Amino-Terminal Propeptide of Type III Procollagen: a New Prognosis Indicator in Human Ovarian Cancer Antti Kauppila,1 Ulla Puistola, Juha Risteli, and Leila Risteli

[CANCER RESEARCH 49. 1885-1889, April 1, 1989] Amino-terminal Propeptide of Type III Procollagen: A New Prognosis Indicator in Human Ovarian Cancer Antti Kauppila,1 Ulla Puistola, Juha Risteli, and Leila Risteli

Department of Obstetrics and Gynecology, and Collagen Research Unit, Biocenter, and Department of Medical Biochemistry, University ofOulu, 90220 Oulu, Finland

ABSTRACT formed in equimolar proportions to collagen. In addition to malignant diseases, increased PIIINP concentrations have been To investigate the clinical usefulness of the ammo-terminal propeptide found in acromegaly (19), during childhood, puberty, and preg of type III procollagen (PIIINP) as an indicator of ovarian cancer nancy, and in patients with liver diseases (see Refs. 20 and 21). behavior, 30 patients with advanced epithelial malignancy were monitored with serial serum PIIINP and CA-125 determinations before and during Both collagen synthesis and degradation probably affect the treatment. serum concentration of PIIINP. Initially, PIIINP and CA-125 concentrations were each separately The radioimmunoassay of PIIINP used in our previous study increased in 87% of the cases and, simultaneously, in 77% of the cases. (14), which was developed against the am Â¡no-terminalsegment In monitoring treatment responses, PIIINP and CA-125 were identical of type III procollagen, isolated from fetal calf skin, detected in 17 patients (57%), both being good predictors of the clinical behavior several PIIINP antigens of different molecular sizes in human of the disease in 16 cases and poor predictors in one case. In 13 patients serum. Because the concentrations of the medium-sized PIIINP (43%) they were complementary to each other. In three cases PIIINP antigens responded most precisely to the changes in the tumor alone and in one case CA-125 alone were clinically useful prognosis volume of ovarian cancer (14), we have modified our PIIINP indicators. During the period of complete clinical response to cytotoxic RIA to preferentially identify antigens of this size (22). The chemotherapy of 16 patients, the CA-125 concentrations decreased to new PIIINP RIA was developed against the amino-terminal normal before the clinical disappearance of the tumor in eight cases. PIIINP did so in only two cases, thus correlating more precisely with the propeptide of human type III procollagen. In this study, we presence of malignancy. In second-look laparotomies, PIIINP concentra have studied the clinical significance of PIIINP by comparing tions correlated with the presence of occult cancer better than those of its concentrations with the clinical course of ovarian cancer, CA-125. In predicting recurrent malignancy in patients with transient and we have used CA-125 as a reference indicator. complete response, PIIINP and CA-125 were clinically equal. According to the present data, PIIINP concentrations often give infor mation not obtainable by CA-125, thus being useful in monitoring the MATERIALS AND METHODS clinical behavior of ovarian cancer. Patients and Therapy. The present study material comprised 30 patients with primary (n = 24) or recurrent (n = 6) advanced ovarian INTRODUCTION cancer (Table 1). The age of the patients varied from 40 to 72 yr (median, 56 yr). In 4 patients the follow-up time was 12 mo or less, CA-125, an indicator of epithelial ovarian cancer cell unti and in the other patients, from 1 to 3 yr. Diagnosis of ovarian cancer genicity, has been widely investigated in this malignancy, par was made from histopathological specimens taken at laparotomy in ticularly in monitoring the treatment response (1-10). How each case. Histopathologically, all 30 tumors were epithelial (19 serous, ever, in 10 to 30% of ovarian cancers, this antigen is not 2 mucinous, 3 endometrioid, and 6 anaplastic). The recurrent disease expressed (1, 3, 6), and during treatment, normal values are was pelvic and/or intraabdominal in 5 patients. One patient had only common in cases of manifest or occult malignancy (4, 5,8-10). paraaortic lymph node mÃ©tastases. In addition, increased concentrations have been observed in We used different cytotoxic chemotherapy combinations. The 1-day AP regimen, comprising alkeran (25 mg) and c/.v-platinum (40 mg/nr) endometrial cancer (11), endometriosis (12, 13), inflammatory i.v. infusions, and the 1-day CAP regimen, comprising cyclophospha diseases (6, 12), pregnancy (2, 6, 12), and during menstruation mide (500 mg/m2), Adriamycin (40 mg/m2), and m-plai inum (50 mg/ of healthy women (12). m2) i.v. infusions, were used as first-line chemotherapy, with an interval We recently observed that the serum concentrations of the of 4 wk. In cases of failure we continued with a p.o. combination of amino terminal PIIINP,2 are increased in advanced ovarian cyclophosphamide (150 mg/m2 a day for 5 days), carmofur (500 mg/ cancer, and they correlate with the clinical behavior of the m2 a day for 2 wk), and hexamethylene melami ne (150 mg/m2 a day disease (14). Other investigators have also found serum PIIINP for 2 wk), or an i.v. 1-day combination of karboquon (3.5 mg/m2), concentrations to be increased in some patients with different methotrexate (150 mg/m2), and 5-fluorouracil (600 mg/m2). types of malignancies (15). PIIINP is likely to reflect the At second-look operation, performed in 5 patients with CR, all interaction of cancer with the extracellular matrix and connec macroscopic tumors were extirpated, and in cases with no macroscopic tive tissue stroma, a process which is crucial in the invasive residual tumor, multiple peritoneal biopsies were taken for histopath spread of malignancy (16-18). Two specific properties of ological evaluation. As regards the clinical treatment responses, CR, PR, NC, and PD PIIINP make it especially interesting in carcinoma and suggest were estimated according to the criteria suggested by the committee of that it has potential as an index of collagen metabolism, (a) Its the WHO (23). precursor molecule, type HI procollagen, is one of the most Serum concentrations of CA-125 were determined during the treat abundant interstitial precursors of collagen, and (Â¿>)PIIINP is ments at intervals of 1 to 2 mo, and sometimes cytotoxic chemotherapy was changed or second-look laparotomy performed on the basis of CA- Received 5/25/88; revised 10/21/88; accepted 12/28/88. 125 recordings. At each visit, before cytotoxic chemotherapy was given, The costs of publication of this article were defrayed in part by the payment blood samples were taken and stored at -20'C until assayed for PIIINP. of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Assays. The concentrations of antigens related to PIIINP were ' To whom requests for reprints should be addressed. 1The abbreviations used are: PIIINP, propeptide of type III procollagen; assessed with a rapid (total time required, 3 to 4 h) equilibrium radioimmunoassay (22). The solid-phase second-antibody separation RIA, radioimmunoassay; AP, alkeranx/j-platinum; CAP, cyclophosphamide: Adriamycin:cÂ»-platinum; CR, complete response; PR, partial response; NC, no reagent was kindly provided by Farmos Diagnostica (Oulunsalo, Fin change; PD, progressive disease. land). Both the intraassay and the interassay variations were around 1885

