Document DdBgQKnEa0OY3b8vzk63Bgea

may act presv:;apcjcaliv; 1 Jopiimiiiecontaining terminals to conr.roi dopamine rdesfe. VC'e thank Dr it. K. ferry and Prof, B. F. Tomlinson (Newcastle Ireneitsi Hospital' for supplying samples 1 rom cases oi'ATD. M.R.O i< 1V'i-<uE.oi,`or Imvorsuv Dep-iio['Pharmacology. Kdsnbu r<:h HH:< // Celia M. Yates Yvonne Allison J. Simpson NW-.ipa. i.ctl'.'TMii.'wv. { ni v ofPaihology. .itNUT'Tl HsS]/l;ai, *: din bur j. A. F. j. Maloney A. Gordon TO i 20 -( oc 80-| o o i 70-j ;c --- ij 50 A o o o 0 7Hi- LANCET, OCTOBER 20, 1979 o Alive at 5yr s u;sd m 5yr o MITOTIC INDEX IN CARCINOMA OF THE LUNG Sir,--In clinical trials aimed at improving survival-rates in carcinoma of the bronchus, the results are usually stratified according to stage and histological type and, as far as is pos sible, like is compared with like for both treatment arms. Un fortunately, we cannot stratify lung cancers according to the most important variable of all--namely, growth-rate. Geodes'* and others have suggested that in this condition survival-times are still determined by the growth-rate of the tumour rather than by the treatment. There is considerable evidence to sup port this view. Doubiing-times, measured from serial chest X-rays, vary by a factor of five. The presence of residual tumour after resection is compatible with five-year survival3 and long-term survival has also been recorded after radio therapy alone for lung cancer. However, it is unlikely that such patients are cured, for when tumours are resected after high doses of radiation, 60--701% are found to contain viable tumour,3 and patients do die of their tumours live years or more after radiotherapy.4 ----------- ----------- ------------ f---------- j ------- 1------- *----1-- 0 10 20 30 40 50 60 Mitotic number Mitotic numbers in 14 long-term survivors with bronchogenic cancers and in 15 who died in less than 5 years. We have completed a study which may give more informa tion on the growth rates of bronchogenic carcinomas. We counted the number of rmtotic figures in immediately fixed, small biopsy specimens taken for diagnosis, on a series of highpower fields from two groups of patients treated by radio therapy. 14 cases had survived over five years and 15 less than five years. The identity of these two groups was unknown to the pathologist doing the counts. There was no statistical dif ference m age, sex, histological type, or radiotherapy dose in the two groups. With respect to TNM stage, the long-term sur vivors were at a slight disadvantage. Long-term survivors had statistically fewer mitoses than did short-term survivors (p<0-01) (see figure). This suggests that measurements are time-consuming, expensive, and often expose the patient to doses of radioactive tracers. We suggest that some measurement of this type be included in the protocol of any clinical! trial which aims to improve treatment of lung cancer. If not, the results will be subject to an uncertainly--namely, the extreme variability in natural progession of this disease. Mourn Vernon Hospital, Northwood, Middlesex HA6 2RN R. D. JaMLS A. T. DAVY MAGNESIUM IN LUNG CANCERS OF OAT-CELL TYPE survival after radiotherapy in the dosage given is determined primarily by growth-rate of the primary tumour. We intend to repeat this work on surgically treated patients before reporting it fully. We recognise that mitotic figures may not be an accurate measure of growth-rates; they will depend on thickness of sections, site of biopsy, and time to fixation. Nevertheless, other studies have suggested that mitotic index gives at leaf "'"rst measure of growth-rate.5*6 More detailed Sir,--Parsons and his co-werkers have reported the regres sion of lung-cancer tumour mass in patients on a magnesium and potassium depletion diet.1,2 We have found that tumour tissue from oat-edi type lung cancer contains more magnesium than does tissue from other types of cancer or normal soft tis sue. This suggests defective magnesium metabolism in oat-cell cancer and could provide a rationale far the Parsons regimen. Ail tissues were obtained at necropsy and the tumours were classi fied, by standard histopathological techniques, in the laboratories that provided the specimens. 100-200 mg from each specimen was minced it. Hatton . * 1 2 ..v.cGcer EG Dcndro-axonic transmission. II. Mor- and put into individual Erleumcver iiasks with 2-5 ml of a mixture ot pholo; * ;* yt; ly-.'Ahwis, bustling and release of rieuioiiansnyhieis tn dopi,; jendntr.