Colorectal cancer

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

in results, emphasising the importance of considering the individual surgeon and surgical technique in the design of any future studies. There is now little doubt that the technique of total mesorectal excision in the surgery of rectal cancer produces good results with a low frequency of local recurrences;’ maybe now is the time for all surgeons who treat rectal cancer to move to what is, we believe, the best surgical option. Although much effort is justifiably being put into the development of adjuvant therapies, we would find it difficult to improve on the view of McArdle that "if by more meticulous attention to detail the results of surgery could be improved, and our results suggest this would not be difficult, the impact on survival might be greater than any of the adjuvant therapies currently under study". Surely the time has come for large well-conducted trials of surgical education and technique? The potential for substantial benefit at not much cost is considerable.

variation

I Martin, D Johnston, P Finan, I Adam, O Mohamdee, N Scott, M F Dixon, P Quirke Centre For Digestive Diseases, General Infirmary at Leeds, Leeds LS1 3EX, UK

1

2

Heald RJ, Ryall RD. Recurrence and survival after total mesorectal excision for rectal cancer. Lancet 1986; i: 1479-82. McArdle CS, Hole D. Impact of variability among surgeons and postoperative morbidity and mortality and ultimate survival. BMJ

1991; 302: 1501-05.

Aluminosis and dementia aluminium pneumoconiosis, after aluminosis, reported exposure to aluminium powder during the 1930s and 1940s.’ We report the followup of one such case with effects on the central nervous system. This patient, born in 1915, worked in the aluminium powder mill between 1944 and 1946 and was not exposed after 1947. Aluminosis was diagnosed in 1946. At the time of our investigation, he was a 78-year-old widower without any children. He was judged to have been healthy earlier in life. There was no family history of Alzheimer’s disease or other dementing diseases. In his own opinion, there were no problems with memory, language, or orientation. His gait was unremarkable. Alternating movements were clumsy. A slight weakness in both arms (Grasset sign positive on both sides) was detected in addition to impairment of fine motor abilities in his hands. Otherwise there were no signs of corticospinal, extrapyramidal, or cerebellar involvement. He was moderately demented (mini-mental state examination [MMSE] 17/30). His speech was not fluent in spontaneous conversation, and he had difficulty in finding specific names for objects and in comprehension. Memory, visuospatial, and simple construction tasks were impaired. A simple reaction time test and psychomotor speed were below average. The parietal fissures were enlarged on magnetic resonance imaging examination; the hippocampus area on both sides was unremarkable. Two small hyperintensities were detected in T2-weighted sequences in the crus cerebri on the left side. The vermis was shorter than expected. No or focal abnormalities general slowing of the electroencephalogram pattern were noted. However, there were episodes of widespread irregular activity. Blood, urine, and cerebrospinal fluid were sampled in acid-washed polypropylene tubes with screwcaps. The sampling procedure was planned to avoid contamination from external sources. Aluminium was measured by atomic absorption spectrometry with a transverse-heated electrothermal atomiser with longitudinal Zeeman-effect background correction (Perkin-Elmer Model 4100 ZL). The

SiR-Several

cases

were

1154

of

accuracy of the method was checked by analysing Seronorm urine and serum. His cerebrospinal fluid contained a high concentration of aluminium (259 µg/L, normally <10 µg/L).2,3 Serum and urine concentrations of aluminium were normal. Laboratory tests including thyroid hormones and vitamin B 12 were unremarkable. Blood pressure was 160/95

mm Hg. This patient showed

clear signs of dementia, but there was evidence of cerebrovascular disease. The recorded motor disturbances were not consistent with the Alzheimer type of dementia. He had a heterozygotic twin brother who had normal intellectual function (MMSE 26/30). It is of note that the aluminium concentration of the cerebrospinal fluid was much higher than the reported values in Alzheimer patients or in non-demented subjects.2,j This dementia associated with a very high exposure to aluminium is perhaps more similar to the dialysis type of dementia. However, most patients with dialysis dementia have died within a year of the onset of symptoms.’ The first case of aluminosis and dementia with motor disturbances after exposure to aluminium powder was described by McLaughlin and co-workers in 1962,’’ this man also developed difficulty with speech and he also had attacks of clonic jerking of his left leg and later left arm without loss of consciousness. no

We thank Olof Björklund, Carlfors Bruk, for his assistance and his company for financial support.

Bengt Sjögren, Karl Göran Ljunggren. Ove Almkvist, Wolfgang Frech, Hans Basun Department of Occupational Medicine, National Institute of Occupational Health, S-171 84 Solna. Sweden; Industrial Health Centre (Hälsocentralen), Jönkoping; Alzheimer Disease Research Centre, Department of Clinical Neuroscience and Family Medicine, Huddinge University Hospital, Huddinge; and Department of Analytical Chemistry, University of Umeå, Umea

1

2

Sjögren B, Elinder CG. Aluminium and its compounds. In: Zenz C, Dickerson OB, Horvath EP Jr, eds. Occupational medicine, 3rd ed. St Louis: Mosbey-Year Book, 1994: 458-65. Basun H, Forssell LG, Wetterberg L, Winblad B. Metals and trace elements in plasma and cerebrospinal fluid in normal ageing and Alzheimer’s disease. J Neural Transm Park Dis Dement Sect 1991; 4: 231-58.

3

4

5

Kapaki EN, Zoumas CP, Segditsa IT, Zenos DS, Papageorgiou T. Cerebrospinal fluid aluminium levels in Alzheimer’s disease. Biol Psychiatry 1993; 33: 679-81. Schreeder MT, Favero MS, Hughes JR, Petersen NJ, Bennett PH, Maynard JE. Dialysis encephalopathy and aluminium exposure: an epidemiologic analysis. J Chronic Dis 1983; 36: 581-93. McLaughlin AIG, Kazantzis G, King E, Teare D, Porter RJ, Owen R. Pulmonary fibrosis and encephalopathy associated with the inhalation of aluminium dust. Br J Ind Med 1962; 19: 253-63.

Assignment of a familial Alzheimer’s disease locus between D14S289 and D14S53 SIR-A gene for early-onset familial Alzheimer’s disease (AD) is located on the long arm of chromosome 14 (14q24.3)’ within about 20 centimorgans (cM) between D14S52 and D14S42. The familial AD locus must be assigned to a sufficiently narrow region to clone the disease gene. We conducted linkage studies and haplotype analyses with markers on chromosome 14 for one large early-onset Japanese familial AD pedigree that had no mutations in the amyloid precursor protein gene exons and no association with apolipoprotein E4 allele. Genomic DNAs were prepared from Epstein-Barr-virustransformed lymphoblasts of 19 family members, including 5 affected persons (mean age of onset, 47-8 years). The diagnosis of affected members was achieved by National