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Biomedical subjects

L F Massuger

Publications and source records attributed to L F Massuger.

At least 19 recordsLinked to original sources

Surveillance of women at high risk for hereditary ovarian cancer is inefficient.

To determine the effectiveness of annual gynaecological screening (pelvic examination, transvaginal ultrasound, and CA-125), a prospective cohort study of women at high risk for hereditary ovarian cancer was conducted. Women were offered DNA analysis followed by either annual screening or prophylactic bilateral salpingo-oophorectomy (BSO). Study population consisted of 512 high-risk women (median follow-up 2.07 years, range 0-9.4 years): 265 women (52%) had a BRCA mutation. Persisting abnormalities indicated diagnostic surgery in 24 women resulting in one primary ovarian cancer FIGO stage IIIc was found. The effectiveness of screening was studied by calculating the probability of finding ovarian cancers in the BRCA-1 and BRCA-2 carrier group and comparing this to the identified number of ovarian cancers. The number of ovarian cancer patients found at surveillance was in accordance with the predicted number of ovarian cancers. A total number of 169 women underwent prophylactic BSO: one ovarian cancer stage IIb was found. In conclusion, the surveillance programme for hereditary ovarian cancer does identify patients with ovarian cancer but is very inefficient considering the high number of surveillance visits and the advanced stage of ovarian cancer in the identified patient. For prevention of advanced stage ovarian cancer, prophylactic BSO from age 35-40 years is a more efficient alternative.

Adult↗

High prevalence of premalignant lesions in prophylactically removed breasts from women at hereditary risk for breast cancer.

PURPOSE: Women with a hereditary predisposition for breast cancer have an extremely high risk of developing invasive breast carcinoma, and many women consider prophylactic mastectomy to avoid this risk. The use of prophylactic mastectomy is still debated. Identification of frequent premalignant lesions in mastectomy specimens would support the preventive concept of prophylactic mastectomy. PATIENTS AND METHODS: We performed a prospective study of breast specimens from 67 women at extremely high genetic risk of breast cancer, with or without previous breast cancer, who were undergoing prophylactic mastectomy (66% were carriers of a BRCA1 or BRCA2 mutation). Breast specimens were studied by radiographic and macroscopic examination of 5-mm tissue slices, with subsequent histology of suspicious lesions and random samples from each quadrant of the breast and the nipple area. RESULTS: In 57% of the women, one or more different types of high-risk histopathologic lesions were present: 37% atypical lobular hyperplasia, 39% atypical ductal hyperplasia, 25% lobular carcinoma-in-situ, and 15% ductal carcinoma-in-situ. A 4-mm invasive ductal carcinoma was found in one woman with ductal carcinoma-in-situ. None of these lesions was detected at palpation or mammography, which were performed before the mastectomy. The presence of high-risk lesions was independently related to age older than 40 years (odds ratio, 6.6; P =.01) and to bilateral oophorectomy before prophylactic mastectomy (odds ratio, 0.2; P = 0.02). CONCLUSION: Many women at high risk of hereditary breast cancer develop high-risk histopathologic lesions, especially after the age of 40 years. Surveillance does not detect such high-risk histopathologic lesions.

Adult↗

Vascular endothelial growth factor in ovarian cyst fluid.

BACKGROUND: The purpose of the current study was to determine vascular endothelial growth factor (VEGF) concentrations in cyst fluid from malignant, borderline, and benign ovarian tumors, and to correlate these data with preoperative serum VEGF concentrations and clinicopathologic characteristics. METHODS: One hundred seven ovarian cysts were removed and punctured for cyst fluid collection. Histologic diagnosis revealed 25 malignant, 12 borderline, and 70 benign ovarian tumors. The VEGF concentrations of all the cyst fluid specimens as well as in 37 preoperatively collected serum samples were determined by making use of a sandwich type double determinant enzyme linked immunoadsorbent assay based on a combination of 4 polyclonal antibodies. RESULTS: Statistically significantly higher VEGF concentrations were found in cyst fluid from malignant (median, 21.5 microg/L) compared with borderline (median, 3.2 microg/L; P = 0.01) or benign tumors (median, 1.3 microg/L; P < 0.0001). Preoperative serum VEGF concentrations were significantly higher in patients with malignant (median, 0.63 microg/L; range, 0.016-17.7 microg/L) compared with nonmalignant tumors (median, 0.28 microg/L; range, 0.016-0.89 microg/L; P = 0.008). A significant correlation of preoperative serum VEGF was found with VEGF cyst fluid concentrations (r = 0.38; P = 0.02). Significantly higher VEGF cyst fluid concentrations were found in serous malignant (median, 31.9 microg/L) compared with mucinous malignant tumors (median, 4.7 microg/L; P = 0.004). Not significant, though higher median VEGF cyst fluid concentrations were found in advanced International Federation of Gynecology and Obstetrics (FIGO) Stage II, III, and IV, histologic Grade 2 and 3, patients with residual tumor greater than 2 cm, with malignant cells in ascites or peritoneal washings, or with recurrent disease, as compared with FIGO Stage I, histologic grade 1, patients with less than or equal to 2-cm residual tumor, without malignant cells in ascites/peritoneal washings, or without recurrent disease, respectively. CONCLUSIONS: It has become clear from the increased study sample that ovarian tumors of different histologic etiology vary in VEGF cyst fluid concentrations, with the highest VEGF cyst fluid concentrations in malignant tumors. The prognostic significance of VEGF cyst fluid concentrations in advanced FIGO stage seems to be of limited value but may be important in the selection of high risk FIGO Stage I and borderline types. Data from this study indicate a possible role for VEGF as a serum tumor marker.

