GYNECOLOGIC
ONCOLOGY
36,
371-375 (1990)
Clinical Value of Sialyl SSEA-1 Antigen in Patients with Ovarian Cancer M. SUZUKI, M.D., Department
of Obstetrics
M. OHWADA, M.D., and
Gynecology,
Jichi
Received March
The efficacy of sialyl SSEA-1 antigen(SLX), a tumor-associated carbohydrateantigen, as a test for gynecologicalcancerwas investigated. The test was found to be positive in 64.5% of all patientswith ovarian cancers;this rate is lowerthan that obtained with CA 125. On the other hand, relatively few false-positive resultswere observed.Testswere false-positivein 25.0% of patients with endometrialcysts;25.0% of womenin the first trimester of pregnancy and 0.0% of menstruatingwoman had falsepositive results,Thesepercentageswerelower than thosefor CA 125. It is concludedthat SLX is a tumor marker with inferior sensitivity and high specificity, comparedwith CA 125. Since, positive tests with SLX in patients with ovarian cancer mostly overlapped the positive tests for CA 125, the usefulnessof a combinationassaywas consideredto be low. The SLX test was positive in 18.6 and 25.0% of patients with cervical cancer and endometrialcancer, respectively, and it wasconcludedthat SLX is uselessas a serum tumor marker for uterine cancer. 81990 Academic
Press, Inc.
INTRODUCTION
Sialyl SSEA-1 antigen (SLX), which belongs to the type 2 chain carbohydrate antigens, is defined by the new monoclonal antibody FH-6 prepared by Hakomori and co-workers [1,2]. It is seldom observed with immunoperoxidase staining in various normal adult tissues, but since it is clearly observed in cancer tissue, including gastric, colonic, lung, breast, and renal cancers [3], and since it is observed in the sera of cancer patients, at an especially high incidence in those with lung cancer [2,4], it is noted as a serum tumor marker. In the gynecological field, development of a serum tumor marker using a monoclonal antibody especially for ovarian cancer has been actively carried out, and CA 125, prepared by Bast et al. in 1981 [5], is in wide clinical use because of its high sensitivity for ovarian cancer [6,7]. However, CA 125 is not specific for ovarian cancer and it frequently shows false-positive readings in benign diseases such as endometrial cyst [8-l 11. Development of a serum tumor marker with high specificity as well as
AND T. TAMADA, Medical
School,
M.D.
Tochigi,
Japan
22, 1989
high sensitivity is still awaited. By comparing SLX, a new serum tumor marker, with CA 125, we investigated whether or not SLX is useful as a serum tumor marker for gynecological cancer, particularly ovarian cancer. MATERIALS
AND METHODS
Sera were collected from 194 patients in the Obstetrics and Gynecology Department of Jichi Medical School. The specimens were collected before treatment and included 31 from patients with ovarian cancer (9 with serous adenocarcinoma, 7 with mutinous adenocarcinoma, 6 with undifferentiated carcinoma, 3 with endometrioid carcinoma, 2 with clear cell carcinoma, and 1 each with Krukenberg tumor, dermoid cyst with malignant transformation, squamous cell carcinoma, and endodermal sinus tumor), 28 from patients with benign ovarian tumors (11 with dermoid cyst, 10 with mutinous adenoma, and 7 with serous adenoma), 8 from patients with endometrial cysts, 59 from patients with uterine cervical cancer (53 with squamous cell carcinoma and 6 with adenocarcinoma), and 16 from patients with endometrial cancer. Clinical staging according to the International Federation of Gynecology and Obstetrics (FIGO) showed 8 cases of stage I, 2 cases of stage II, 8 cases of stage III, 7 cases of stage IV, and 6 recurrences of ovarian cancer. For cervical cancer, 6 cases were stage 0, 18 cases of stage I, 17 cases of stage II, 11 cases of stage III, 2 cases of stage IV, and 5 recurrences; and for endometrial cancer, 10 cases of stage I, 1 case of stage II, 3 cases of stage III, and 2 recurrences. In addition, sera collected from 32 women in the first trimester of pregnancy and from 20 women during their menstrual period were frozen and stored at -70°C until assay. A sialyl SSEA-1 antigen RIA kit, prepared by Otsuka Assay Laboratories (Tokushima, Japan), was used for SLX measurement by a solid-phase immunoradiometric sandwich assay method. Intra- and interassay coefficients of variation did not exceed 5.0%. The cutoff value deter-
371
0090-8258/90S1.50 Copyright 0 1990 by Academic Press, Inc. All rights of reproduction in any form reserved.
