Incidence of lymph node metastases in clinical early-stage mucinous and seromucinous ovarian carcinoma: a retrospective cohort study.

OBJECTIVE: The use of lymph node sampling during staging procedures in clinical early-stage mucinous ovarian carcinoma (MOC) is an ongoing matter of debate. Furthermore, the incidence of lymph node metastases (LNM) in MOC in relation to tumour grade (G) is unknown. We aimed to determine the incidence of LNM in clinical early-stage MOC per tumour grade. DESIGN: Retrospective study with data from the Dutch Pathology Registry (PALGA). SETTING: The Netherlands, 2002-2012. POPULATION OR SAMPLE: Patients with MOC. METHODS: Histology reports on patients with MOC diagnosed in the Netherlands between 2002 and 2012 were obtained from PALGA. Reports were reviewed for diagnosis, tumour grade and presence of LNM. Clinical data, surgery reports and radiology reports of patients with LNM were retrieved from hospital files. MAIN OUTCOME MEASURES: Incidence of LNM, disease-free survival (DFS). RESULTS: Of 915 patients with MOC, 426 underwent lymph node sampling. Cytoreductive surgery was performed in 267 patients. The other 222 patients received staging without lymph node sampling. In eight of 426 patients, LNM were discovered by sampling. In four of 190 (2.1%) patients with G1 MOC, LNM were present, compared with one of 115 (0.9%) patients with G2 MOC and three of 22 (13.6%) patients with G3 MOC. Tumour grade was not specified in 99 patients. Patients with clinical early-stage MOC had no DFS benefit from lymph node sampling. CONCLUSIONS: LNM are rare in early-stage G1 and G2 MOC without clinical suspicion of LNM. Therefore, lymph node sampling can be omitted in these patients. TWEETABLE ABSTRACT: Lymph node sampling can be omitted in clinical early-stage G1 and G2 mucinous ovarian cancer.

High levels of soluble MICA are significantly related to increased disease-free and disease-specific survival in patients with cervical adenocarcinoma.

Downregulation of major histocompatibility complex class I chain-related molecule A (MICA) and upregulation of human leukocyte antigen G (HLA-G) on the tumor cells are important immune escape mechanisms for different epithelial tumors. In addition, upregulation of the soluble forms of the latter molecules in serum leads to peripheral T-cell and natural killer (NK)-cell tolerance. As for cervical cancer, it remains unknown whether soluble MICA (sMICA) and soluble HLA-G (sHLA-G) concentrations are related to tumor characteristics or patient survival rates. We measured sMICA and sHLA-G in pre-treatment sera of a large cohort of cervical cancer patients (n = 366) by enzyme-linked immunosorbent assay (ELISA). We detected a median sMICA of 174.73 pg/ml and a median sHLA-G of 5.35 U/ml. We did not find an association between sHLA-G levels and clinicopathological characteristics. In adenocarcinoma, low sMICA concentration was positively related to recurrent disease, a higher International Federation of Gynecology and Obstetrics (FIGO) stage and vaginal involvement (Mann-Whitney U-test; P = 0.018, P = 0.042 and P = 0.013, respectively). In the latter patient group, high sMICA levels were associated with better disease-free survival (DFS) and disease-specific survival (DSS) (P = 0.011 and P = 0.047). After adjusting for confounding factors, high sMICA proved to be an independent predictor for a better DFS and DSS [HR 0.16; 95% confidence interval (CI) 0.04-0.64; P = 0.009 and HR 0.12; 95% CI 0.03-0.50; P = 0.004]. sHLA-G did not influence survival in cervical cancer patients, regardless of histology. We conclude that cervical adenocarcinoma patients with high sMICA levels have an increased DFS and DSS. This data warrants a prospective trial to study the functional role of sMICA in cervical adenocarcinoma.

Development and internal validation of a prognostic model for survival after debulking surgery for epithelial ovarian cancer.

