414
Letters
to
the Editor
FIBRIN/FIBRINOGEN DEGRADATION PRODUCTS IN PLEURAL EXUDATE
S!R,—The coagulative and fibrinolytic properties of malignant
ovarian
tumours are
reflected in the
occurrence
of fibrin/
fibrinogen degradation products (F.D.P.) in the serum in as many as 72% of all such patients.’ We have reported2 the presence of high concentrations of F.D.P. in ascitic fluid in patients with ovarian cancer. In a later study we found F.D.P. in maligascitic fluid in mean concentrations of 1908 (s.D.i:750) in ascitic fluid of benign tumours 63 ±101 g/ml, and in fluid from patients with hepatic cirrhosis 388+93 p.g/ml. Even the lowest values in the malignant group were higher than the highest value found in the benign groups.3 We have now analysed pleural exudate from 37 patients with various malignant tumours and from 8 patients with heart-failure. Laurell’s immunochemical method was used.4 The results are given in the figure. nant
jjtg/ml,
between F.D.P. in and in heart-failure.
Comparison tumours
pleural exudate
in various
malignant
found in high concentrations in most of the samof pleural exudate from the group with the tumours, but in low concentrations in the patients with cardiac failure. However, in 2 malignant cases the values were within the range of those found in the patients with heart-disease. Thus, the concentrations found in pleural exudate did not distinguish between malignant and non-malignant as clearly as did those in ascitic fluid. Cytological examination, which was negative in all the heart cases was positive in only 9 (24%), suspected in 6 (16%), and negative in 22 (60%) of the malignant cases suggesting that determination of F.D.P. in pleural exudate is of greater diagnostic value than cytology. F.D.P. were
ples
Gynæcology, Internal Medicine, Radiotherapy Clinics, University of Lund, Allmänna Sjukhuset,
and
B. ASTEDT G. ADIELSSON W. MATTSSON
214 01 Malmö, Sweden
1. 2. 3. 4.
Åstedt, B., Svanberg, L., Nilsson, I. M. Br. med.
MALIGNANT PLEURAL EFFUSION AS COMPLICATION OF CHRONIC LYMPHOCYTIC LEUKÆMIA SIR,-Malignant pleural effusion is an infrequent complication of chronic lymphocytic leukarmia (c.L.L.).12 We have seen a patient who had a chronic leukaemic infiltration of the pleura by small lymphocytes. Electron microscopy and surfacemarker analyses suggested that the lymphocytes in the pleural effusion were identical to those in the peripheral blood. The patient, a 58-year-old White man, was in excellent health until December, 1974, when C.L.L. was diagnosed on bonemarrow aspiration. He was symptom-free until March, 1975, when he developed malaise and easy fatiguability. He was treated with chlorambucil, then cyclophosphamide, and then a combination of cyclophosphamide, vincristine, and prednisone, but responded to none of these regimens despite the use of full dosages. He was referred to the University of Chicago where low-dose radiotherapy (500 rad,) was administered over 3 weeks to a painfully enlarged spleen with no response. In November, 1975, the patient experienced severe fatigue and shortness of breath. Physical examination suggested a pleural effusion and X-ray examination confirmed this impression. A thoracentesis with pleural biopsy was performed. The pleural fluid was an exudate with specific gravity 1.018, protein 37 g/1, glucose 107 mg/dl (simultaneous blood-glucose 120 mg/dl), and lactic acid dehydrogenase 24 units; the cell-count was 5000/p.l with a smear showing only mature lymphocytes. The peripheral-blood count was 30 000/jjd with 90% mature lymphocytes, platelets 9000/µl, haemoglobin 10.9g/dl, and hsmatocrit 34%. A bone-marrow aspiration revealed infiltration with mature lymphocytes, again consistent with C.L.L. Skin test with purified protein derivative of tuberculin of intermediate strength was negative. Numerous cytological examinations of the pleural fluid as well as bacterial, fungal, and tuberculosis cultures were negative. The pleural biopsy showed infiltration with mature lymphocytes. A post-thoracentesis chest X-ray failed to reveal any hilar adenopathy or intrapulmonary lesion. Despite numerous thoracenteses, one bronchoscopy, and two pleural biopsies, no infectious aetiology for the pleural effusion could be found. Total body radiotherapy of 125 rad was then administered over 35 days with little effect in controlling the effusion or the disease. Quinacrine was administered twice intrapleurally with control of the effusion and symptomatic relief. The patient died two months later; at necropsy there was no evidence of a pleural effusion. An organising fibrohasmothorax was found. The results of surface markers on lymphocytes in the peripheral blood and in pleural fluid are : Specimen Patient’s peripheral blood Patient’s pleural effusion Control (simultaneous) peripheral blood *Polyvalent surface immunoglobulin.