-!. :n the subsianua nigra and cnolinergic den drites m the :ic,,stnatum. ivoci /(<?; 1979; 370: 71-83. 12. Maker PL, McGcer EG, I'rmenon VT. Denciro-axonk transmission. I, Evi dence from receptor binding of dopaminergic and cholinergic agents. BratnRts 1979; 369: 43 >~4 !. i. Geiides DM. The natural histor1. G lung cancer based on rates of tumour growth. BrJ Dii Chest 1975; 73: 1 -17.' concentrated nitric acid and 60T perchloric acid (1:2). 'The flasks were then placed directly on a hot plate and the contents boiled until dry. Trichloroacetic acid (5 ml of 5`?,) was added to each flask, and this solution was assayed for magnesium using the titan-yellow method.1 These titan-yellow magnesium measurements have recently been con firmed bv atomic-absorption spectroscopy on chose materials soli avail able. 2 Shields TW. The fate of patients after Incomplete resection of bronchial car cinoma. Surg Gynecol ObsUC. 197-1; 569--72. Roswit H, Higgins C,A, Shields W. Kcehn R j. i'reopcrative radiation therapy Oat-cell type cancer tissue contained larger amounts of mag nesium (range 7-9--15-6 mmoi/'kg wet tissue) than did any oi ter carcinoma ol the lung, Front Radiation Ther Oncoi 1970; 5: 163--76. - ;'..-ienci JR, Rehahn M. Lute deaths fter resection for bronchia! carcinoma. Hr 7 Du Chest 1979; 73: 1S-29. 5. *-h raV!Hie growth characteristics of king cancer and Its application to 1. Parsons EM. Howards GF, Anderson DK et ai. Regression of malignant tumours in magnesium and potassium depletion induced by die! anu haemodialysis. Lancet 1974;243- 44. treatment design .Seen in Oco! 1974; 3: 167- 74. 2. Parsons EM. Hypoitalawnia and hvpornagnesamia as a mode of cancer ther b.Miilaisc HT. Chavaudrii S, Tubiana hi. The relationship between growth apy. SrJ Radio/1978;51: 149. ' 3 rate, .abeding index and histological type o> human solid tumours, liter J 3. Basinski DK. Magnesium ilium veiiowi. Stand Methods Clin Chern 196-1 5: 137--42. ' the LANCET, OCTOBER 20, 1979 853 TS S S U? 5 A 0 N' SJUM Tissue Mg'' (mmol/kg we; tissue.1 j MeaniSD Out-cell Honours (T--~6j Other tumours (n~5) Glioma Fibroma Meningioma 15-6," 12-3,*' 9-4'T io-s, 20-;, 7.9 / 11 -0 3.7 ) 2-9, 2-9 j 3-4,4-5 1 I 1 3 5-5*0-7 j * patients with myasthenic syndrome. the other type of cancer tissue measured (2-9--4-5} (see table). The difference was significant (Student's t test; p<0-005). Skeletal muscle contains more magnesium than any other normal soft tissue,4 so the fact that the magnesium content of oat-cell type cancers was much larger than the content of nor mal human skeletal muscle (6-S + 0-4 mmol/kg, n=10)5 sup ports the hypothesis of abnormal, magnesium metabolism as sociated with oat-cell carcinoma leading to magnesium accumulation in the tumour. Furthermore, this hypothesis provides a rational basis for magnesium and potassium deple tion therapy for inoperable lung cancer. Oat-cell cancer is occasionally associated with neuromuscu lar weakness, called the "myasthenic" syndrome.6''' The patho physiological mechanism of this syndrome is exactly the same as the defect in neuromuscular transmission caused by in creased levels of magnesium (i.e., a reduction in the quanta' content). The finding of an increased magnesium content in oat-cell type lung cancers may therefore have implications for our understanding of the "myasthenic" syndrome. \X'e thank Dr F. R. Singer for the use of his atomic-absorption apparatus and Dr T. Okamoso (Chiba University), Dr E. j. Hawley (V. A. Hospital, Washington, D.C.), Dr H, H. itabashi (Harbor General Hospital, Torrance, California), Dr R. Miller (University of Oregon), and Dr K. M. A. Sheikh for supplying materials. We also thank Dr j. P. Van Der Meulen and Dr L. P. Weiner for their support. This work was supported in part by the Robert E. and May R. Wright Foundation and National Institute of Health grams CA-22S85 andNS-13685. Deparunem of Neurology, School ofMedicine, University ofSouthern California, Koichi Ishikawa Wit,LIAM JACK DrISKELL JOHN KERCH EnGELHARDT Iajs Angeles, California 90033, ll.S.A. DOREEN K.EIKO KaTASE LATENCY PERIOD FOR MESOTHELIOMA Sir,--Some texts1 and published papers2 ieave the impres sion that mesothelioma due to asbestos is a tumour that de velops in old age, a very long time after exposure. In Ontario this is by no means always true. The Workmen's Compensa tion Board of Ontario has, since 1970, been compensating cases of mesothelioma attributable to occupational asbestos exposure. Claims have been accepted for 26 cases that had occurred between 1958 and 1978. Most have been workers in industries with high potential exposures, mainly to chrysotile fibres. The age at diagnosis (or death) Iras ranged from 37 to 78 years with a mean of 56-0. Latency, defined as the period from first known exposure to diagnosis, has ranged from 6 to 44 years with a mean of 26-9 (we cannot rule out additional earlier non-occupationai exposure), 19 of the cases were 141 ''UilserM. Magnesium metabolism. Ergehn Physiol i%7; 55: 185-296. Kohn RR, Keve H, Rolierson K Role of magnesium itvthe variation of swell ing abilii v of human muscle with age. Exp Celt Res 1961; 2S-. i 70- 75. 