Adenocarcinoma, Mucinous↗

Post-radiotherapy contrast enhancement changes in fast dynamic MRI of cervical carcinoma.

This pilot study determines fast dynamic gadolinium enhanced MRI contrast enhancement parameters (onset of enhancement and time to peak enhancement) before and after radiotherapy in 10 cervical carcinoma patients. Before radiotherapy, onset of enhancement and time to peak enhancement were early, with a median of 4.5 and 5.2 seconds, respectively. High-grade tumors showed early enhancement, compared with low-grade. After radiotherapy, contrast enhancement patterns differed. In survivors, onset of enhancement after radiotherapy was later than before radiotherapy. In non-survivors, onset of enhancement after radiotherapy was still early. The median difference in onset of enhancement before and after radiotherapy in survivors and non-survivors was an increase of 3.2 and a decrease of 1.1 seconds, respectively. Early onset of enhancement after radiotherapy was a better predictor for survival than a high-signal intensity zone on post radiotherapy unenhanced T1/T2-weighted MRI. It is concluded that enhancement parameters from fast dynamic Gd-enhanced MR images can provide additional functional information with regard to tumor vascularization, and may have prognostic significance. It complements clinical examination and unenhanced MRI in determining the effectiveness of radiotherapy treatment in cervical carcinoma. Future studies will focus on the clinical utility and improvements of the estimation of contrast-enhanced parameters with this new technique.

Contrast Media↗

Glutathione S-transferases P1-1 and A1-1 in ovarian cyst fluids.

PURPOSE: The purpose of the present study was to determine the gluthathione S-transferases (GST) P1-1 and A1-1 levels in cyst fluid from malignant, borderline, and benign ovarian tumors. The clinical relevance of these enzymes in cyst fluid was investigated, including the possible relation with resistance to chemotherapy. METHODS: A total of 90 ovarian cysts were punctured for cyst fluid collection. GSTP1-1 and GSTA1-1 concentrations were determined by ELISA in cyst fluid from 23 malignant, 9 borderline, and 51 benign primary ovarian tumors, and levels were correlated with histopathological data. RESULTS: Significantly higher GSTP1-I concentrations were found in cyst fluid from malignant (median: 477 ng/ml), compared with benign (median: 52 ng/ml) ovarian cysts (p < 0.0001), as well as in fluid from borderline (median: 366 ng/ml) compared with benign cysts (p < 0.0001). No significant differences were found in cyst fluid GSTA1-1 concentrations between the histologic subgroups. In cyst fluid from malignant tumors higher GSTPI-1 and lower GSTAI-1 concentrations were found in patients with worse prognostic factors: FIGO II-III-IV, grade 2-3, residual tumor > 2 cm, presence of ascites, patients with recurrent disease, and survival, but differences were not significant. In the subgroup of patients that received cisplatin-based chemotherapy (n = 14) significantly higher GSTP1-1 (p = 0.01) concentrations were found in patients with recurrence compared with patients without recurrence. Considering only FIGO stage I patients, a differentiation could be made between patients with or without recurrence based on cyst fluid GSTP I - I concentrations. CONCLUSIONS: Determination of glutathione S-transferases P 1-1 in cyst fluid samples from ovarian tumors can be of additiona] value in the differentiation between histologic subgroups. In case of possible low malignant potential cysts where sampling of the most representative tissue can be an issue, determination of GSTP- I concentrations in cyst fluid may optimise histopathologic classification. Cyst fluid GSTP1-1 seems to be a good marker for aggressiveness of the ovarian tumor, and it may predict response to chemotherapy.