372
SUZUKI.
OHWADA,
AND TAMADA
mined was 38 U/ml [12]. Serum CA 125 was measured using an RIA kit (Centocor) and a solid-phase sandwich assay. The cutoff value determined was 35 U/ml.
U/ml 47.2 f16.7
76.0 +_65 5
67.0 f74.8
215.6 f423.5
70.0 f35.4
126.3 f140.7
.
1000
RESULTS Serum SLX Levels in Ovarian
1
Cancer Patients
The serum SLX level in patients with ovarian cancer by clinical staging by FIG0 is shown in Fig. 1. The level for stage I patients was 42.3 & 12.0 U/ml (mean + SD). However, the levels for stage II and III were 58.5 2 51.6 and 201.9 & 358.3 U/ml, respectively, which are high. Levels exceeding the cutoff value were observed in 20 of the 31 patients (64.5%) with ovarian cancers. Fifty percent of patients (4/8) in stage I exceeded the cutoff value, but the rates in advanced cases in stages III and IV were higher, 87.5% (7/8) and 85.7% (6/7), respectively. There was no difference in mean SLX level among the various histological types, but only 42.9% of patients with mutinous adenocarcinoma were positive, i.e., had levels above 38 U/ml (Fig. 2). On the other hand, serum CA 125 was positive in 90.3% (28/31) of all patients with ovarian cancers, thus exceeding the SLX rate. The relationship between serum SLX level and serum CA 125 level is shown in Fig. 3. No patient with a positive serum SLX level and a negative serum CA 125 level was obU/m 42.3 f12.0
58.5 f51.5
201.9 f358.3
63.3 1t52.0
f
34.5 9.2
Y f f Y
.
.
.
iUJ E 100
3 ii v)
38
.
1
. ; .
.
. a
.
SAC
MAC
UDC
EMC
.
CCC
Others
FIG. 2. Serum SLX levels (means f SD) in patients with ovarian cancer classified by histological types. SAC, serous adenocarcinoma; MAC, mutinous adenocarcinoma; UDC, undifferentiated carcinoma; EMC, endometrioid carcinoma; CCC, clear cell carcinoma.
served. Conversely, eight patients with a negative serum SLX and a positive serum CA 125 were observed. SLX was confirmed to be inferior to CA 125 in sensitivity. All three patients with a negative SLX and a negative CA 125 had mutinous adenocarcinoma.
.
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.
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.
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25.0 I 1
Early
6 5 .6
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(32)
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1
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.::::>::::::,:.: :.I:::::::::: :::,::::::::::::y ,.,,;,.,., ;;, ,. .;,.,.;. :.:.,..,. .:,,.:. $$ ~:~*~.c~ '.'.'.'."';$y I .:.: :::::.::::::::::: ,::::.,.:.: .,.,.,.,.;,., ,.,.,.; .;,.;,. .,. . ... . ... :.:. . .:.:z:.:..\.:. .:.:. .:.;.:.:.:.:.:.:.:: :,;::>;: :,:,:,:,:,:,j:, ::::,::::::::,:::,:(::::::.:: :.:.~:A..:.:+:.:.:~.~ :(,:.:.:.:.:,:.,.~.,.,.,., ..,I. .A., ...:...:,:.~~:\ >>>:.>j:.:.:. .,.,.,.,.,.,.,.,., ,.,.,.,.,.,., I
\\
: .. . .. ..A......~...~.~. :. :. .. . ... ..,.,.. i
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I
100
Serum
with SLX was considered. SLX belongs to the group of type 2 chain carbohydrate antigens, which are generally noted to be inferior in sensitivity and higher in specificity in cancer, as compared with type 1 chain carbohydrate antigens represented by CA 19-9 [17-191. SLX was interpreted to be a material with the characteristics of type 2 chain carbohydrate antigens. However, since the positive results with SLX and CA 125 in ovarian cancer were confirmed to overlap, improvement in the diagnosis of ovarian cancer by combination assay was judged to be almost hopeless. Investigation of ovarian cancers by histological typing showed that the incidence of a positive SLX test in mutinous carcinoma was low (43.9%) and similar to that with CA 125 1201. Investigation by clinical stage showed that the incidence of positive tests in advanced cases in stages III and IV was high, but -the incidence of positive tests in stage I was low. Development of a tumor marker with high sensitivity to mucinous carcinoma and high sensitivity to early-stage cancer is needed and awaited. The SLX test was positive in cervical cancer and endometrial cancer in only 18.6 and 25.0%, respectively, and it was considered to be useless as a marker of uterine cancer.