OBJECTIVE: Predicting survival of patients with epithelial ovarian cancer (EOC) is based on prognosis of the population. Combining prognostic factors could facilitate survival prediction on the level of the individual patient. The aim of this study was to develop a prognostic model to predict five-year disease specific survival in patients with EOC, and to evaluate whether this would add to prediction based on prognosis of the population. PATIENTS AND METHODS: A retrospective cohort study was performed of all EOC patients treated with primary debulking and adjuvant chemotherapy or neo-adjuvant chemotherapy and interval debulking surgery in three gynaecological-oncologic centres between 1998 and 2010. Primary outcome was 5-year disease-specific survival. We developed a Cox proportional hazard model using the LASSO-method to select the best combination of characteristics from 12 potential predictors and to correct for overfitting. Performance of the model was expressed as calibration and discrimination (c-statistic). A nomogram was developed to increase the clinical applicability of the model. RESULTS: Of 840 patients with EOC 462 (55%) died within 5 years due to the disease. A combination of FIGO stage, residual tumour after surgery, primary or interval surgery, histology, performance status, age, amount of ascites and a family history suggestive of breast/ovarian cancer best predicted 5-year survival. The final model showed accurate calibration and the c-statistic was 0.71 (95% CI 0.69-0.74). CONCLUSIONS: Five-year survival in all stage EOC patients can be predicted accurately using available characteristics. After external validation the model can be used for counselling of patients.

Genetic counseling of patients with ovarian carcinoma: acceptance, timing, and psychological wellbeing.

The new Dutch guidelines on hereditary and familial ovarian carcinoma recommend genetic testing of all patients with epithelial ovarian cancer (EOC). With this study, we aimed to obtain insight into (1) the acceptance and timing of the offer of genetic counseling in women with EOC, (2) reasons for accepting or declining genetic counseling, and (3) psychological differences between women who did and did not have genetic counseling. A multicenter questionnaire survey was performed in patients with EOC in four Dutch oncology centers. The questionnaire addressed whether, how, and when genetic counseling was offered, women's arguments to accept or decline genetic counseling, and included the Cancer Worry Scale (CWS) and the Hospital Anxiety and Depression Scale (HADS). A total of 67 women completed the questionnaire, of which 43 had genetic counseling. Despite a wide variability in the timing of the offer of genetic counseling, 89% of the women were satisfied with the timing. No significant differences were found between the CWS and HADS scores for the timing of the offer of genetic counseling and whether or not women had genetic counseling. Taking the small sample size into account, the results tentatively suggest that genetic counseling may have limited impact on the psychosocial wellbeing of women with EOC. Therefore, we assume that implementation of the new guidelines offering genetic counseling to all patients with EOC will not cause considerable additional burden to these patients.

Transient inhibition of Calyculin A induced premature chromosome condensation by hyperthermia.

The analysis of chromosomal aberrations by premature chromosome condensation (PCC) induced by Calyculin A (Cal) is feasible in tumor biopsies from patients and has the potential to predict sensitivity to radiotherapy. As hyperthermia (HT) improves radiotherapy outcome in certain tumor sites, it was investigated whether PCC induction is still possible after temperatures reached in the clinic. Human cervical carcinoma (CaSki) and lung carcinoma (SW-1573) cells were incubated with Cal to induce PCC immediately after 1 h treatment at temperatures ranging from 41 degrees C to 43 degrees C and after recovery for up to 24 h after treatment with 43 degrees C. Levels of phosphorylated Cdc2 (at the Tyr15 residue), histone H3 (at the Ser10 residue) and Cyclin B1 were investigated by immunoblotting. The amount of cells positive for phosphorylated histone H3 was determined by flow cytometry. Temperatures > or =42.5 degrees C inhibited the induction of PCC by Cal, while recovery of PCC-induction was observed at >20 h after treatment in both cell lines. The phosphorylation status of Cdc2 as well as of histone H3 in cells treated with Cal directly after HT at 43 degrees C was similar to that of cells treated with Cal alone or treated with Cal 24 h after HT at 43 degrees C. HT alone did not affect the levels of phosphorylated Cdc2, while phosphorylation levels of histone H3 were increased as compared with control status of these two proteins. Phosphorylated and total Cyclin B1 levels were not influenced by any of the treatments. Flow cytometric analysis confirmed that HT at 43 degrees C did not interfere with phosphorylation of histone H3. Our data indicate that HT transiently inhibits PCC induction by Cal in a temperature-dependent manner. Therefore, an interval of at least 24 h after HT should be applied before taking tumor biopsies for karyogram analysis of patients treated with temperatures above 42.5 degrees C.

