Bionzed & Pharnzacotlzer( 1992) 46,453-464 0 Elsevier,Paris

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Dossier Management of patients with ovarian cancer lusing monoclonal antibodies S Lastoria’ , N Panza’, G Esposito’, E vegara’ , L Castelli* , C Caracb’, C Battista’, G Pacilio*, M Salvatore’ ‘~e~~~~,~entsof nuclei medicine, Nat~onai Cancer Institute “G. Parfaie”, University2nd Pdedical School “Federico II” -Napoil: %nroiog~ Branch CardarelliHospital Napoli. Naples, Italy (Received 1 October 1992: accepted 2 November 1992)

Summary - We describe in detail the current trend using monoclonal antibodies to diagnose ovarian cancer either in vitro or in vivo. The approach with such powerful reagents allows to differentiate in virro tumor histotypes and to detect in peritonea1 washings the presence of a few neoplastic cells which characterize the minimal disease. The detection of elevated sera levels of ovarian cancer-associated antigens, such as CA-125 and TAG-72, allows the monito~ng, follow-up of these patients and the response to therapy with great accuracy. We focused our attention on the role in vivo of iabeffed monoclonaf antibodies, mainly for diagnostic purposes. Radioimmunoscintigraphy has been found to be more reliable than CT and US to detect foci of disease mainly in patients already treated by surgery, overcoming all the problems usually encountered with these two procedures, radioimmunoscintigraphy I monoclonal antibodks I ovarian tumor Rhmt? - Utilisation des aoticotps monuclonaux dans le cancer de I’owire. Nous dkcrivons en ditaif la mgthode cozzrante qui utilise les ~z~corps mo~oc~o~~ pour le diagnostic in vitro ou in vivo du cancer de l’ovaire. L’upproche avec de tels agents puissants pernzet de diffkrencier in vitro des histotypzs tunzoraux et de localiser dans ie lavage du peritoine fa presence de petites quantitb de celizdes neoplasiques qui caract&risent la nzaludie mininzak rrisiduelle. La d&e&on de niveaux PIeves d’antig&zes associ&s au cancer de i’ovaire tel que CA 125 et TAG 72 permet la surveillance de la maladie et la re’ponse d la th&apie avec une tris botzne pr&ision. &j&z. nous concentrons notre attention sur ie rcite in vivo des anticorps nzonoclona~ nzarqzks principuLenzent d des fins diagnosziques. La radio-imm~oscientigraph~, en eflet. s’est rev&&e plus s&e que fe scanner et I’&bogruphie, principalement dans in iocuiisation des foyers de maiadte chew les patients deja trait& par la chirurgie, surmontant ainsi IOUSles problemes fr6quemment rencontrks avec ces deux merhodes.

mdioimnucnoscinriie

/ anticorpsmonoclonaux/ cuncer de I’owire

The production of monoclonal antibodies (MAbs) has provided a large number of new specific reagents for investigations in cancer research, where clinical applications of this technique are rapidly being applied. Since Rohler and Milstein [40], in 1975, introduced the MAb technology, the field of tumor immunology has been revolutionized. In fact, it has been possible to identify, define and bind, in vitro and in viva, tumor associated antigens

(TAAs). The majority of TAAs, so described, have been found to express different malignancies and in tracer amounts by normal adalt tissues. Over the last decade, MAbs reactive with ovarian TAAs have been generated [2,8,54, 551; their reactivity has been evaluated, and clinical applications (either in vivo or in vitro) have been developed. At present, the applications of MAbs in the diagnosis and investigation of ovarian cancer are directed in four directions: immunohistology, immunocytology, serology for screenand nuclear medicine. ing and follow-up,

ovarian Radioimmunodetection of epithelial tumor-sites using labelled MAbs has been widely investigated, showing elevated levels of sensitivity and specificity rather than in other tuirors (melanoma, colon, gliomas) 113, 24, 29, 42. 51, 561. In addition, radioimmunotherapy with elevated doses of radioactivity bound to MAbs, mainly using the intraperitoneal route of administration, has been attempted showing some advantages ve.+-sus other common strategies. In the present report, we outline the major advances made in the diagnosis and follow-up using MAbs directed toward ovarian cancer TAAs, focusing our interest both in vitro or in vivo appli-. cations, mainly in radioimmunodetection.