The B cells
lymphocytes
evidenced cell surface. as
SIg(%)* 71 62 11
E
rosettes
6 3 70
in the peripheral blood and effusion were by the polyvalent immunoglobulins on the
Scanning (s.E.M.) and transmission (T.E.M.) electron microson pleural fluid and peripheral blood done on the same day showed the cells in the pleural fluid to be similar to the lymphocytes circulating in the peripheral blood (see figure). Massive pleural effusion as a result of pleural infiltration bv C.L.L. cells is seen in only about 13% of patients with C.L.1’3 Our patient had lymphocytes infiltrating the pleura; these cells were B lymphocytes identical to those in the circulating blood. They were very probably the cause of the effusion since there was no histological or bacteriological evidence of an infection copy studies
’
J. 1971, iv, 458.
Astedt, B., Svanberg, L., Nilsson, I. M. Lancet, 1972, ii, Svanberg, L., Astedt, B. Cancer, 1975, 35, 1382. Laurell, C. B. Analyt. Biochem. 1966, 15, 45.
1312.
1. Wintrobe, M. M. Clinical Hematology; p. 1520. Philadelphia, 1974 2. Gunz, F., Baikie, A. Leukemia; pp. 228, 732. New York, 1974. 3. Green, R. A., Nichols, N. J. Am. Rev. resp. Dis. 1959, 80, 833.
415
hypotension during these periods. We advise patients who have sites of access for haemodialysis not to allow their body-weight to fall below target levels in very hot weather, and to increase their oral fluid intake accordingly. Wessex Regional Transplant St. Mary’s Hospital, Portsmouth
Unit,
CHARLES A. C. CLYNE MAURICE SLAPAK
DUCHENNE CARRIER DETECTION
SIR,-In advocating the use of haemopexin for discriminating between normals and carriers of Duchenne-type muscular dystrophy, Dr Danieli and Dr Angelini (July 10, p. 90) present their results in a somewhat misleading fashion. When assessing the usefulness of a quantitative test in distinguishing between normals and abnormals, it is necessary to evaluate the amount of overlap between the two frequency distributions, and this Scanning and transmission electron microscopy pleural effusion.
of
peripheral
blood and
Therapy, including alkylating agents alone and in combination with vincristine and prednisone, as well as total body radiotherapy, was without benefit. Instillation of quinacrine intrapleurally controlled the malignant B cell effusion;4 this therapeutic effect is considered non-specific.I was
supported in part by training grant no.
Thomas Moore Fund. The Franklin McLean Memorial Research Institute is operated by the University of Chicago for the U.S. Energy Research and Development Administration under contract E(11-1 )-69.
Department of Medicine,
Hematology/Oncology,
University of Chicago, Chicago, Illinois 60637, U.S.A.; and Franklin McLean Memorial Research Institute and Cancer Research Center,
University of Chicago
even
M.R.C. Clinical Research Centre, Northwick Park Hospital, Harrow, Middlesex
M.
J. R. HEALY
PHS 1-T32
AM07134-01, the Leukemia Research Foundation, Inc., and the
Section of
be considerable
means
lA,’ (top left). S.E.M. of peripheral blood. Note moderately villous surface of most cells. An occasional ruffle is present. iB: (top right). T.E.M. of peripheral blood. Lymphocytes have slightly irregular nucleus with prominent nucleolus. Surface shows numerous villi. (C) (bottom left). S.E.M. of patient’s pleural effusion. Most cells have villi and occasional ruffle. (D) (bottom right). T.E.M. of pleural effusion. Slightly irregular nuclei present, as are prominent nucleoli. Surface shows villi and occasional broad-based projection. Reduced toof x 6000 (B and D) and x 8600 (A and C).