6. Brain R, Henson RA. Neurological syndromes associated with carcinoma. __ Lancet i958; ii: 971-75. ' ulmqvisi D, Lambert EH. Detailed analysis of neuromuscular transmission ui patients with the myasthenic syndrome sometimes associated svitlt brot:_ ehagenic carcinoma. .-Viavo CHn Proc 1 968; 43: 689-71 3 `Morgan VKC, Seaton A. Occupational lor.e diseases. Philadelphia- \VB Saunders, 19 o. 3h2 - McDonald AD, .McDonald JC. .Mesothelioma after crocicioiitc exposure dur ing gas mask manufacture. E'roo Res 197S, 17: 340-46. pleural in origin and 7 peritoneal. Our series is small, but cer tainly does not fit the textbook picture. F.lmes and Simpson3 nave suggested that latency for this tumour may be 2 function of dose. This may account for our observations. Medical Branch, Medical Services Division, Workmen's Compensation Board, 1 oromo, Ontario, Canada M4W 5C3 A- GHOVIi. C. SlEWART CHROMOSOMES. LEUKAEMIA, AND OCCUPATIONAL EXPOSURE TO LEUKJEMOGENIC AGENTS Sir,---It has been suggested that patients presenting with de novo acute non-lymphotic leukaemia (ANI.L) who experienced occupational exposure to a possible carcinogenic agent, are more likely to show chromosome abnormalities in the bonemarrow at diagnosis than are patients with no history of such exposure.4 This information was obtained by a retrospective survey of hospital notes, although Mitdman et a!.4 were fully aware of the shortcomings of this procedure. Using a similar approach and the same criteria for assessment of exposure, we have been unable to demonstrate a correlation with chromoso mal findings in patients treated at the Royal Marsden Hospital (table r) .The cytogenetic findings on these patients have been correlated with survival and the results are to be published6 but the analysis of chromosomal status in relation to occupa tion reported here has not been made previously. Unlike Mitdman et al. we did r.ot find more non-random chromosomal abnormalities amongst the "exposed" than "nori-exposed" patients. The scries were comparable in that m1 both about 50(7 of the patients had chromosomal abnormali ties in the bone-marrow at diagnosis and this frequency accords with the findings of the 1977 Helsinki workshop/' However, the two series differed in that the chromosomal ab normalities in the cases reported by the Swedish group were all clonal, whereas our series includes patients with non-ciona! changes.5 TABLE I----- ASSOCIATION BETWEEN CHROMOSOMAL ABNORMALITY IN ANU. AND HISTORY OF EXPOSURE AT WORK TO POTENTIALLY LEU K ALMOG E N iC AG E !'! T $ Mitdman et al/ Royal Marsden J No Chromosomes Exposure exposure Exposure Abnormal 19 $ ' 12 Normal 4 25 Ki Total 23 33 22 No no. exposure patients 22 i 23 62 45 23 Association Positive p)-OOT None (p~=0-70) An excess of males in the exposed category is found in bosh the Swedish and British .series p----0-015), the exposedsnonexposed ratios being 15:12 lor males and 8:21 for females in the Swedish series and 19:17 and 3:28, respectiveiv, in our senes. This is a reflection of the method used to assess expo sure, most of the females: being recorded as housewives and therefore in 3 non-er.postd occupation. ' l-iiu,-, J'-C, SiniiT-or. M ; Ok clinical aspects o! ::vj,n:in'i:-.::na (t/uri 7 Med I 9i:. 4 5; 41 f 29 "" 4.Mm4i-r:^n Brand; Nilsson i'U. Rekiiion i-itnony ixetipatiorta! cunosurc io potential !1 u1; penu; ca rei ri 0aes) rc iicurw. climcai tincimc:, and bone inarrou chrumo-nmes in acute iioti-L'is-ipdo-.-.i,;; leukemia Blood 1978; 52: 1229 ..?7. Luv.-Ser SI). Snnmii'rs-ail- B.M, Clink II .Mad). .McLLvuii- TJ Cytogenetic loiiov.-ur studies :n acute non-'yitiiibccyuc k-ultii-utia Hr ) ttamaio!. on press 6. i-irst ii-.iL-rii.monai Workshop on Chromosomes in L-.nikienisa. Chromosomes in acute non-ivniphoeytic k'ti k.x-mia 3<\r Hx-otoioi) 9*"; 39: 3) i - 16.