5% at the concentrations found during the study. Duplicate 200-^1 CA-125 (IU/L) serum samples were used for the test. Analysis of the serum specimens 200010005003002001008030201016141210862CAP\ of 88 blood donors gave a reference interval of 1.7 to 4.2 Mg/liter (mean Â±2 SD) for healthy adults. Women had a lower mean concentration than men, but the difference was not statistically significant. The serial samples of each patient were analyzed in the same run. \\, CA-125 was measured by a simultaneous sandwich solid-phase RIA \ using a commercial kit (Abbot CA 125 RIA; Abbott Diagnostic Divi \^K1 sion, North Chicago, IL). The sensitivity was 5 lU/liter, and the coefficient of variation, 9% at the level of 83 ID/ml. All specimens â€¢¿\*â€”â€”¿ were assayed in duplicate. CA-125 values exceeding 30 ID/liter were .^VN^-^.â€¢ regarded as pathological (3). "*~ ~ ~ * Criteria of Biochemical Responses. The presence of three consecutive 12 18 recordings of PIIINP concentrations below the upper limit of the 5003002001005020101210862CAP reference interval was regarded as indicative of a treatment response, (*'"s^_ and persistence of PIIINP levels above this, or a rise above the interval after an initial decline in three consecutive recordings, was regarded as indicative of persistence or reappearance of the malignancy. The same criteria were applied to CA-125 in this study. For estimation of the "^\ ^â€” start of response or appearance of recurrent cancer, the first of the ^___Â¿"x*^r "*-,â€”¿^~â€”â€”¿â€”¿ normal or pathological recordings, respectively, was recognized. 1/'^--^^r-.-*.-^â€”.-*'/'^~"-*.â€¢¿~--.-â€”â€¢¿â€¢â€”".'