vitro al

Kcatiois:

histop

The histological diagnosis of ovarian cancer, based upon cellular morphology and features, is quite easy. However, two problems can be encountered by pathologists. The first is the differential diagnosis of lymphomas, sarcomas of soft tissues and anaplastic ovarian tumors; the second is to differentiate patients with diseminated intraabdominal tumors and normal ovaries. The diagnosis between primary ovarian tumor and metastatic disease from other common epithelial tumors is important to address in order to have the most specific and sensitive plan of chemotherapy. Common epithelial

and vimentin in the stromal counterpart of mixed tumors (desmin is mainly exprecsed irk sarcomatsus areas). Table I summarizes the characteristics of the most frequently used MAbs in ovarian cancer diagnosis. They have been classified into two with nongroups: Group 1, MAbs reactive mutinous common epithelial tumor types (ie OC125, OC-133, etc) and Group 2, MAbs reactive with mutinous tumors (ie ID3, ID5, etc). However, overlapping between these two groups is common. In addition, other MAbs are reactive with different epithelial malignancies (ie B72.3, CEA, HMFGl and 2 etc). Carcinoembryonic antigen. Immunocytochemical analysis of CEA may, under some circumstances, aid the differential diagnosis, although it has been shown that CEA is neither organ nor tumor specific [15]. CEA has been found in all common epithelial tumors apart from serous and undifferentiated carcinomas. Benign, borderline lesions and mutinous tumors most frequently contain CEA. However, the distribution of this antigen in benign lesions and Brenner’s tumor is significantly lower than that found in neoplastic counterparts. The distribution into cells differs: in benign lesions, CEA is localized on the luminal surface of epithelial cells, while in malignant lesions it is more often distributed in the cytoplasm [21].

TAAs Table I. Monoclonal antibodies

Intermediate filaments intermediate-sized filamenis nave been classified, according to their molecular weight, number of polypeptides and immunological reactivity, into five distinct sui,groups: cytokeratins, desmin, vimentin, glial fib,bhllary acidic protein, and neurofilaments [41]. Cytokeratins have strictly been found in epithelial cells. Ganjei et al [25] demonstrated that a strong immunoreactivity was limited, using non pre-digested paraffinembedded sections, to Brenner’s tumors, the squamous component of endometrioid carcinoma and carcinosarcoma. Nagle et al [45], using frozen sections, demonstrated localized cytokeratins in all the common types of epithelial ovarian tumors. Other authors [9] were able to localize cytokeratins in epithelial components and desmin

reactive

with ovarian

tumors. MOAhS oc- 125 oc-133 BC-2

ID 3 ID 5 B72.3 NDOG2 CA 19.9 OWL 3 HMFG 1-2 MOv-18 A-EGF

Reactive

Antiaens

Kda gp 50 Kda gp Tenascin Unknown Unknown IO6 Kda gp 69 Kda PALP Mucin Unknown HMFG 38 Kd gp EGFr 200

Istotwe

Non mutinous Mutinous Mutinous/Non mutinous

Kda = kilodalton; gp = glycoprotein: PALP = placental alkaline phosphatase; HMFG = Human milk fat globule; EGFr = EpidermalGrowth Factor Receptor.

455 Amylase. Anti-amylase Mabs are able to detect this antigen in ovarian serous carcinoma, carcinomas of the fallopian tubes and serous papillary carcinomas [30]. Myoglobin. The detection of this antigen may be useful in evaluating heterologous skeletal muscle elements in mixed mesodermal tumors [43]. Ovarian TAAs. CA- 125 glycoprotein (expressed by serous, endometrioid and clear cell neoplasms) is identified by OC- 125 MAb (2). CA-I 25 is not expressed by mutinous histotype. Conversely, Bhattacharya et al [7, 81 have developed a MAb reactive with an antigen expressed only by mutinous tumors of the ovary. Recently, antiTAG-72 (tumor associated glycoprotein 72) and anti-EGFr (epidermal growth factor receptor)