3.
4.
5.
6.
7.
8.
REFERENCES 9.
1. Fukushi, Y., Nudelman, E., Levery, S. B., Hakomori, S., and Rauvala, H. Novel fucolipids accumulating in human adenocarcinema. III. A hybridoma antibody (FH6) defining a human cancerassociated difucoganglioside (V13NeuAcV’III’Fuc,nLc,), J. Biol. C/rem. 2.59, 10511-10517 (1984). 2. Kannagi, R., Fukushi, Y., Tachikawa, T., Noda, A., Shin, S., Shigeta, K., Hiraiwa, N., Fukuda, Y., Inamoto, T., Hakomori, S., and Imura, H. Quantitative and qualitative characterization of
10.
11.
human cancer-associated serum glycoprotein antigens expressing fucosyl or sialyl-fucosyl type 2 chain polylactosamine, Cancer Res. 46, 2619-2626 (1986). Fukushi, Y., Kannagi, R., Hakomori, S., Shepard, T., Kulander, B. G., and Singer, J. W. Location and distribution of difucoganglioside (VI’NeuAcV’III’FucznLc6) in normal and tumor tissues defined by its monoclonal antibody FH6, Cancer Res. 45, 37113714 (1985). Imura, H., Endo, J., Ohkura, H., Ishii, M., Ariyoshi, Y., Abe, O., Masamune, O., Nishimoto, Y., Fukushi, Y., Orikasa, S., Hakomori, S., and Kannagi, R. Initial basic and clinical evaluation of a solid-phase immunoradiometric assay for sialyl SSEA-1 antigen. 2. Evaluation of clinical significance, Japan J. Cancer Chemother. 14, 1322-1331 (1987). Bast, R. C., Jr., Feeney, M., Lazarus, H., Nadler, L. M., Colvin, R. B., and Knapp, R. C. Reactivity of a monoclonal antibody with human ovarian carcinoma, J. Clin. Invest. 68, 1331-1337 (1981). Bast, R. C., Jr., Klug, T. L., John, E. S., Jenison, E., Niloff, J. M., Lazarus, H., Berkowitz, R. S., Leavitt, T., Griffiths, C. T., Parker, L., Zurawski, V. R., Jr., and Knapp, R. C. A radioimmunoassay using a monoclonal antibody to monitor the course of epithelial ovarian cancer, N. Engl. J. Med. 309, 883-887 (1983). Schilthuis, M. S., Aalders, J. G,, Bouma, J., Kooi, H., Fleuren, G. J., Willemse, P. H. B., and Debruijn, H. W. A. Serum CA 125 levels in epithelial ovarian cancer: Relation with findings at secondlook operations and their role in the detection of tumour recurrence, Brit. J. Obstet. Gynaecol. 94, 202-207 (1987). Kuzuya, K., Nozaki, M., and Chihara, T. Evaluation of CA 125 as a circulating tumor marker for ovarian cancer, Acta Obstet. Gynaecol. Jupon. 38, 949-957 (1986). Takahashi, K., Kijima, S., Yoshino, K., Shibukawa, T., Murao, F., and Kitao, M. Differential diagnosis between uterine myoma and endometriosis using CA 125 as a new tumor marker of ovarian carcinoma, Asia-Oceania .I. Obstet. Gynaecol. 12, 99-103 (1986). Suzuki, M., Sekiguchi, I., and Tamada, T. Investigation of the possibility of CA 125, a new tumor marker, in screening ovarian cancers including the study of false positive cases, Acta Obstet. Gynaecol. Jupon. 37, 2658 (1985). Barbieri, R. L., Niloff, J. M., Bast, R. C., Jr., Schaetzl, E., Kist-
SIALYL
SSEA-I ANTIGEN
ner, R. W., and Knapp, R. C. Elevated serum concentrations of CA-125 in patients with advanced endometriosis, Fertil. Steril. 45, 630-634 12.