12 18 24 RESULTS 1000500300 ,*v^-*^v^^\\"â€¢ Initial PIIINP and CA-125 Concentrations. In this patient population a clinical CR was obtained in 18 cases (Table 1). It was transient, from 4 to 23 mo (median, 8 mo), in 11 cases. In 200100SO3020101412108642AP 7 cases the CR still continues (4-, 6-, 17-, 22-, 26-, 32-, and 37- mo duration). A PR of short duration (from 3 to 6 mo) was observed in 4 cases, and a state of NC of varying length (from 4 to 18 mo) in 8 patients. â€¢¿vâ€¢Â«â€¢.-â€¢--<__._.''"â€¢-.e â€¢¿ Increased CA-125 and PIIINP concentrations were each found in 26 of the total of 30 cases (87%). In the group of 24 12Months primary ovarian cancers, the respective frequency figure was 92% for both CA-125 and PIIINP. CA-125 and PIIINP were Fig. 1. Serum concentrations of PIIINP (â€¢)and CA-125 (â€¢)in patients showing a complete response to cytotoxic chemotherapy after radical surgery falsely negative 4 times each, twice in the same patient. In the (top) and debulking surgery (middle and the bottom) of advanced ovarian cancer. reference material of 145 subjects (48 female blood donors, 47 At the bottom, note the normal CA-125 recording at the time of operation. In the postmenopausal women, and 50 patients with benign ovarian response line, the closed circle indicates the presence of a measurable tumor, the open triangle, a partial response; and the open circle, a complete response. tumors), there were 3 cases with values higher than 4.2 /Â¿g/liter. AP indicates a combination of alkeran and r/.v-plaiinum: and CAP, a combi General Comparison of PIIINP and CA-125 during Therapy. nation of cyclophosphamide, Adriamycin, and c/.vplatinum. There were no significant differences in the initial CA-125 and PIIINP concentrations between responders and nonresponders (data not shown). In the 7 cases with a continuing CR, both to be a reliable sign of recurrent cancer in association with CR, indicators (n = 3) or PIIINP alone (n = 3) correlated with the and of progression in patients with PR or NC (Figs. 2 to 4). In the total material, CA-125 alone was clinically useful in 1 clinical behavior of the disease (Table 1; Fig. 1, upper and middle panels). In two cases only CA-125 was already initially case (3%), PIIINP alone in 3 cases (10%), and CA-125 and normal (Fig. 1, lower panel), and in one case both indicators, PIIINP simultaneously in 25 cases (83%). Among these 25 being thus clinically useless for treatment monitoring. cases, there were 9 cases (36%) where the information obtained by CA-125 and PIIINP determinations differed. In 1 case both During the treatment of patients with transient CR (Figs. 2 and 3), PR, or NC (Fig. 4), the fluctuation in the PIIINP level markers were simultaneously clinically useless (3%). Put to was much less than that of CA-125. However, the persistently gether, CA-125 and PIIINP were clinically of equal value in 17 elevated PIIINP level, although often relatively stable, proved of the 30 cases (57%), both being good predictors of clinical behavior of the disease in 16 cases and poor in 3 cases. Com Table 1 The general clinical usefulness of CA-125 and PIIINP in different plementary information (see below) was obtained in 13 cases response categories (43%). Clinically useful As regards the histopathology of the tumors, PIIINP, like Response CA-125 NP III Clinically CA-125, was most useful in anaplastia and serous adenocarci- category n Both (Identical) (Complementary) alone" alune' useless" nomas. In endometrioid and mucinous carcinomas, their clini CR+CRPRNC71148303104825(3)(3)(4)(6)(16)(0)(7)(0)(2)(9)010013000310001 cal value was poorer, but they often complemented each other (Table 1). PIIINP and CA-125 Concentrations in Relation to CR. A CR was obtained in 16 cases (Table 2). The decrease of CA-125 " In one endometrioid tumor, both markers were simultaneously normal all concentrations to normal preceded the CR in 8 cases by 1 to 8 the time, irrespective of the tumor load. * In one case (serous tumor), PIIINP was normal all the time. mo. A normal PIIINP level was reached in 2 patients 2 and 7 c In 3 cases (one serous, one mucinous, and one endometrioid tumor), CA-125 mo before the CR, and in 6 patients 2 to 6 mo after the CR. was normal all the time. NP III, The concentrations of CA-125 and PIIINP were continuously 1886