Intestinal handling-induced mast cell activation and inflammation in human postoperative ileus.

BACKGROUND: Murine postoperative ileus results from intestinal inflammation triggered by manipulation-induced mast cell activation. As its extent depends on the degree of handling and subsequent inflammation, it is hypothesised that the faster recovery after minimal invasive surgery results from decreased mast cell activation and impaired intestinal inflammation. OBJECTIVE: To quantify mast cell activation and inflammation in patients undergoing conventional and minimal invasive surgery. METHODS: (1) Mast cell activation (ie, tryptase release) and pro-inflammatory mediator release were determined in peritoneal lavage fluid obtained at consecutive time points during open, laparoscopic and transvaginal gynaecological surgery. (2) Lymphocyte function-associated antigen-1 (LFA-1), intercellular adhesion molecule-1 (ICAM-1) and inducible nitric oxide synthase (iNOS) mRNA as well as leucocyte influx were quantified in non-handled and handled jejunal muscle specimens collected during biliary reconstructive surgery. (3) Intestinal leucocyte influx was assessed by 99mTc-labelled leucocyte single photon emission computed tomography (SPECT) - computed tomography (CT) scanning before and after abdominal or vaginal hysterectomy. RESULTS: (1) Intestinal handling during abdominal hysterectomy resulted in an immediate release of tryptase followed by enhanced interleukin 6 (IL6) and IL8 levels. None of the mediators increased during minimal invasive surgery except for a slight increase in IL8 during laparoscopic surgery. (2) Jejunal ICAM-1 and iNOS mRNA transcription as well as leucocyte recruitment were increased after intestinal handling. (3) Leucocyte scanning 24 h after surgery revealed increased intestinal activity after abdominal but not after vaginal hysterectomy. CONCLUSIONS: This study demonstrates that intestinal handling triggers mast cell activation and inflammation associated with prolonged postoperative ileus. These results may partly explain the faster recovery after minimal invasive surgery and encourage future clinical trials targeting mast cells to shorten postoperative ileus.

Kinetics and tissue distribution of the radiolabeled chimeric monoclonal antibody MOv18 IgG and F(ab')2 fragments in ovarian carcinoma patients.

Twenty-four patients suspected of having ovarian carcinoma received i.v. injection with a combination of radiolabeled intact IgG (1 mg) and F(ab')2 fragments (1 mg) of the chimeric monoclonal antibody MOv18, each form labeled with 1.85 MBq 131I or 125I. Laparotomy was performed either 2 or 6 days after injection, and the uptake of radioactivity was determined in a total of 329 biopsies of normal and malignant tissues. The mean elimination half life in plasma of cMOv18 IgG and F(ab')2 was 70 +/- 8 (SD) and 20 +/- 5 h, respectively. The mean uptake of IgG in tumor biopsies was 3.6-fold higher two days after injection and 6.9-fold higher than the uptake of F(ab')2 6 days after injection. Uptake in normal tissues was 3.3 and 5.5 times higher for IgG at 2 and 6 days, respectively. Two days after injection, the mean ratio of the uptake in tumor:normal tissue/patient was 3.8 +/- 1.5 and 4.0 +/- 1.8 for radiolabeled cMOv18 IgG and F(ab')2, respectively. Six days after injection, this was 6.7 +/- 4.7 for Ig G and 5.7 +/- 4.1 for F(ab')2. cMOv18 IgG has a longer circulation time in blood, a higher uptake in tumor and normal tissues, and a longer retention time compared to the F(ab')2 fragments. However, the tumor:normal tissue ratios are similar. The results do not warrant a definite conclusion as to which antibody form is most suitable for therapeutic application of antibodies but provide a more firm basis for rational design of therapeutic targeting studies using immunoconjugates.