have been used in the diagnosis and characterization of epithelial tumors. Results obtained by our group using B72.3 in a series of 47 specimens (14 removed from patients with benign and 33 with malignant ovarian lesions), showed a sensitivity of 92% in malignant biopsies, while only 15% of benign lesions were positive. The reactivity ranged from 4 to 90% of neoplastic cells for each individual biopsy. A faint positivity was also found in normal ovarian tissues within corpora albicantia. Additional studies of immunocytochemistry, according to I-Isu’s method [38], were performed on ascites from 12 cases, demonstra!ing that only neoplastic cells expressed TAG-72, while macrophages, lymphocytes and mesothelial cells were negative. The use of flow-cytometry (FC) allows to quantify the antigcnic status of neop!astic cells in fluid collections. In our experience, the number of cells TAG-72 positive in ascites, collected from seven consecutive patients, varied from 29 to 96% [43]. This evidence may suggest that FC should be performed as a preliminary procedure to select the best MAb to use in viva for radioimmnpiodiagnosis or radioimmunotherapy as well as to measure the effect of biological response modifi-

I:

Nanomoleslliter

Fig la. Digitized

autoradiographic image of differentiated mutinous ovarian cancer section incubated with ‘?-B72.3 (83.3 nanomolesli). intense and homogeneous uptake is observed. The B72.3 binding occurs with both neopiastic foci and mucin deposits. b. A 250 x enlargement of a contiguous section stained for IP with 872.3. Positive staining for neoplastic ceil clusters. Other ceils (lymphocytes. macrophages. etc) were not stained.

Fig 2. Binding curves obtained from TAG-72 positive ovarian tumor (whose total binding image ts,;pwn in fig la). The i472.3 in incubation x-axis represents the concentration of solutions expressed as nanomoiesli. The y-axis represents the ‘%B72.3 bound to the tumor as pmoieslgram. (0) is the total binding (TB) of ‘z5i-872.3 to the tissue; (v) is the nonsaturab)e binding (NSB) and (--) represents the specific binding obtained subtracting the NSB from the TB curve. (nlnxB = 260 pmoies:g; Ka 1.6 x IO’).

4.56 en tie interieukins, interferons, on the antigenic expression.

growth factors)

Guadagni tit 01 [31] have, for instance, demonstrated the upregulation of TAG72 after stimulus with alfa, beta and gatiiha interferons, on the surface of neoplastic colonic, pancreatic and ovarian human cells from ascites. These data suggest that a significant improvement of tumor targeting by means of MAbs can be achieved stimulating the antigenic over-expression. While immunohistochemistry represents a qualitative, at maximum a semiquantitative technique able to detect the expression of target TAAs in tumor biopsies, in vim quantitative autoradiography (IV-QAR) allows to exactly determine the molar concentration of such antigens. Two major advantages have been .achieved with IV-QAR: of TAAs expressed in ij the assessment pmoleslgram of tissue, ii) the determination of the aliquot of MAb specifically bound to the tissues with relative affinity constant (Ka). This technique is based on the incubation of contiguous 8 pm sections from frozen tissues with increasing solutions of MAb I-12%labe!led with or without a lOO-fold excess of unlabelled MAb. After the saturation study, the sections are exposed together with standards of I-125 (known activities, measured by gamma spectroscopy) with single coated, hypersensitive X-ray films. The optical densities (ODs) of standards, measured by a dedicated video-camera, were plotted against their specific activities, and a standard curve was obtained. Then, the ODs within sections were measured and the activities in pCi/g directly obtained. In figure 1 a a digitized image of IV-QAR is shown; where I-125 B72.3 binding to ovarian carcinoma is well depicted. In figure lb a contiguous IP stained section further confirms the binding of B72.3’ to neoplastic cells, while lack of reactivity with lymphocytes and macrophages infiltrating the tumor nodule is demonstrated. In figure 2 the typical curve obtained fitting experimental points allows to determine Ka and Bmax of the B72.3 with the tumor. A more precise characterization in the identification of MAbs to use in vivo can be attempted using the IV-QAR: ij The number of antigenic molecules within tumors’ tissues represents a key factor for in vivo specific tumor targeting and ii) the target antigen selected with relative specific MAb should be selected on the basis of the frequency of expression in molar concentrations greater than 30 pmoles/g. Finally, IV-QAR

shows, versus biochemical techniques, two advantages: it does not overestimate antigenic content and it gives the exact distribution of positive tumor cells with respect to section-architecture. However, this technique is not widely used, being performed only by a few experienced laboratories.

In vitro applications:

serum markers

Several TAAs have been proposed as good markers for patients with ovarian tumors, in order to make a diagnosis and/or for monitoring. However, no TAA has been demonstrated to be useful and sensitive for screening tests in ovarian tumors.