CA-125 (IU/L) CA-125 (IU/L) SECOND-LOOK PIIINP

30 4 20

10 AP CAP

12 Months

Fig. 3. Serum concentrations of PIIINP and CA-125 in a patient with an inoperable Stage III ovarian cancer (serous adenocarcinoma) with a rapid short lived response period followed by rapid progression of the disease. Both indicators correlated closely with the clinical course of the disease. For symbols, see the legends to Figs. 1 and 2.

CA-125 CIU/L) PIIINP (ug/l) 16 â€¢¿ 2000 1000.

500 300 200

100

SO 30 20 10 ACF Fig. 2. Serum concentrations of PIIINP and CA-12S in patients showing a transient complete response to cytotoxic chemotherapy after explorative laparot- 12 18 24 omy of advanced ovarian cancer. In each case, CA-12S levels decreased to normal 5000 IS before clinical disappearance of the tumor, whereas PIIINP levels remained 3000 elevated before and during clinical remission. In each case, CA-125 started to 2000 increase before clinical progression. At bottom, the PIIINP measurements were stopped at the time of the second-look operation, which gave no evidence of a 1000 tumor. The CA-125 determinations were continued on a 2(3)-mo basis until the third-look operation which was made because of increased CA-125 concentra 500 tions. A single mesenterial metastasis (diameter, 2 to 3 cm) was found and 300 extirpated. For the symbols, see the legend to Fig. 1. In addition, the closed square 200 in the response line indicates clinical progression. CCHx indicates a combination 100 of carmofur, cyclophosphamide, and hexamethylenmelamin; and KMxF, a com bination of karboquon, methotrexate, and 5-fluorouracil. 50 30 20 increased in 3 and 6 cases, respectively, indicating clinically 10 AP CAP occult disease. 12 18 PIIINP and CA-125 Concentrations in Relation to PD. There Months were 11 patients with a transient CR (Table 3). Their CA-125 Fig. 4. Serum concentrations of PIIINP and CA-125 in patients with recurrent concentrations were continuously increased in 4 patients, and (top) or primary (bottom) advanced ovarian cancer which responded to therapy in 5 patients the increase in CA-125 concentration preceded a by stabilization of the tumor. CA-125 decreased to normal for a short period in clinical PD by 3 to 13 mo, in one patient by 1 mo only and in one patient (bottom), but otherwise the indicators were above the reference limits, in line with the clinical picture. one patient it was delayed by 5 mo. In one patient with a For symbols, see the legends to Figs. 1 and 2. In addition, the closed triangle persistently increased PIIINP concentration, the late increase indicates no change in the tumor. in CA-125 concentration indicated a second-look operation which revealed a recurrent cancer with a diameter of 2 cm in 19 mo, in one patient by 2 mo, whereas in one patient the the mesen teriu in of the sigmoideum (Fig. 2, lower panel). PIIINP concentration was normal all the time. In 2 patients, PIIINP concentrations were constantly elevated in 6 patients. CA-125 and PIIINP were simultaneously increased during the In 4 patients the PIIINP increase preceded clinical PD by 3 to CR period. The predictive value of increased CA-125 or PIIINP 1887