Experimental and clinical analysis of the characteristics of a chimeric monoclonal antibody, MOv18, reactive with an ovarian cancer-associated antigen.

Monoclonal antibody (Mab) MOv18 preferentially reacts with gynecological carcinomas. We have analyzed the characteristics of murine MOv18 (m-MOv18) and chimeric MOv18 (c-MOv18). We found no differences in affinity and binding to IGROV1 cells between c-MOv18 as IgG and F(ab')2 fragments and m-MOv18. In nude mice bearing IGROV1 xenografts, maximum tumor uptake 6-15 hr after i.v. injection of radiolabeled m-MOv18 IgG, c-MOv18 IgG, c-MOv18 F(ab')2 and a control IgG, 2C7, was 10%, 11%, 3% and 4.5% of the injected dose/g (%ID/g), respectively. M- and c-MOv18 IgG retained this level for several days, while c-MOv18 F(ab')2 and 2C7 cleared rapidly from the tumor. Uptake in normal tissues was low, with the exception of high uptake in kidneys for c-MOv18 F(ab')2. Tumor/blood ratios for c-MOv18 F(ab')2 were sixfold higher than for IgG. Radiation absorbed doses to tumor tissue delivered by 10 microCi iodinated m-MOv18 IgG, c-MOv18 IgG and c-MOv18 F(ab')2 were 39 cGy, 49 cGy and 5 cGy, respectively. A cocktail of 125I-c-MOv18 IgG and 131I-c-MOv18 F(ab')2 injected i.v. into an ovarian cancer patient, localized specifically in the tumor. Ovarian cancer tissue samples obtained 2 days postinjection showed a mean uptake of 1.2 x 10(-3) and 2.7 x 10(-3) %ID/g for c-MOv18 IgG and c-MOv18 F(ab')2, respectively. Results from these in vitro and in vivo experiments indicate that c-MOv18 has promise as a Mab for clinical use.

Distribution of OV-TL 3 and MOv18 in normal and malignant ovarian tissue.

AIMS: To analyse the distribution of OV-TL 3 and MOv18 in normal ovarian tissue to determine which antibody is most suitable for (radio)immunotherapy of ovarian carcinoma. METHODS: The distribution of OV-TL 3 and MOv18 was determined using immunohistochemistry and flow cytometry. RESULTS: Epithelial and other cells in many tissues, and leucocytes in peripheral blood, bone marrow and spleen stained positively with OV-TL 3. The staining pattern of MOv18 in normal tissues was more restricted and was confined to epithelial cells in the lung, kidney, pancreas, salivary gland, ovary, Fallopian tubes, and cervix. Reactivity was also observed with pneumocytes in the lung, tubuli in the kidney, acinar cells in the salivary gland and pancreas, in the placenta, and with Kupffer cells in the liver. The staining pattern of chimeric MOv18 was identical with the murine form. OV-TL 3 and MOv18 reacted with 100% and 98% (45/46) of the 46 tested epithelial ovarian cancers, respectively. In ovarian carcinoma tissue homogeneous staining of epithelial cells was observed with OV-TL 3 and more heterogeneous staining with MOv18. In 12 and nine patients, respectively, a difference in staining intensity for OV-TL 3 and MOv18 was observed between various tumour samples from the same patient. CONCLUSION: MOv18 has greater therapeutic potential because of its restricted reactivity with normal tissues and especially, in contrast to OV-TL 3, its lack of reactivity with haematopoietic cells.

Sentinel node detection in cervical cancer.

BACKGROUND: For superficial tumors such as melanoma, breast, and vulvar cancer, sentinel node detection prevents unnecessary extensive lymph node dissections. Sentinel node detection has not yet proved feasible in tumors, such as cervical cancer, that drain to deep pelvic lymph nodes. TECHNIQUE: We injected technetium-99m colloidal albumin around the tumor allowing preoperative lymphscintigraphy and intraoperative gamma probe detection of sentinel nodes. For visual detection, blue dye was injected at the start of surgery. EXPERIENCE: In six of 10 eligible women who had Wertheim-Meigs operations for cervical cancer stage Ib, one or more sentinel nodes could be detected by scintigraphy. Intraoperative gamma probe detection was successful in eight of ten women, whereas visual detection found sentinel nodes in only four. They were found as far as the common iliac level. One woman had positive lymph nodes, of which one was a sentinel node. CONCLUSION: Identification of sentinel nodes using radionuclide is possible in women with cervical cancer and potentially identifies women in whom lymph node dissection can be avoided.

