoprotein with red wine

- 14

the study period. Fasting venous blood samples were taken at days -14, 0, and +14. Plasma LDL was prepared by ultracentrifugation (d 1-006-1-063 g/mL) and oxidation of LDL was investigated by measuring conjugated with dienes formed 2,2’-azobis (4-methoxy-2,4dimethylvaleronitrile ; V-70). Oxidation of LDL was longer at day 14 (lag time 54-7 [SE 26] min) than at day 0 (49-1 [2-2] min). There was no difference in oxidation of LDL between day -14 and day 0 (figure). Our results provide direct evidence that regular and longterm consumption of red wine, but not ethanol, inhibited LDL oxidation in vivo. It is suggested that red wine intake may reduce atherosclerosis and morbidity and mortality from coronary heart disease. In this context, out study provides a plausible explanation for the "French paradox"5 (the apparent incompatibility of a high-fat diet with a low incidence of coronary heart disease).

14

Kurata, H Tanahashi, H Koda,

Division of Clinical Nutrition, National Institute of Health and Nutrition, 162 Tokyo, Japan; and Research Institute for Enology, Institute for Fundamental Research, Suntory Ltd, Osaka

1

2

3 4

5

Whitehead TP, Thorpe GHG, Maxwell SRJ. An enhanced chemiluminescent assay for antioxidant capacity in biological fluids. Anal Chim Acta 1992; 266: 265-77. Frankel EN, Kanner J, German GB, Parks E, Kinsella JE. Inhibition of oxidation of human low-density lipoprotein by phenolic substances in red wine. Lancet 1993; 341: 454-57. Serafini S, Ghiselli A, Ferro-Luzzi A. Red wine, tea, and antioxidants. Lancet 1994; 344: 626. Esterbouer H, Gebicki J, Puhl H, Jurgens G. The role of lipid preoxidation and antioxidants in oxidative modification of low density lipoproteins. Free Radical Biol Med 1992; 13: 341-90. Renaud S, de Lorgeril M. Wine, alcohol, platelets, and the French paradox for coronary heart disease. Lancet 1992; 339: 1523-26.

Treatment of frostbite with iloprost SIR-The pathophysiology of frostbite is poorly understood. Cold can directly freeze the tissue with formation of ice crystals and irreversible disruption of cellular structures. When water is transformed to ice, the osmolality in the extracellular space increases and leads to passive diffusion of water from the intracellular space. Cell dehydration modifies protein structure, alters membrane lipids, and cellular pH. Another mechanism is related to reactive vascular changes with reflex arterial and venous constriction after exposure to cold. This mechanism is very similar to the pathophysiology of critical ischaemia and causes vascular stasis. Cold also increases blood viscosity causing sludging. Endothelial cell damage increases capillary membrane permeability which causes loss of proteins and fluid and an increase in blood viscosity. Platelet aggregation is activated by the damaged endothelium. All these factors can result in occlusion of the microvasculature by thrombi. Initially it is difficult to predict the extent of frostbite. Treatment amounts to preventing a superficial injury from becoming a deep one, and management includes warming up, thawing, local therapy,

early sympathectomy, anticoagulation, fibrinolysis, vasodilators, haemodilution, and surgery.’ Iloprost, a stable metabolite of prostacyclin 12, inhibits platelet aggregationis cytoprotective,3 and has profibrinolytic activity.’ Vasodilatory activity that improves blood supply to collateral vessels could also be a potential reason for its benefit in the treatment of frostbite.’ We report our experience of treating frostbite with iloprost.

We treated 5

patients (average

extremity, in exposure

to

1

men) with

age 35 years; 4

frostbite (second and third degree); in 4

the lower in all cases

cases on

case on the fingers. The cause was extremely cold temperature (1

combined with barbiturate intoxication after

case

was

suicide of the with had a 1 injury paralysis spinal patient attempt, lower extremities and loss of sensation, the other patients were exposed to cold and moisture at high altitude). Warming up was done for all patients on admission to our department. All were treated with intravenous iloprost, starting with a dose of 0-5 ng/kg increasing over the next 3 days to 2 ng/kg for a minimum of 14 days and a maximum of 42 days. Additional therapy was full heparinisation with a low-molecular heparin and cortisone to lower an extremely high fibrinogen in 1 patient. All patients showed relief of pain after 1-3 days of treatment so that analgesia was stopped. Perfusion was substantially improved and all patients showed full recovery; amputation was not necessary in any patient. In view of what is known about the pathophysiology of frostbite, which is very similar to that of critical limb ischaemia, we believe that therapy with iloprost could be a very potent treatment. a