This work
when the difference between the samis ple (as here) highly significant. In the present instance, if a common standard deviation for the normal and carrier groups is assumed, this is estimated at ±18-23 and the distance between the mean values is only 1.63 times this. If (conventionally) we place the upper limit of normal at 2 standard deviations above the mean, this comes to 103-21, and assuming a gaussian distribution (perhaps rashly) some 63% of carriers will have levels lower than this. It would be interesting to know in detail the joint distribution of haemopexin and creatine phosphokinase in the two groups, since it is possible, as the Italian workers suggest, that combining the two tests would give notably better discrimination than either one by itself. can
JACOB BITRAN RADHA GANAPATHY JOHN E. ULTMANN HARVEY M. GOLOMB
HEAT AND HÆMODIALYSIS
SIR,-We think that the hot weather was responsible for loss of sites of vascular access in four of our dialysis patients. The average temperature recorded by the Southampton Weather Centre over three days from June 30 was 31 - 4C. In this period, two well-established arteriovenous fismlae, one Scribner shunt, and one vein graft which had functioned faultlessly for four years, all clotted irretrievably. Three patients had lost a mean of 1.6 kg (3.3% of total target body-weight) over the previous 24 h, and one patient had come off dialysis 2 kg under the normal target weight. Two of the patients had intakes of less than 450 ml during that period. ’e feel that the increased insensible body loss of fluid due the heat, compounded in two cases by poor fluid intake, probably resulted in a rise in the hfematocht, thus creating an creased thrombotic tendency. There was no evidence of
was shown to Dr Danieli and Dr Angelini, whose reply follows.-ED.L. SIR,-We welcome the opportunity to explain more fully our statements. As our letter emphasised, the haemopexin test used in association with the c.P.K. test raises the level of detection of Duchenne muscular-dystrophy carriers. We did not propose that this test would be a substitute for the c.P.K. test since there is some overlap between the two distributions of individual values (see accompanying figure); what we intended to convey was that there is a statistically significant difference between normals and carriers; for the moment we can confirectly given as number of observations, means, s.E.M., and confidence intervals). We do not know whether some technical improvement would enhance the possibility of discrimination between normals and carriers; for the moment we can confidently state that haemopexin levels higher than 96 mg/dl (sam-
This letter
’o
1 Baron, J. M., Ultmann, J. E. Chemotherapy 2
of Malignant Neoplasms. Springfield, Illinois, 1973. ann, J. E., Gellhorn, A., Osmos, M., Hirschberg, E. Cancer, 1963, 16, 383
Hiemopexin levels in 26 controls and in 27 recognised carriers. Solid vertical line shows the means, the dashed vertical lines the limit of 1.96 standard deviations. The value indicated by an arrow belongs to a probable carrier (two affected sons, but without previous family cases), who in repeated tests always showed normal c.P.x.
activity.
Letters
to
the Editor
FIBRIN/FIBRINOGEN DEGRADATION PRODUCTS IN PLEURAL EXUDATE
S!R,—The coagulative and fibrinolytic properties of malignant
ovarian
tumours are
reflected in the
occurrence
of fibrin/
fibrinogen degradation products (F.D.P.) in the serum in as many as 72% of all such patients.’ We have reported2 the presence of high concentrations of F.D.P. in ascitic fluid in patients with ovarian cancer. In a later study we found F.D.P. in maligascitic fluid in mean concentrations of 1908 (s.D.i:750) in ascitic fluid of benign tumours 63 ±101 g/ml, and in fluid from patients with hepatic cirrhosis 388+93 p.g/ml. Even the lowest values in the malignant group were higher than the highest value found in the benign groups.3 We have now analysed pleural exudate from 37 patients with various malignant tumours and from 8 patients with heart-failure. Laurell’s immunochemical method was used.4 The results are given in the figure. nant
jjtg/ml,
between F.D.P. in and in heart-failure.
Comparison tumours
pleural exudate
in various
malignant
found in high concentrations in most of the samof pleural exudate from the group with the tumours, but in low concentrations in the patients with cardiac failure. However, in 2 malignant cases the values were within the range of those found in the patients with heart-disease. Thus, the concentrations found in pleural exudate did not distinguish between malignant and non-malignant as clearly as did those in ascitic fluid. Cytological examination, which was negative in all the heart cases was positive in only 9 (24%), suspected in 6 (16%), and negative in 22 (60%) of the malignant cases suggesting that determination of F.D.P. in pleural exudate is of greater diagnostic value than cytology. F.D.P. were
ples
Gynæcology, Internal Medicine, Radiotherapy Clinics, University of Lund, Allmänna Sjukhuset,
and
B. ASTEDT G. ADIELSSON W. MATTSSON
214 01 Malmö, Sweden
1. 2. 3. 4.
Åstedt, B., Svanberg, L., Nilsson, I. M. Br. med.