Table 2 Temporal relationships of the decreases in the serum concentrations of CA-125 and PIIINP to the complete response of 16 patients having a nonradical in some less usual subtypes of epithelial ovarian malignancy. operation The origin of CA-125 and PIIINP is different. CA-125 is a No. of patients membrane antigen of epithelial ovarian cancer cells, whereas PIIINP antigenicity is derived from synthetic and/or degrada indicatorsContinuouslyConcentration of tivi; metabolism of type III collagen. As regards ovarian malig normal CR)ContinuouslyEarly decrease (mo before 8(1,2,2,5, 2 (2,3)65 20 nancy, PIIINP expression may take place inside or outside the 6, 6, 7, 7) tumor, or in both locations, and it thus reflects a totally different increased 3 carcinogenic process than CA-125. Despite this difference, the Late decrease (mo after CR) 0 (2, 3, 4, 4, 6) 00 changes in CA-125 and PIIINP concentrations were surpris Infrequent samplingCA-1253 2PIIINP2 1BothI ingly similar in many cases. It is possible that expression of Table 3 Temporal relationships of the increases in the concentrations of CA-125 these antigens is controlled by the same unknown factor(s), and PIIINP to the clinical manifestation of recurrent cancer in II patients with possibly involved in the regulation of the growth of cancer. The transient complete response activity of the epithelial and stremai components of ovarian No. of patients cancer could possibly be assessed separately by CA-125 and indicatorsContinuouslyConcentration of PIIINP measurements. It is likely that the changes in the increased activity of these tissue elements run parallel (18). EarlyPD)Late increase (mo before 6(1,2,4,5, (2,4,017,19)Both2 200 It was interesting that, in some cases, small i.p. lesions, even 11, 13) microscopic ones, were associated with increased serum PIIINP increase (mo after PD) 1(5) Continuously normalCA-1254 0PIIINP64 concentrations, whereas in the case with only lymph node involvement, it was normal. This suggests that the site of the lesion is important as regards PIIINP expression. The release levels in three consecutive determinations before clinical relapse process of PIIINP into the blood stream may differ between was 82% for each. In 4 patients with PR and in 8 patients with tissues. In an i.p. location, ovarian cancer cells may induce a NC, CA-125 and PIIINP remained simultaneously increased highly increased turnover of type III procollagen without any all the time. detectable deposition. Accordingly, very high concentrations of PIIINP and CA-125 Concentrations at Second-Look Laparot- PIIINP were found in malignant ascitic fluid (50- to 100-fold omy. In the 8 second-look laparotomies of 5 patients (twice in higher than in serum) (14). PIIINP production may be related 3 patients) during CR, macroscopic cancer was found in 4 to the malignancy itself or to activation of fibroblasts or meso- patients, with elevated CA-125 in 3 cases and normal CA-125 thelial cells. We have also found that serum PIIINP concentra in 1 case, and elevated PIIINP in each case. Microscopic cancer tions are often increased in patients with a nongynecological was detected 3 times. CA-125 was increased in 2 of these cases intraabdominal malignancy,3 which supports the concept that (Fig. 2, middle panel), and it was normal (Fig. 2, lower panel) PIIINP is particularly useful in intraabdominal carcinomas. in one case, whereas PIIINP was increased in each case. In one case, with a pathological finding only in cytological examina tion, CA-125 was normal and PIIINP increased (Fig. 2, lower REFERENCES panel). In this case, recurrent malignancy manifested itself in 21 mo. PIIINP was thus more precise than CA-125 in 3 of 8 1. Bast, R. C, Jr., Klug, T. L., St. John, E., Jenison, E., Niloff, J. M., Lazarus, H., Berkowitz, R. S., Leavitt, T., Griffiths, C. T., Parker, L., Zurawski, V. second-look laparotomies. R., 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. 