Radioimmunotargeting in ovarian carcinoma patients with indium-111 labeled monoclonal antibody OV-TL 3 F(ab')2: pharmacokinetics, tissue distribution, and tumor imaging.

Safety and feasibility of tumor targeting with radiolabeled monoclonal antibodies was studied in 28 patients suspected of having ovarian carcinoma, after i.v. administration of 1 mg F(ab')2 fragments of the murine monoclonal antibody OV-TL 3, labeled with 150 MBq Indium-111. There were no adverse reactions, hematological and biochemical serum parameters were stable. In one patient a (subclinical) HAMA-response was found. Plasma clearance of the immunoconjugate was biphasic with half lives of t(1/2)}alpha = 1.4+/-0.8 h and t(1/2)}beta = 25.1+/-3.7 h, resulting in an optimal time period for immunoscintigraphy at 24-48 h after administration. In 20 patients, undergoing extensive explorative surgery, a total of 271 samples of tumorous and normal tissues were analyzed for radiolabel uptake and tumor presence. The mean uptake in tumor deposits was 5.6 times (range 2.2-19.3) as high as the uptake in normal tissues (fat, peritoneum, muscle, skin). The diagnostic accuracy of immunosctigraphy was compared with that obtained with computer tomography, magnetic resonance imaging, ultrasonography and physical examination. While pelvic localizations were equally well detected by all methods, 48% of the abdominally located tumor deposits were correctly diagnosed by immunoscintigraphy, with only 12% detected by ultrasonography, 8% by CT-scanning and physical examination, and 6% by MRI. Immunoscintigraphy has potential as a diagnostic tool in ovarian cancer patients and biolocalization results justify further research into the therapeutic application of labeled monoclonal antibodies.

[The diagnostic value of immunoscintigraphy using the monoclonal antibody OV-TL3 in patients with ovarian carcinoma]. / De diagnostische waarde van de immunoscintigrafie met het monoklonale antilichaam OV-TL3 bij patiënten met ovariumcarcinoom.

Immunoscintigraphy, using radiolabeled monoclonal antibodies directed against tumor associated antigens, is a relatively new method for the detection of tumour localizations. The diagnostic accuracy of immunoscintigraphy was compared with computer tomography, magnetic resonance imaging, ultrasound, physical examination, and the CA 125 serum assay in patients suspected of having primary or recurrent ovarian cancer. One mg of the murine monoclonal antibody OV-TL3 F(ab')2 was labeled with 4 mCi 111Indium and administered intravenously to 28 patients. No adverse reactions were noted. Twenty patients underwent extensive explorative laparotomy 3 to 8 (median 4 days) days after injection of the immunoconjugate, allowing a histopathological verification of the actual tumour status of each patient. The sensitivity of immunoscintigraphy for the detection of ovarian cancer was at least equal to that of the other diagnostic methods. However, with immunoscintigraphy more tumour localizations were identified.

HLA-G expression is an independent predictor for improved survival in high grade ovarian carcinomas.

Aberrant expression of human leukocyte antigens (HLA) class I has prognostic importance in various cancers. Here, we evaluated the prognostic value of classical (A/B/C) and nonclassical (G/E) HLA expression in 169 high grade epithelial ovarian cancer samples and linked that to clinicopathological characteristics and survival. Expression of HLA-A, -B/C, or -E was not correlated with survival. Survival was prolonged when tumours expressed HLA-G (P = 0.008) and HLA-G was an independent predictor for better survival (P = 0.011). In addition, HLA-G expression was associated with longer progression-free survival (P = 0.036) and response to chemotherapy (P = 0.014). Accordingly, high expression of HLA-G mRNA was associated with prolonged disease-free survival (P = 0.037) in 65 corresponding samples. Elevated serum-soluble HLA-G levels as measured by enzyme-linked immunosorbent assay in 50 matched patients were not correlated to HLA-G protein expression or gene expression nor with survival. During treatment, sHLA-G levels declined (P = 0.038). In conclusion, expression of HLA-G is an independent prognostic factor for improved survival in high grade epithelial ovarian cancer and a predictor for platinum sensitivity.