Adult↗

High-resolution proton nuclear magnetic resonance spectroscopy of ovarian cyst fluid.

Most ovarian tumors are cystic structures containing variable amounts of fluid. Several studies of ovarian cyst fluid focus on one specific metabolite using conventional assay systems. We examined the potential of (1)H-nuclear magnetic resonance spectroscopy in evaluation of the overall metabolic composition of cyst fluid from different ovarian tumors. Ovarian cyst fluid samples obtained from 40 patients with a primary ovarian tumor (12 malignant and 28 benign) were examined. After deproteinization and pD standardization, we performed (1)H-NMR spectroscopy on a 600 MHz instrument. With (1)H-NMR spectroscopy we found detectable concentrations of 36 metabolites with high intersample variation. A number of unassigned resonances as well as unexpected metabolites were found. We introduce an overall inventory of the low-molecular-weight metabolites in ovarian cyst fluid with corresponding resonances. Significant differences in concentration (p < 0.01) were found for several metabolites (including an unknown metabolite) between malignant and benign ovarian cysts. Furthermore, higher concentrations in malignant- and lower in benign fluids were found compared to normal serum values, indicating local cyst wall metabolic processes in case of malignant transformation. We conclude that (1)H-nuclear magnetic resonance spectroscopy can give an overview of low-molecular-weight proton-containing metabolities present in ovarian cyst fluid samples. The metabolic composition of cyst fluid differs significantly between benign and malignant ovarian tumors. Furthermore, differences between benign subgroups possibly related to histopathological behaviour can be detected. The presence of N-acetyl aspartic acid and 5-oxoproline exclusively in serous cystadenoma samples is remarkable. Future studies will concentrate on these findings and explore the possibilities of extrapolating information from the in vitro studies to in vivo practice, in which metabolic differences between malignant and benign subtypes can be of great importance in a pre-operative phase.

Adult↗

The role of MR imaging in invasive cervical carcinoma.

In this article the role of MR imaging in the management of cervical cancer is reviewed and illustrated. The appearance of the normal uterine cervix and of cervical carcinoma is shown. Important factors for optimal MR imaging of cervical carcinoma are reviewed. The value of MR imaging in the staging of cervical carcinoma is illustrated by showing parametrial invasion and lymph node involvement. Finally, the value of MR imaging staging is compared with clinical staging, CT staging, and surgical findings. The role of new imaging techniques, such as fast dynamic enhanced MR imaging, is described.

Cervix Uteri↗

Uterine malignant leiomyoblastoma (epithelioid leiomyosarcoma) during pregnancy.

A case of uterine malignant leiomyoblastoma (UML) which was initially mistaken for uterine leiomyoma on two different occasions is presented. About 20 cases of uterine leiomyoblastoma taking a malignant course have been described in the literature. This case of UML is the first diagnosed during pregnancy. In retrospect, tumor tissue removed from the uterus 4 years earlier already showed histological signs of UML. The large and metastatic tumor showed nuclear atypia, a moderate mitotic index, and tumor cell necrosis, indicating malignancy. Treatment consisted of hysterectomy, bilateral salpingo-oophorectomy, and debulking of most other tumor masses. In the literature, radio- and chemotherapy have not proved to be effective in these tumors. Hormonal therapy has only been used in 2 patients. In this patient, hormonal influence on tumor growth may be substantial. The tumor was progesterone- and estrogen-receptor positive and increased in size rapidly during pregnancy. Since little is known about these tumors further studies are necessary to evaluate hormonal influences both as a causative factor and as a therapeutic possibility.

Adult↗

Leiomyomatosis peritonealis disseminata: does malignant transformation occur? A literature review.

Leiomyomatosis peritonealis disseminata (LPD) is a rare smooth muscle tumor. In the literature more than 100 cases have been described. LPD is characterized by multiple small nodules on the peritoneal surface, mimicking a malignant process with metastases, but generally demonstrates benign histologic features. Exposure to estrogen seems to play an etiologic role. Many patients have uterine leiomyomas as well. The diagnosis of LPD is easily made on biopsy. Reduction of estrogen exposure is generally sufficient to cause regression of LPD. Surgical castration or gonadotrophin releasing hormone agonists seem good alternatives in the case of progression or recurrence of LPD. In six patients a malignant leiomyosarcoma has been described shortly after the diagnosis of LPD was made. Five of these patients did not have uterine leiomyomas or exposure to exogenous or increased endogenous estrogen. The relationship with pregnancy in the sixth patient may be coincidental. Whether malignant transformation of LPD occurs remains uncertain. Characteristics of these patients differ from those of LPD patients and may indicate a high malignant potential, necessitating a different approach.