Fig 3. Correlationof clinical status of disease and circulating levels of CA-125 Regressionof the disease was assumed as the lack of signs (complete remission: CR) a reduction of more than 50% of tumor size without increase of lesions (partial remission: PR). Progression of the disease (PD) was assumed as the increase of the tumor size > 25% of new lesions.

457 Prospective studies demonstrated that CEA and bHCG were neither sensitive nor specific as markers for ovarian tumors. Panza et, al 1471 demonstrated that the use of these two markers in ovarian cancer is unacceptable. In fact, raised levels of CEA and P-HC6 bHCG were respectively measured in 25 and 5% of 56 patients with active disease. In 1983, Bast et ai [3] introduced the determination of a glycoprotein ovariantumor-associated, termed Cancer Antigen- I25 (CA-125). This antigen is recognized either in the serum or in other body fluid coIIection by OC-125 and its results are expressed only by epithelial non-mutinous ovarian histotypes.The cut-off usually used for the CA-125 has been fixed at 35Wml and has been determined using a control group of healthy patients. The levels of CA-125 measured in patients with ovarian tumors were greater than the cut-off limits. Relationships between serum CA-125 values and clinical trend of disease have also been demonstrated (fig 3): decreasing levels of CA-125 corresponded to clinical regression. Conversely, raised levels of CA-125 corresponded to progression of disease. In addition, in many patients, elevation of CA-125 occurred several months before the onset of clinical symptoms of neoplastic disease [lo, 12, 39, 46, 471. However, the main feature of CA-125 seems to be the monitoring of response to the therapy and the early diagnosis of recurrence aiter complete remission (fig 4). It remains to be assessed what the role of this tumor marker is in screening tests for early diagnosis of ovarian cancer [lo, 461 and to differentiate tumors of unknown origin [46] involving ovaries. Moreover, increased levels of CA-125 have been found in non-neoplastic conditions: menstruation [SZ]. pregnancy [32], peritonitis [50] and non-neoplastic ascites [6]. Thus, in patients with minimal disease, laparoscopy with peritoneal washing is required to differentiate between minimal disease and clinical remission. Studies have also been performed measuring serum levels of CA-19.9 111, 343, CA-15.3 f33, 351, ferritin and recently TAG-72 [22, 23). Preliminary data failed to demonstrate the useful role of these markers in patients with small primary tumors or minimal disease. At present, our experience is restricted to the use of ferritin, CA 15-3 and TAG-72. No satisfactory results have been determined measuring ferritin. In fact, high leveis of this TAA have been observed in patients with long-term clinical remission. One of the causes of these disappointing results is due to the

use of heteroantisera against a pool of isoferritins. Recent studies showed that acidic ferritins are more strictly related to malignancies than the basic forms. Thus, this marker in ovarian cancer could be reproposed and reiaves:igazed. in 47 patients with active ovarian cancer and in 15 patients in clinical remission, CA-153 was titred using an IRMA assay. This marker was less sensitive than CA-125. In addition, no significant synergism between these two TAAs was found in our series. The association of two or more TAAs has been proposed to improve the sensitivity and specificity of the test [4, 5, 23,231. Mabs OC-125 and OC 19-9 and CEA did not offer satisfactory results, probably because OC-125 and 19-9 are reactive with two different epitopes of the same gl~coproteic antigen 14, 51 and the low rate of incidence of mutinous type can be taken into account. On the other hand, interesting results have been obtained by measuring both CA-125, NB170K (a TAA purified from epithelial ovarian cancer, investigated by Bast and his group) antigens. Finally, the assay of TAG-72 seems to have a clinical impact alone or in association with CA125 for a more complete management of patients with ovarian cancer [20]. Radioimmunoscintigraphy

The basic principle of radioimmunoscintigraphy (RIS) is based on i) in vivn administration of labelled MAbs direct against TAAs expressed on the neoplastic cell surface and, ii) tbe specific binding of MAb with the target TAA. The availability of MAbs reactive with TAAs hardly expressed by tumors and not expressed by normal tissues created the theoretical conditions to visualize, by external gamma, imaging tumors in humans. Pioneering studies using ~lyclonal antibodies were performed in the early ’60s with controversial results [26, 27, 361. The development of hybridoma technology and subsequently of molecular biology provided murine and human/chimeric MAbs that are currently used, ensuring lars,e amounts of homogenous and highly reactive reagents. Iodine isotopes (I-123 and I-131) have been used to label the IgGs, using mild chemical reagents to avoid the lack of immunoreactivi~ of MAb. Afterwards. techniques to couple radiometals to these proteins were developed and fndium- 111 (In-l .t1) or Technetium-99m (Tc-99m) were introduced. The main advantages of Tc-99m and In-l 11 are rep:esented by the favorable gamma emission for imaging