MALIGNANT PLEURAL EFFUSION AS COMPLICATION OF CHRONIC LYMPHOCYTIC LEUKÆMIA SIR,-Malignant pleural effusion is an infrequent complication of chronic lymphocytic leukarmia (c.L.L.).12 We have seen a patient who had a chronic leukaemic infiltration of the pleura by small lymphocytes. Electron microscopy and surfacemarker analyses suggested that the lymphocytes in the pleural effusion were identical to those in the peripheral blood. The patient, a 58-year-old White man, was in excellent health until December, 1974, when C.L.L. was diagnosed on bonemarrow aspiration. He was symptom-free until March, 1975, when he developed malaise and easy fatiguability. He was treated with chlorambucil, then cyclophosphamide, and then a combination of cyclophosphamide, vincristine, and prednisone, but responded to none of these regimens despite the use of full dosages. He was referred to the University of Chicago where low-dose radiotherapy (500 rad,) was administered over 3 weeks to a painfully enlarged spleen with no response. In November, 1975, the patient experienced severe fatigue and shortness of breath. Physical examination suggested a pleural effusion and X-ray examination confirmed this impression. A thoracentesis with pleural biopsy was performed. The pleural fluid was an exudate with specific gravity 1.018, protein 37 g/1, glucose 107 mg/dl (simultaneous blood-glucose 120 mg/dl), and lactic acid dehydrogenase 24 units; the cell-count was 5000/p.l with a smear showing only mature lymphocytes. The peripheral-blood count was 30 000/jjd with 90% mature lymphocytes, platelets 9000/µl, haemoglobin 10.9g/dl, and hsmatocrit 34%. A bone-marrow aspiration revealed infiltration with mature lymphocytes, again consistent with C.L.L. Skin test with purified protein derivative of tuberculin of intermediate strength was negative. Numerous cytological examinations of the pleural fluid as well as bacterial, fungal, and tuberculosis cultures were negative. The pleural biopsy showed infiltration with mature lymphocytes. A post-thoracentesis chest X-ray failed to reveal any hilar adenopathy or intrapulmonary lesion. Despite numerous thoracenteses, one bronchoscopy, and two pleural biopsies, no infectious aetiology for the pleural effusion could be found. Total body radiotherapy of 125 rad was then administered over 35 days with little effect in controlling the effusion or the disease. Quinacrine was administered twice intrapleurally with control of the effusion and symptomatic relief. The patient died two months later; at necropsy there was no evidence of a pleural effusion. An organising fibrohasmothorax was found. The results of surface markers on lymphocytes in the peripheral blood and in pleural fluid are : Specimen Patient’s peripheral blood Patient’s pleural effusion Control (simultaneous) peripheral blood *Polyvalent surface immunoglobulin.
The B cells
lymphocytes
evidenced cell surface. as
SIg(%)* 71 62 11
E
rosettes
6 3 70
in the peripheral blood and effusion were by the polyvalent immunoglobulins on the
Scanning (s.E.M.) and transmission (T.E.M.) electron microson pleural fluid and peripheral blood done on the same day showed the cells in the pleural fluid to be similar to the lymphocytes circulating in the peripheral blood (see figure). Massive pleural effusion as a result of pleural infiltration bv C.L.L. cells is seen in only about 13% of patients with C.L.1’3 Our patient had lymphocytes infiltrating the pleura; these cells were B lymphocytes identical to those in the circulating blood. They were very probably the cause of the effusion since there was no histological or bacteriological evidence of an infection copy studies
’
J. 1971, iv, 458.
Astedt, B., Svanberg, L., Nilsson, I. M. Lancet, 1972, ii, Svanberg, L., Astedt, B. Cancer, 1975, 35, 1382. Laurell, C. B. Analyt. Biochem. 1966, 15, 45.
1312.
1. Wintrobe, M. M. Clinical Hematology; p. 1520. Philadelphia, 1974 2. Gunz, F., Baikie, A. Leukemia; pp. 228, 732. New York, 1974. 3. Green, R. A., Nichols, N. J. Am. Rev. resp. Dis. 1959, 80, 833.
415
hypotension during these periods. We advise patients who have sites of access for haemodialysis not to allow their body-weight to fall below target levels in very hot weather, and to increase their oral fluid intake accordingly. Wessex Regional Transplant St. Mary’s Hospital, Portsmouth
Unit,
CHARLES A. C. CLYNE MAURICE SLAPAK
DUCHENNE CARRIER DETECTION
SIR,-In advocating the use of haemopexin for discriminating between normals and carriers of Duchenne-type muscular dystrophy, Dr Danieli and Dr Angelini (July 10, p. 90) present their results in a somewhat misleading fashion. When assessing the usefulness of a quantitative test in distinguishing between normals and abnormals, it is necessary to evaluate the amount of overlap between the two frequency distributions, and this Scanning and transmission electron microscopy pleural effusion.
of
peripheral
blood and
Therapy, including alkylating agents alone and in combination with vincristine and prednisone, as well as total body radiotherapy, was without benefit. Instillation of quinacrine intrapleurally controlled the malignant B cell effusion;4 this therapeutic effect is considered non-specific.I was
supported in part by training grant no.