2. Niloff, J. M., Knapp, R. C., Schaetzl, E., Reynolds, C., and Bast, R. C., Jr. DISCUSSION CA 125 antigen levels in obstetric and gynecologic patients. Obstet. Gynecol., 64:703-707, 1984. This study confirmed (14) that the serum concentration of 3. Kivinen, S., Kuoppala, T., Leppilampi, M., Vuori, J., and Kauppila, A. PIIINP is commonly increased in advanced primary and recur Tumor-associated antigen CA 125 before and during the treatment of ovarian carcinoma. Obstet. Gynecol., 67:468-472, 1986. rent ovarian cancer, and that the changes in PIIINP concentra 4. Berek, J. S., Knapp, R. C., Malkasian, G. D., Lavin, P. T., Whitney, C., tions correlate with the clinical course of the disease. In this Niloff, J. M., and Bast, R. C. CA 125 serum levels correlated with second- respect the magnitude of the fluctuation in the concentration look operations among ovarian cancer patients. Obstet. Gynecol., 67: 685- 689, 1986. of PIIINP was smaller than that of CA-125. It is clinically 5. Krebs, H.-B., Goplerud, D. R., Kilpatrick, S. J., Myers, M. B., and Hunt, A. important that, in 43% of the cases, only one indicator, either Role of CA 125 as tumor marker in ovarian cancer. Obstet. Gynecol., 67; PIIINP or CA-125, was useful for clinical purposes, or there 473-477, 1986. 6. Halila, H., Stenman, U.-H., and SeppÃ¤lÃ¤,M.Ovarian cancer antigen CA 125 were other major differences between them. levels in pelvic inflammatory disease and pregnancy. Cancer (I'llila.), 57: In accordance with previous reports (1, 3, 6, 24-26), CA-125 1327-1329, 1986. antigenicity was not expressed in 13% of the cases, and the CA- 7. Schwartz, P. E., Chambers, S. K., Chambers, J. T., Gutmann, J., Katopodis, N., and Foemmel, R. Circulating tumor markers in the monitoring of 125 concentration commonly decreased to normal, months gynaecologic malignancies. Cancer (Phila.), 60: 353-361, 1987. before a clinical CR. In 3 of the 8 cases with a residual tumor 8. Rome, R. M., Koh, H., Fortune, D., and Cauchi, M. CA 125 serum levels and secondary laparotomy in epithelial ovarian tumours. Aust. NZ J. Obstet. at second-look laparotomy, CA-125 levels were normal (5, 8- Gynecol., 27: 142-145, 1987. 10). Hence, during the regressive or silent state of ovarian 9. Patsner, B., and Day, T. G. Predictive value of CA-125 levels in advanced cancer, CA-125 appears to be an inaccurate indicator of the ovarian cancer. Am. J. Obstet. Gynecol., 156: 440-441, 1987. 10. Alvarez, R. D., To, A., Boots, L. R., Shingleton, H. M., Hatch, K. D., presentation of this malignancy. PIIINP was always correctly Hubbard, J., Soong, S. J., and Potter, M. E. CA 125 as a serum marker for positive at the second-look laparotomies, and it normalized poor prognosis in ovarian malignancies. Gynecol. Oncol., 26:284-289,1987. 11. Duk, J. M., Aalders, J. G., Fleuren, G. J., and de Bruijn, H. W. A. CA 125: only in two patients before the clinical CR. On the other hand, a useful marker in endometrial carcinoma. Am. J. Obstet. Gynecol., 155: in this and previous (3-5, 10) studies, CA-125 sensitively de 1097-1102, 1986. 12. Pittaway, D. E., and Fayez, J. A. The use of CA-125 in the diagnosis and tected silent progression of ovarian cancer, as also did PIIINP. management of endometriosis. FÃ©rtil.Steril., 46: 790-795, 1986. The present results also showed that CA-125 and PIIINP complemented each other in some serous adenocarcinomas and 3 Unpublished data. 1888