458 CUNICAL EVIDENCE OF DISEASE

/ml)

SECOND LOOK

700

MDENCE OF DISEASE AT RADIO-IMMUNOSCINTIGFlAPHY I

F

CUNICAL EVIDENCE

CUNICAL EVIDENCE OF DISEASE RADIOLOGICAL

300

100 35 300 200 100 35

CHEMOTHERAPY

13

5

7

9

11

13

13

5

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13

Fig 4. Serial determinations of CA-125 in eight patients in CR, who had recurring ovarian carcinoma during follow-up. In the majority of cases, raised CA-125 levels preceded clinical evidence of disease (symptoms, imaging findings).

459 with a significant reduction in the length of the studies. Systemic and intraperitoneal (IP) routes of injection have been used to administer labelled MAbs. The rationale for the IP administration is based on the spreading of ovarian tumor which frequently occurs in the peritoneal cavity and the advantages on tumor/non tumor ratios which can be achieved lowering the radiation dose to healthy organs and tissues. Several studies have been performed with different MAbs and isotopes [14, 28, 37, 48, 531. The main results can be summarized as follows: i) high levels of sensitivity and specificity obtained, greater than 80%; ii) high levels of percentage of injected dose bound to tumors if compared with those measured in melanoma, coion iymphoma and other human malignant tumo& iii) ability ;o demonstrate occult lesions (peritoneal cakes, nodules etc) missed by ultrasounds (US) and computed tomography (CT). English groups focused their studies on MAbs reactive with antigens expressed on human milk fat globules (HMFGl and 2) labeled with I-123 and 131 and In-l 11 demonstrating sensitivity greater than 80%. Granowska et al [28], using a computerized program of acquisition were able to create a probability map based upon mathematical analysis of the MAb kinetics in the body during the entire study.This approach allowed to diagnose subclinical lesions missed by other imaging modalities and definitely confirmed by secondlook laparotomy. Perkins et al [49] and Dutin ef al [19] tested in vivo the clinical role of “‘In OC-125 F(ab’)2, in the diagnosis of ovarian cancer, mainly for the detection of lesions missed by US and CT. In addition, they proved the further diagnostic imemission single-photon using provement tomography to detect lesions smaller than 1 cm in diameter. From a clinical point of view, the remarks with GC-125, in 47 pathis in fC~!C’A’-OF for ovarian can.cer, demonstrated that RIS had higher sensi;ivity and specificity rather than US and CT [191. Thus, a patient with a negative RIS had a high probability of being disease-free; in fact, negative predictive value (NPV) was greater than 80% while if CT and US were negative, a recurrence cannot be excluded (NPV c 80%). Furthermore, the most accurate staging of these patients occurs adding the information obtained by RIS with that from CT. Thus, the RIS should be included in the diagnostic strategy of ovarian cancer recurrence.

Similar results have been obtained in our institutions using B72.3 MAb labelled with I-131. B72.3 [42, 431 reacts with both mutinous and non mutinous ovarian tumors, while it is not reactive with normal ovary, benign lesions, mesothelial cells, lymphocytes and macrophages in ascites. We have studied 27 patients with active disease (20 papillary serous, two mutinous, three endometrioid and two undifferentiated carcinomas) and seven disease-free. A sensitivity of 34% was recorded in the detection of abdominal lesions with or without concomitant ascites. No false positive lesions were depicted. In figures 5 and 6, examples of ovarian tumor detection are shown. Intraperitonea! studies were performed by Colcher et al [ 161 to evaluate the advantage of IP route of administration versus the systemic one. The study was designed injecting intravenously I125 B72.3 and intraperitoneally I-131 B72.3 to measure the percentage of both preparations bound to tumors. In 65% of lesions (total = 33)

Fig 5.