(1986).
Imura, H., Endo, J., Ohkura, H., Ishii, M., Ariyoshi, Y., Abe, O., Masamune, O., Nishimoto, Y., Fukushi, Y., Orikasa, S., Hakomori, S., and Kannagi, R. Initial basic and clinical evaluation of a solid-phase immunoradiometric assay for sialyl SSEA-I antigen. 1. Evaluation of assay conditions and normal values, Japan. J. Cancer
Chemother.
14, 1315-1321
(1987).
13. Barrelet, V., and Mach, J. P. Variations of the carcinoembryonic antigen level in the plasma of patients with gynecologic cancers during therapy, Amer. J. Obstet. Gynecol. 121, 164-168 (1975). 14. DiSaia, P. J., Haverback, B. J., Dyce, B. J., and Morrow, C. P. Carcinoembryonic antigen in patients with gynecologic malignancies, Amer. J. Obsfet. Gynecol. 121, 159-163 (1975). 15. Knauf, S., and Urbach, G. I. The development of a double-antibody radioimmunoassay for detecting ovarian tumor-associated antigen fraction OCA in plasma, Amer. J. Ohstet. Gynecol. 131,780787 (1978). 16.
Knauf, S., and Urbach, G. I. A study of ovarian cancer patients
IN OVARIAN
375
CANCER
using a radioimmunoassay for human ovarian tumor-associated antigen OCA, Amer. J. Obstet. Gynecol. 138, 1222-1223 (1980). 17. Kannagi, R., Miyake, M., Zenita, K., Itai, S., Hiraiwa, N., Shigeta, K., Hirashima, K., and Hino, A. Cancer-associated carbohydrate antigens: Modified blood group substances and onco-developmental antigens on tumor cells, Gnnn Monogr. Cancer Res. 34, 15-28 18.
(1988).
Kannagi, R., Hakomori, S., and Imura, H. Cancer-associated serum glycoprotein antigens expressing type 1 and type 2 chain polylactosamines, in Altered glycosylation in tumor cells (S. Hakomori, C. Reading, and D. Marcus, Eds.), Alan R. Liss, pp. 279294 (1988).
19. Koprowski, H., Steplewski, Z., Mitchell, K., Herlyn, M., Herlyn, D., and Fuhrer, P. Colorectal carcinoma antigens detected by hybridoma antibodies, Somat. Cell Genet. 5, 957-972 (1979). 20. Kabawat, S. E., Bast, R. C., Welch, W. R., Knapp, R. C., and Colvin, R. B. Immunopathologic characterization of a monoclonal antibody that recognizes common surface antigens of human ovarian tumors of serous, endometrioid, and clear cell types, Amer. J. C/in.
Patho/.
79, 98-104
(1983).
ONCOLOGY
36,
371-375 (1990)
Clinical Value of Sialyl SSEA-1 Antigen in Patients with Ovarian Cancer M. SUZUKI, M.D., Department
of Obstetrics
M. OHWADA, M.D., and
Gynecology,
Jichi
Received March
The efficacy of sialyl SSEA-1 antigen(SLX), a tumor-associated carbohydrateantigen, as a test for gynecologicalcancerwas investigated. The test was found to be positive in 64.5% of all patientswith ovarian cancers;this rate is lowerthan that obtained with CA 125. On the other hand, relatively few false-positive resultswere observed.Testswere false-positivein 25.0% of patients with endometrialcysts;25.0% of womenin the first trimester of pregnancy and 0.0% of menstruatingwoman had falsepositive results,Thesepercentageswerelower than thosefor CA 125. It is concludedthat SLX is a tumor marker with inferior sensitivity and high specificity, comparedwith CA 125. Since, positive tests with SLX in patients with ovarian cancer mostly overlapped the positive tests for CA 125, the usefulnessof a combinationassaywas consideredto be low. The SLX test was positive in 18.6 and 25.0% of patients with cervical cancer and endometrialcancer, respectively, and it wasconcludedthat SLX is uselessas a serum tumor marker for uterine cancer. 81990 Academic
Press, Inc.