13. Kauppila, A., Telimaa, S., RÃ¶nnberg,L., and \ non. J. Placebo-controlled 20. Risteli, L., and Risteli, J. Radioimmunoassays for monitoring connective study on serum concentrations of CA-125 before and after treatment of tissue metabolism. Rheumatology, 10: 216-245, 1986. endometriosis with danazol or high-dose medroxyprogesterone acetate alone 21. Risteli, L., Puistola, U., Hohtari, H., Kauppila, A., and Risteli, J. Collagen or after surgery. FÃ©rtil.Steril., 49: 37-41, 1988. metabolism in normal and complicated pregnancy: changes in the aminoter- 14. Risteli, L., Kauppila, A., MÃ¤kilÃ¤,U.-M., and Risteli, J. Aminoterminal mmal propeptide of type III collagen in serum. Eur. J. Clin. Invest.,/7: 81- propeptide of type III procollagenâ€”an indicator of intraperitoneal invasion *6< 19*7- in ovarian carcinoma? Int. J. Cancer, 41:409-414, 1988. 22- Â«'steli,J., Niemi, S., Trivedi, P., MÃ¤entausta,P., Mowat, A. P., and Risteli, 15. Hatahara, T., Igarashi, S., and Funaki, N. High concentrations of Sterminai }â€¢â€¢RaP'dequilibrium assay for the ammo-terminal propeptide of human type peptide of type III procollagen in the sera of patients with various cancers, â€ž¿Ã•l',Ã•)rOCÂ°"Tn'u n !.15-718'Â¿988- ...... wiih special reference to liver cancer. Gann, 75: 130-135, 1984. 23' Mlllfr' A" B" Hoogstraten B., Staquet, M and Winker A. Report.ng ,,..,,,_.â€ž .. , _ â€ž¿ results of cancer treatment. Cancer (Phila.), 47:207-214, 1981. 16. Van den Hooff, A. Connective tissue changes in cancer. Int. Rev. Connect. -,. ^ _. i. r T i u u j Â»Ã¬;_ Ã¹ /-i- â€¢¿iâ€¢¿-i- t lissue. Kes., 10: in 395-432,int ATI IODI1983. 24. Crombacn,antigen (CA G., 125) Zippel, in ovarian H. H., cancer. and Wurtz, Cancer H. ClinicalDetect. Prevent., significance 8: of135-139, cancer 17. Liotta, L. A. Tumor invasion and mÃ©tastasesâ€”roleofextracellular matrix: 1985 Rhodes memorial award lecture. Cancer Res., 46: 1-7, 1986. 25. Einhorn, N., Bast, R. C., Jr., Knapp, R. C., Tjerneberg, B., and Zurawski, 18. Van den Hooff, A. Connective tissue as an active participant in the process V.R. Preoperative evaluation of serum CA 125 levels in patients with primary of malignant growth. Anticancer Res., 6: 775-780, 1986. epithelial ovarian cancer. Obstet. Gynecol., 67: 414-416, 1986. 19. Verde, G. G., Santi, I., Chiodini, P., Cozzi, R., Dallabonzana, D., Oppizzi, 26. Cruickshank, D. J., Fullerton, W. T., and Klopper, A. The clinical signifi- G., and Liuzzi, A. Serum type III procollagen propeptide levels in agrome- canee of preoperative serum CA 125 in ovarian cancer. Br. J. Obstet, galic patients. J. Clin. Endocrinol. Metab., 63: 1406-1410, 1986. Gynaecol., 94: 692-695, 1987.

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Antti Kauppila, Ulla Puistola, Juha Risteli, et al.

Cancer Res 1989;49:1885-1889.

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