Intratumor heterogeneity of morphometric and stereologic variables in primary ovarian tumors and their omental metastatic deposits.

OBJECTIVE: To compare quantitative pathologic variables assessed in primary ovarian tumors and metastatic tumor deposits in the omentum and compare their prognostic value. STUDY DESIGN: In 29 cases of advanced ovarian cancer the mean nuclear area (MNA), volume-weighted mean nuclear volume (vv), volume percentage epithelium (VPE) and mitotic activity index (MAI) were assessed in both the primary ovarian tumor and its metastatic deposits in the omentum. Differences were evaluated using the Wilcoxon rank sum test for paired observations, and coefficients of variation were calculated in each case over the values obtained from the tumor in the ovary and omentum. RESULTS: Intraobserver and interobserver reproducibility of MNA, VPE and MAI were all good to very good except for the interobserver reproducibility for vv, which was moderate. MNA and vv, correlated well, both in the primary ovarian tumor (r = .88) and omental metastasis (r = .87). No significant differences were found between the assessments of MNA, vv, and MAI in the primary ovarian tumor and its omental metastasis, whereas significant differences were found for VPE. However, in some patients the nuclei tended to be larger and the VPE lower in the omental metastasis than in the primary ovarian tumor. No important impact of the origin of tumor tissue was reflected in the prognostic value of the nuclear features. Patients were grouped prognostically differently for the assessment of MAI and VPE in the primary ovarian tumor and its omental metastasis. CONCLUSION: Quantitative pathologic variables for prognostic purposes are best assessed in the primary ovarian tumor. Measurements in the metastatic deposits may be helpful in understanding processes of metastasis in advanced ovarian cancer.

Minor human antibody response to a mouse and chimeric monoclonal antibody after a single i.v. infusion in ovarian carcinoma patients: a comparison of five assays.

The human anti-(mouse Ig) antibody (HAMA) response was measured in serum of 52 patients suspected of having ovarian carcinoma who had received an i.v. injection of either the murine monoclonal antibody (mAb) OV-TL 3 F(ab')2 (n = 28, 1 mg) or the chimeric mouse/human mAb MOv18 (cMOv18; n = 24, 3 mg). Serum samples were taken before injection and 2-3 and 6-14 weeks after administration. A double-antigen or bridging assay was developed to detect responses against both murine as well as chimeric antibodies. In addition, an indirect enzyme-linked immunosorbent assay (ELISA) as well as three commercially available assays were used to study antibody response against the murine antibody OV-TL 3. With both the double-antigen (bridging) assay and the indirect ELISA 1 of the 28 patients (4%) injected with murine OV-TL 3 F(ab')2 showed a HAMA reaction 6 weeks after injection, which was demonstrated to be a mixed anti-isotypic and anti-idiotypic response. None of the 24 patients injected with the chimeric MOv18 showed an anti-chimeric antibody response. The various commercially available assays demonstrated conflicting results. The double-antigen- or bridging assay is a reliable method to detect anti-murine and anti-chimeric antibodies. The assay can be easily adapted for use with human antibodies. The immunogenicity of OV-TL 3 F(ab')2 and cMOv18 in patients is low, making both antibodies candidates for immunotherapy.

Tumor uptake of intravenously administered radiolabeled antibodies in ovarian carcinoma patients in relation to antigen expression and other tumor characteristics.