Posterior view of the abdomen 120 hours after injection of “‘In B72.3. In an asymptomatic patient, whose eraminations werenegative (CT, US and CA-125 assay), uptake of 872.3 clearly shows a tumor nodule over the dome of the bladder. The involvement was subsequenily confirmed at secondlook surgery.

patients and can ensure elevated % ID of radioactivity and the role that RIS can have in the assessment of therapy.

Conclusion

Fig 6. Anterior view of the abdomen and pelvis showing a large mass in the left iliac fossa, due to recurrent ovarian carcinoma involving bowel and peritoneum, with intense uptake of “‘In-B723 (Image performed 48 h after injection).

the percentage of uptake was greater for IP administered MAb; in 10% was equal and in 25% was greater for intravenously injected MAb. The approach of IP route demonstrated that the percentage of injected dose bound to tumors was greatly affected by the tumor size [14]. In fact, in lesions greater than 2 cm, the levels of radioactivity were realistically low (O.OOl-O.O03%ID), increasing up to 0.01 for lesions < 2 cm and up to 0.4-2.2%ID for cell clusters. This evidence leads to positive speculation in therapy using beta minus radionuclides such as Yttrium-90 1371 or the synergism with biological response modifiers to upregulate the antigenic overexpression [31]. Recently, a new MAb has been under investigation by Italian groups. The MOv-18 MAb [ 1, 17, 181 recognizes a 38 Kd protein which binds to folate. Thus, this TAA is termed folate binding protein (FBP) [ 171. The results are very promising [18] because the high FBP levels in tumors could affect the assessment of the therapy in these

The use of MAbs, in the last decade has drastically modified the diagnosis of ovarian cancer either in vivo or in vitro. Immunohistochemistry as well as cytocbemistry enabled us to better define tumor histotypes, mainly in the diagnosis of borderline cases. By means of these techniques, the examination of peritoneal washings and/or ascites often enables the differentiation between patients with microscopic residual disease and previously treated disease-free patients. Thus, it has been possible to detect subclinical disease; allowing therapeutic regimens to be effective when tumor-nodules have small sizes. In addition, serum markers’ monitoring (mainly CA-125 and TAG-72) represents a sensitive approach to the diagnosis of rerurrences or advanced primary tumors (stage III and IV according to the FIG0 Classification) as well as following the response to therapy. However, the exact location of tumor sites is a basic requirement to specifically address the therapy. A number of Techniques are currently employed for the diagnosis and follow-up of patients with ovarian cancer Recent studies comparing results by US with the operative and pathological findings of patients harbouring ovarian tumors with results have shown that correct staging occurred in only 48%. In particular, US has serious limitations in the detection of lymphoadenopathy and serosal metastases. The limitation in detecting peritoneal and omental metastases is shared by CT, which is also unable to differentiate between benign ovarian masses and Stage I cancer, and between post-surgical fibrosis and recurrence. The main difficulty in assessing CT images of patients with recurrent disease is due to the macroscopic abnormality in the pelvic anatomy resulting from previous surgery. On this basis, the introduction of labelled MAbs opened new horizons in the diagnosis of the patients with ovarian cancer. The RIS is not affected by concomitant ascites, and further. the use of alternative routes of injection improves the capability to visualize the peritoneal cakes which escape to CT and US imaging for their thickness. Positive RIS has been documented in patients with negative serum markers. Drawbacks for RIS are the use of isotopes with long half life lie

461 1i 13 1) that prolonged the study to seven days and the production of human anti-mouse antibodies (HAMA). The advent of ggmTc-labelIed MAbs, the use of SPECT, the use of chimeric MAbz or single-chain binding antigen should allow us to overcome these problems increasing the potentiality of tumor targeting with MAbs.

and in combination with CA 125. Br J Cancer 52, 131 l2 Chatal JF, Ricollean G, Fumoleau P et ai (1983) Radioimmunoassay of the CA-125 antigen in epithelial 'ovarian carcinomas. Cancer Defect prev 6, 624 l3 Chatal JF, Fumoleau

P, Saccavini

JC er al (1987)

Immunoscintigraphy of recurrences of gynwologic carcinomas. J Nucleic Med 28, 1807

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Management of patients with ovarian cancer using monoclonal antibodies.

We describe in detail the current trend using monoclonal antibodies to diagnose ovarian cancer either in vitro or in vivo. The approach with such powe...
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