Adult↗

Cytologic examination to detect clear cell adenocarcinoma of the vagina or cervix.

OBJECTIVE: The aim of this study was to determine the sensitivity of cytopathologic examination for the detection of vaginal or cervical clear cell adenocarcinoma (CCA). METHODS: Systematic collection in the Dutch automated nationwide pathology archive of all cytology and histology data of women with CCA, born in The Netherlands after 1947 was performed. All cytologic examinations within 2 years prior to histological diagnosis of CCA were included. RESULTS: Ninety patients with CCA have been registered. Forty-nine of these patients had cytologic examinations prior to histology. Eighty-five percent of cervical CCAs were preceded by a positive cervical smear. One hundred percent of vaginal CCAs were preceded by a positive vaginal smear. Cervical smears are relatively insensitive to detect vaginal CCA. Vaginal smears were often omitted. Only 2 apparently false-negative smears were found. The mean numbers of smears in diethylstilbestrol (DES)-exposed and nonexposed women were minimally different: 1.0 and 0.8, respectively. This suggests an only modest impact of the awareness of DES as a risk factor. FIGO tumor stage I was preceded more frequently by cytology than the higher tumor stages. CONCLUSION: The majority of CCA cases can be detected at an early stage by yearly clinical and cytological examinations, which must comprise cervical as well as vaginal sampling. Since CCA may also occur in postmenopausal women, for the purpose of secondary prevention of CCA regular cytologic examinations of DES-exposed women must be continued after menopause.

Adenocarcinoma, Clear Cell↗

An illustration of the clinical relevance of detecting human antimouse antibody interference by affinity chromatography.

Elevated Cancer antigen 125 (CA 125) serum concentrations (up to 221 kU/1) were measured in a 39 year old woman with a positive family history of breast cancer. The serum determinations were performed with the automated Immulite OM-MA chemiluminescent enzyme immunoassay system (Diagnostic Products). Laparoscopic evaluation of the ovaries did not reveal any abnormalities. CA 125 measurements in the same patient using the automated IMx immunoassay system (Abbott) demonstrated normal serum levels. Using a previously reported chromatography procedure IgG type human antimouse antibody activity was found to be present in the serum samples explaining the falsely elevated levels. To prevent this interference the manufacturer modified the assay system by replacing the monoclonal M11 detection antibody with a rabbit polyclonal antibody. Using the modified OM-MA CA 125 assay results were comparable with the IMx values.

Adult↗

1H-magnetic resonance spectroscopy: a new technique to discriminate benign from malignant ovarian tumors.

BACKGROUND: Currently used techniques such as ultrasound, computed tomography, and magnetic resonance imaging are not fully capable of differentiating benign from malignant ovarian tumors. Magnetic resonance spectroscopy (MRS) may help solve this clinical problem by analyzing the composition of fluid from ovarian cysts. METHODS: The authors studied fluid samples from 28 different ovarian cysts. Nine patients were found to have a malignant ovarian tumor whereas 19 patients had benign cysts. Single pulse 1H-Nuclear Magnetic Resonance spectra were obtained in all fluid samples. RESULTS: Compared with the group of benign epithelial cysts (n = 17) the 8 malignant epithelial ovarian cysts had significantly higher levels of lactate, isoleucine, valine, 3-hydroxybutyric acid, methionine, and alanine (P < 0.05). In two benign cysts (endometrioma and mature teratoma) surprisingly high levels were found for a large number of compounds. Values were as high as 100-fold the values in fluid from benign cysts. CONCLUSIONS: 1H-NMR spectroscopy demonstrates significant differences in metabolite concentration between benign and malignant ovarian cysts. This ultimately may lead to the noninvasive differential diagnosis of ovarian tumors by in vivo MRS.

Diagnosis, Differential↗

[Circulatory arrest following sulprostone administration in postpartum hemorrhage].

In a woman aged 39 cardiac arrest occurred 3.5 hours after administration of 250 micrograms sulprostone directly into the uterine wall for a post-partum haemorrhage after manual removal of the placenta. A long period of resuscitation was necessary. After further evaluation the woman demonstrated specific contraindications to the administration of sulprostone. as formulated by the French authorities: age > 35 years, heavy cigarette smoking, and cardiovascular risk factors. In the Netherlands sulprostone is registered for intravenous administration only. We would strongly advise against administration directly into the uterine wall.

Abortifacient Agents, Nonsteroidal↗

Dosimetric analysis of chimeric monoclonal antibody cMOv18 IgG in ovarian carcinoma patients after intraperitoneal and intravenous administration.