Thomas Moore Fund. The Franklin McLean Memorial Research Institute is operated by the University of Chicago for the U.S. Energy Research and Development Administration under contract E(11-1 )-69.
Department of Medicine,
Hematology/Oncology,
University of Chicago, Chicago, Illinois 60637, U.S.A.; and Franklin McLean Memorial Research Institute and Cancer Research Center,
University of Chicago
even
M.R.C. Clinical Research Centre, Northwick Park Hospital, Harrow, Middlesex
M.
J. R. HEALY
PHS 1-T32
AM07134-01, the Leukemia Research Foundation, Inc., and the
Section of
be considerable
means
lA,’ (top left). S.E.M. of peripheral blood. Note moderately villous surface of most cells. An occasional ruffle is present. iB: (top right). T.E.M. of peripheral blood. Lymphocytes have slightly irregular nucleus with prominent nucleolus. Surface shows numerous villi. (C) (bottom left). S.E.M. of patient’s pleural effusion. Most cells have villi and occasional ruffle. (D) (bottom right). T.E.M. of pleural effusion. Slightly irregular nuclei present, as are prominent nucleoli. Surface shows villi and occasional broad-based projection. Reduced toof x 6000 (B and D) and x 8600 (A and C).
This work
when the difference between the samis ple (as here) highly significant. In the present instance, if a common standard deviation for the normal and carrier groups is assumed, this is estimated at ±18-23 and the distance between the mean values is only 1.63 times this. If (conventionally) we place the upper limit of normal at 2 standard deviations above the mean, this comes to 103-21, and assuming a gaussian distribution (perhaps rashly) some 63% of carriers will have levels lower than this. It would be interesting to know in detail the joint distribution of haemopexin and creatine phosphokinase in the two groups, since it is possible, as the Italian workers suggest, that combining the two tests would give notably better discrimination than either one by itself. can
JACOB BITRAN RADHA GANAPATHY JOHN E. ULTMANN HARVEY M. GOLOMB
HEAT AND HÆMODIALYSIS
SIR,-We think that the hot weather was responsible for loss of sites of vascular access in four of our dialysis patients. The average temperature recorded by the Southampton Weather Centre over three days from June 30 was 31 - 4C. In this period, two well-established arteriovenous fismlae, one Scribner shunt, and one vein graft which had functioned faultlessly for four years, all clotted irretrievably. Three patients had lost a mean of 1.6 kg (3.3% of total target body-weight) over the previous 24 h, and one patient had come off dialysis 2 kg under the normal target weight. Two of the patients had intakes of less than 450 ml during that period. ’e feel that the increased insensible body loss of fluid due the heat, compounded in two cases by poor fluid intake, probably resulted in a rise in the hfematocht, thus creating an creased thrombotic tendency. There was no evidence of
was shown to Dr Danieli and Dr Angelini, whose reply follows.-ED.L. SIR,-We welcome the opportunity to explain more fully our statements. As our letter emphasised, the haemopexin test used in association with the c.P.K. test raises the level of detection of Duchenne muscular-dystrophy carriers. We did not propose that this test would be a substitute for the c.P.K. test since there is some overlap between the two distributions of individual values (see accompanying figure); what we intended to convey was that there is a statistically significant difference between normals and carriers; for the moment we can confirectly given as number of observations, means, s.E.M., and confidence intervals). We do not know whether some technical improvement would enhance the possibility of discrimination between normals and carriers; for the moment we can confidently state that haemopexin levels higher than 96 mg/dl (sam-
This letter
’o
1 Baron, J. M., Ultmann, J. E. Chemotherapy 2
of Malignant Neoplasms. Springfield, Illinois, 1973. ann, J. E., Gellhorn, A., Osmos, M., Hirschberg, E. Cancer, 1963, 16, 383
Hiemopexin levels in 26 controls and in 27 recognised carriers. Solid vertical line shows the means, the dashed vertical lines the limit of 1.96 standard deviations. The value indicated by an arrow belongs to a probable carrier (two affected sons, but without previous family cases), who in repeated tests always showed normal c.P.x.
activity.