INTRODUCTION
Sialyl SSEA-1 antigen (SLX), which belongs to the type 2 chain carbohydrate antigens, is defined by the new monoclonal antibody FH-6 prepared by Hakomori and co-workers [1,2]. It is seldom observed with immunoperoxidase staining in various normal adult tissues, but since it is clearly observed in cancer tissue, including gastric, colonic, lung, breast, and renal cancers [3], and since it is observed in the sera of cancer patients, at an especially high incidence in those with lung cancer [2,4], it is noted as a serum tumor marker. In the gynecological field, development of a serum tumor marker using a monoclonal antibody especially for ovarian cancer has been actively carried out, and CA 125, prepared by Bast et al. in 1981 [5], is in wide clinical use because of its high sensitivity for ovarian cancer [6,7]. However, CA 125 is not specific for ovarian cancer and it frequently shows false-positive readings in benign diseases such as endometrial cyst [8-l 11. Development of a serum tumor marker with high specificity as well as
AND T. TAMADA, Medical
School,
M.D.
Tochigi,
Japan
22, 1989
high sensitivity is still awaited. By comparing SLX, a new serum tumor marker, with CA 125, we investigated whether or not SLX is useful as a serum tumor marker for gynecological cancer, particularly ovarian cancer. MATERIALS
AND METHODS
Sera were collected from 194 patients in the Obstetrics and Gynecology Department of Jichi Medical School. The specimens were collected before treatment and included 31 from patients with ovarian cancer (9 with serous adenocarcinoma, 7 with mutinous adenocarcinoma, 6 with undifferentiated carcinoma, 3 with endometrioid carcinoma, 2 with clear cell carcinoma, and 1 each with Krukenberg tumor, dermoid cyst with malignant transformation, squamous cell carcinoma, and endodermal sinus tumor), 28 from patients with benign ovarian tumors (11 with dermoid cyst, 10 with mutinous adenoma, and 7 with serous adenoma), 8 from patients with endometrial cysts, 59 from patients with uterine cervical cancer (53 with squamous cell carcinoma and 6 with adenocarcinoma), and 16 from patients with endometrial cancer. Clinical staging according to the International Federation of Gynecology and Obstetrics (FIGO) showed 8 cases of stage I, 2 cases of stage II, 8 cases of stage III, 7 cases of stage IV, and 6 recurrences of ovarian cancer. For cervical cancer, 6 cases were stage 0, 18 cases of stage I, 17 cases of stage II, 11 cases of stage III, 2 cases of stage IV, and 5 recurrences; and for endometrial cancer, 10 cases of stage I, 1 case of stage II, 3 cases of stage III, and 2 recurrences. In addition, sera collected from 32 women in the first trimester of pregnancy and from 20 women during their menstrual period were frozen and stored at -70°C until assay. A sialyl SSEA-1 antigen RIA kit, prepared by Otsuka Assay Laboratories (Tokushima, Japan), was used for SLX measurement by a solid-phase immunoradiometric sandwich assay method. Intra- and interassay coefficients of variation did not exceed 5.0%. The cutoff value deter-
371
0090-8258/90S1.50 Copyright 0 1990 by Academic Press, Inc. All rights of reproduction in any form reserved.
372
SUZUKI.
OHWADA,
AND TAMADA
mined was 38 U/ml [12]. Serum CA 125 was measured using an RIA kit (Centocor) and a solid-phase sandwich assay. The cutoff value determined was 35 U/ml.