To study factors that possibly influence the heterogeneous tumor uptake of radiolabeled antibodies, tissues from 34 ovarian-carcinoma patients were obtained 2 to 8 days after i.v. injection with radiolabeled murine OV-TL3 or chimeric MOv18 (cMOv18). The tumor uptake and the ratio of tumor to normal tissue (T/NT) were studied in relation to the histopathological classification, prior treatment, site of tumor, time interval, antigen expression, volume percentage of (malignant) epithelium in the tumor tissue, and the size of the tumor. The results of immunoscintigraphy were also included. In addition, autoradiography using storage phosphor technology was performed on tissue sections from patients injected with iodine-labeled cMOv18. Tumor uptake varied largely, not only between patients, but also between tumor deposits within the same patient. Uptake of OV-TL3 F(ab')2 was higher than of cMOv18 F(ab')2, but the T/NT ratios were similar. The antibody uptake was positively correlated with the pattern of antigen expression and inversely correlated with the time interval between injection and surgery. No correlation was observed with any of the other factors studied. The visibility with immunoscintigraphy was related to the size of the detected lesion, but not to the other factors studied. Autoradiography showed that antibodies preferentially localized in areas with cancer cells, which were immunohistochemically positive for MOv18. In areas with weak antigen expression, autoradiography revealed less activity. The antigen expression by the tumor is an important factor for estimation of the tumor uptake of radiolabeled antibodies.

Comparative evaluation of diagnostic methods in ovarian carcinoma with emphasis on CT and MRI.

A prospective study was performed in 64 patients suspected of having primary or recurrent ovarian epithelial cancer. Physical examination (PE), ultrasonography (US), computer tomography (CT), and magnetic resonance imaging (MRI) were performed and CA 125 serum levels (CA 125) were determined. This evaluation was followed within 3 weeks by laparotomy, which served with the pathology data as the gold standard. Both CT and MRI were, independently, evaluated by two experienced radiologists. The accuracy in diagnosing ovarian carcinoma of both CT (70 and 91%) and MRI (64 and 88%) in patients suspected of primary and recurrent cancer grouped together differed between the two radiologists, but for each radiologist no difference in overall accuracy between CT and MRI was observed. The accuracy of PE was 64%, of US, 67%, and of CA 125, 72%. At surgery, 132 separate tumor locations were present. With CT, 41 and 69% and with MRI, 44 and 56% of these lesions were recognized by the two radiologists, respectively. This was the case in 27% with PE and 34% with US. We conclude that in our setting MRI had no additional value over CT. The interobserver variability was high for both MRI and CT. MRI and CT are both useful diagnostic methods in the diagnosis of ovarian carcinoma.

Influence of the route of administration on targeting of ovarian cancer with the chimeric monoclonal antibody MOv18: i.v. vs. i.p.

MOv18 antibody binds the membrane folate receptor highly expressed on ovarian carcinoma cells. Since ovarian cancer is mainly limited to the peritoneal cavity, locoregional delivery of therapeutics can be an option. The same patient was injected i.v. and i.p. with c-MOv18 IgG labeled with different radionuclides. To study the kinetics of c-MOv18, patients were divided into 2 groups. Fifteen patients received c-MOv18 labeled with (131)I, (125)I and (123)I (for imaging). Seven patients were operated 2 days, 7 patients 6 days and 1 patient 3 days post-injection. Radioactivity was determined in blood, ascites and biopsies of tumor and of several normal tissues. No adverse events occurred. No anti-MOv18 responses were observed. The area under the blood activity vs. time curve (AUC) was significantly lower after i.p. injection for 2 and 6 days post-injection (p = 0.01 and p = 0.02, respectively). At 2 days post-injection, a significant difference in tumor uptake was found in favor of the i.v. route of administration (4.9% and 2.4%ID/kg for i.v. and i.p., respectively; p < 0.0001). Uptake in solid tumor tissue in ovarian cancer patients operated 6 days post-injection was not significantly different (p = 0.79) for both routes (3.8% and 3.9%ID/kg for i.v. and i.p., respectively). In conclusion, no advantage could be demonstrated for the i.p. route with respect to tumor uptake. The i.p. route could be advantageous with respect to bone marrow toxicity since the AUC was significantly lower for the i.p. route. However, within 2 days post-injection, the blood clearance followed the same pattern for both routes.