E Groechenig Landeskrenkenhaus Feldkirch,

Carinagasse 45-47,

A-6800 Feldkirch, Austria

1 Fouray J. Mountain frostbite, current trends in prognosis and treatment (from results concerning 1261 cases). Int J Sports Med 1992; 13 (suppl 1): S193-96. 2 Ehrmann HL, Jaffe EA. Prostacyclin (PgI2) inhibits the development in human platelets of ADP and arachidonic acid-induced shape change and pro-coagulant activity. Prostaglandins 1980. 20: 1103-16. 3 Turker RK, Demirel E. Iloprost maintains acetylcholine relaxations of isolated rabbit atomic strips submitted to hypoxia. Pharmacology 1988; 4

5

36: 151-55. Musial J, Wilczynska M, Sladek K, Cierniewski CS, Nizankowski R, Szceklik A. Fibrinolytic activity of prostacyclin and iloprost in patients with peripheral arterial disease. Prostaglandins 1986; 31: 61-70. Lefer AM, Ogletree MNL, Smith JB, et al. Prostacyclin: a potentially valuable agent for preserving ischemic myocardial tissue in acute myocardial ischemia. Science 1978; 200: 52-54.

Colorectal

cancer

SIR-Adam and colleagues (Sept 10, p 707) quite rightly the importance of surgical technique in the management of rectal cancer. They demonstrate in a careful histopathological assessment that wide excision of rectal cancer which includes a good circumferential margin has an effect on the frequency of local recurrence. However, the frequency of synchronous and metachronous distant metastases (especially liver metastases) is barely addressed. 17% of patients had liver metastases at time of surgery and presumably underwent palliative rectal resection, although this is not clearly stated. The overall 5-year survival rate in patients undergoing a curative resection with circumferential margin involvement was only 15%. It is probable that these patients had liver metastases at the time of initial surgery, and the presence of margin involvement could be regarded merely as a marker of very advanced disease. Was there a correlation between the presence of metastases as shown by preoperative liver scanning and the subsequent finding of circumferential tumour involvement? The outlook for patients with Dukes’ C disease and margin involvement was very poor. Do Adam and colleagues feel that these patients might have been considered for

emphasise

adjuvant therapy-either postoperative radiotherapy chemotherapy? They also fail to mention whether or

or

not

there was a correlation between the presence of clinical fixity of the tumour as determined by rectal examination and subsequent circumferential tumour involvement. If this correlation did exist then perhaps there is an argument for pre-operative radiotherapy in such patients. Indeed, this was the basis for the Medical Research Council preoperative radiotherapy trial (MRC-2). This study indicates, firstly, the need for consideration of adjuvant therapy in poor prognostic subgroups and, secondly, that there is a wide variation in local recurrence rates even in centres of excellence. Both these factors necessitate the need for continuing assessment of adjuvant therapies by means of prospective randomised trials. I

Taylor

Department of Surgery, University College London Medical School, London W1P 7LD, UK

Authors’

reply

SIR-We wholly agree with Taylor that continuing study and trials are needed in this common cancer. Although we recognise that synchronous and metachronous liver metastases are an important clinical problem in the management of rectal cancer, this study was undertaken to address the specific issue of local recurrence and circumferential margin involvement. We therefore did not touch on this problem in our study. Our definition of a palliative resection was one in which the surgeon left macroscopic disease at the end of the procedure; therefore, by definition, any patient with clinically or radiologically detected liver metastases at the time of operation would have undergone a palliative resection. The 5-year survival of 15% in patients with circumferential margin involvement included those undergoing palliative resection, the survival in this group after potentially curative resection being 24%. Circumferential margin involvement is not merely a marker of very advanced disease, as Taylor suggests. Overall, there was a crude relation between advanced disease and circumferential margin involvement; however, this could not account for the large differences in survival seen in patients with and without such involvement after potentially curative resection, who did not have any identifiable liver metastases at the time of operation. We agree that the combination of a Dukes’ C lesion and circumferential margin involvement awarded patients a very poor outlook indeed, but perhaps more important is the finding of better results than one might expect in patients with a Dukes’ C lesion without such margin involvement. The frequencies of local recurrence and 5-year survival in Dukes’ B cancers were 5% and 77%, respectively, and 19% and 60% in Dukes’ C cancers, when the circumferential margin was not involved; however, when it was involved, the figures for Dukes’ B cancers were 62% and 45%, respectively, and for Dukes’ C cancers, 83% and 18%. There may indeed be a role for adjuvant therapy in the group of patients with a positive circumferential resection margin, but the efficacy of any type of treatment in this situation has yet to be determined. We find it impossible to comment about a correlation between clinical fixity of the tumour and circumferential margin involvement but we suspect it would be poor. Computed tomographic examination of the pelvis was not done often enough in this study to comment on its usefulness in assessing resectability or subsequent circumferential margin involvement. Our study represents the surgery of the 1980s and we agree that adjuvant therapies may well have more to offer during the 1990s. Nevertheless, there was enormous 1153