U/ml 47.2 f16.7
76.0 +_65 5
67.0 f74.8
215.6 f423.5
70.0 f35.4
126.3 f140.7
.
1000
RESULTS Serum SLX Levels in Ovarian
1
Cancer Patients
The serum SLX level in patients with ovarian cancer by clinical staging by FIG0 is shown in Fig. 1. The level for stage I patients was 42.3 & 12.0 U/ml (mean + SD). However, the levels for stage II and III were 58.5 2 51.6 and 201.9 & 358.3 U/ml, respectively, which are high. Levels exceeding the cutoff value were observed in 20 of the 31 patients (64.5%) with ovarian cancers. Fifty percent of patients (4/8) in stage I exceeded the cutoff value, but the rates in advanced cases in stages III and IV were higher, 87.5% (7/8) and 85.7% (6/7), respectively. There was no difference in mean SLX level among the various histological types, but only 42.9% of patients with mutinous adenocarcinoma were positive, i.e., had levels above 38 U/ml (Fig. 2). On the other hand, serum CA 125 was positive in 90.3% (28/31) of all patients with ovarian cancers, thus exceeding the SLX rate. The relationship between serum SLX level and serum CA 125 level is shown in Fig. 3. No patient with a positive serum SLX level and a negative serum CA 125 level was obU/m 42.3 f12.0
58.5 f51.5
201.9 f358.3
63.3 1t52.0
f
34.5 9.2
Y f f Y
.
.
.
iUJ E 100
3 ii v)
38
.
1
. ; .
.
. a
.
SAC
MAC
UDC
EMC
.
CCC
Others
FIG. 2. Serum SLX levels (means f SD) in patients with ovarian cancer classified by histological types. SAC, serous adenocarcinoma; MAC, mutinous adenocarcinoma; UDC, undifferentiated carcinoma; EMC, endometrioid carcinoma; CCC, clear cell carcinoma.
served. Conversely, eight patients with a negative serum SLX and a positive serum CA 125 were observed. SLX was confirmed to be inferior to CA 125 in sensitivity. All three patients with a negative SLX and a negative CA 125 had mutinous adenocarcinoma.
.
1000
.
a
0
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l
100
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s z v)
; 0
8
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.
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Early
6 5 .6
Pregnancy
(32)
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I
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1
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,
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I
100
Serum
with SLX was considered. SLX belongs to the group of type 2 chain carbohydrate antigens, which are generally noted to be inferior in sensitivity and higher in specificity in cancer, as compared with type 1 chain carbohydrate antigens represented by CA 19-9 [17-191. SLX was interpreted to be a material with the characteristics of type 2 chain carbohydrate antigens. However, since the positive results with SLX and CA 125 in ovarian cancer were confirmed to overlap, improvement in the diagnosis of ovarian cancer by combination assay was judged to be almost hopeless. Investigation of ovarian cancers by histological typing showed that the incidence of a positive SLX test in mutinous carcinoma was low (43.9%) and similar to that with CA 125 1201. Investigation by clinical stage showed that the incidence of positive tests in advanced cases in stages III and IV was high, but -the incidence of positive tests in stage I was low. Development of a tumor marker with high sensitivity to mucinous carcinoma and high sensitivity to early-stage cancer is needed and awaited. The SLX test was positive in cervical cancer and endometrial cancer in only 18.6 and 25.0%, respectively, and it was considered to be useless as a marker of uterine cancer.
3.
4.
5.
6.
7.
8.
REFERENCES 9.
1. Fukushi, Y., Nudelman, E., Levery, S. B., Hakomori, S., and Rauvala, H. Novel fucolipids accumulating in human adenocarcinema. III. A hybridoma antibody (FH6) defining a human cancerassociated difucoganglioside (V13NeuAcV’III’Fuc,nLc,), J. Biol. C/rem. 2.59, 10511-10517 (1984). 2. Kannagi, R., Fukushi, Y., Tachikawa, T., Noda, A., Shin, S., Shigeta, K., Hiraiwa, N., Fukuda, Y., Inamoto, T., Hakomori, S., and Imura, H. Quantitative and qualitative characterization of
10.
11.
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