In this study the potential of intraperitoneal (i.p.) and intravenous (i.v.) administration of chimeric iodine-131-labelled MOv18 IgG for radioimmunotherapy was determined. The dosimetry associated with both routes of administration of cMOv18 IgG was studied in patients. Eight patients suspected of having ovarian carcinoma received 150 MBq 131I-cMOv18 IgG i.p. Blood and urine were collected and serial gamma camera images were acquired. Another group of four patients received 7.5 MBq 131I-cMOv18 IgG i.v. For all patients, tissue biopsies were obtained at surgery. Activity in the blood after i.p. administration was described by a bi-exponential curve with a mean uptake and elimination half-life of 6.9+/-3.2 h and 160+/-45 h, respectively. For i.v. infusion the mean half-life for the elimination phase was 103+/-12 h. Cumulative excretion in the urine was 17%+/-3% ID and 21%+/-7% ID in 96 h for i.p. and i.v. administration, respectively. Scintigraphic images after i.p. administration showed accumulation in ovarian cancer lesions, while all other tissues showed decreasing activity with time. Tumour uptake determined in the ovarian cancer tissue specimens ranged from 3.4% to 12.3% ID/kg for i.p. administration and from 3.6% to 5.4% ID/kg for i.v. administration. Dosimetric analysis of the data indicated that 1.7-4.3 mGy/MBq and 1.7-2.2 mGy/MBq can be guided to solid or ascites cells after i.p. and i.v. administration, respectively. Assuming that an absorbed dose to the bone marrow of 2 Gy will be dose limiting, a total activity of 4.1 GBq 131I-cMOv18 IgG can be administered safely via the i.p. route and 3.5 GBq via the i.v. route. At this maximal tolerated dose, a maximum absorbed dose to 1-g tumours in the peritoneal cavity of 18 and 8 Gy can be reached after i.p. and i.v. administration, respectively. For the i. p. route of administration, dose estimates for the tumour are even higher when the electron dose of the peritoneal activity is also taken into account: total doses to the tumour of 30 Gy and 22 Gy will be absorbed at the tumour surface and at 0.2 mm depth, respectively. In conclusion, therapeutic tumour doses can be achieved with 131I-cMOv18 IgG in patients with intraperitoneal ovarian cancer lesions with no normal organ toxicity. The i.p. route of administration seems to be preferable to i.v. administration.

Adolescent↗

Fast dynamic contrast enhanced MR imaging of cervical carcinoma.

The first pass phase of contrast material is most important to study vascularization and perfusion of tissue and can be studied using dynamic magnetic resonance (MR) imaging. The purpose of this prospective study was to evaluate the usefulness of pre-contrast vs. post-contrast and fast dynamic MR imaging in the pre-operative staging of cervical carcinomas. To assess the normal onset of enhancement of the uterus and cervix 15 volunteers underwent dynamic MR imaging. Forty-two consecutive patients with invasive cervical cancer underwent pre-operative evaluation using MR imaging. The results of the MR examinations were correlated with clinical (FIGO) staging under anaesthesia (n = 42) and with histopathological findings after operation (n = 26). The staging results of pre-contrast T1-weighted and T2-weighted turbo spin-echo (TSE) MR images, pre-contrast MR images plus post-contrast enhanced (two dimensional fast low angle shot (FLASH 2-D) post contrast), pre-contrast MR images plus post-contrast enhanced plus fast dynamic enhanced (single slice turbo fast low angle shot (turbo FLASH)) MR images compared to histopathology (n = 26) were 77%, 81% and 85% respectively. The improvement was statistically not significant. The result of MR staging compared to clinical staging (n = 42) with pre-contrast MR images was correct in 79% of the cases. Pre-contrast MR images combined with post-contrast MR images did not significantly improve staging accuracy (83%). Pre-contrast plus post-contrast plus fast dynamic MR imaging improved staging to 91%. However, the improvement was only statistically significant for one reader (P = 0.01), whereas the improvement of the second reader was not significant (P = 0.07). The single slice turbo FLASH images showed enhancement of all squamous cell carcinomas (n = 32) with an average onset of 5s (range 4-8s) during the first 45s of bolus injection of gadolinium. The normal cervix showed enhancement with an average of 10s (range 6-14 s). FLASH 2-D post-contrast images showed less intense enhancement of the cervical tumours with respect to the parametria and other surrounding structures. Fast dynamic MR imaging and to a lesser degree post-contrast MR imaging showed a higher level of confidence than pre-contrast MR. Fast dynamic MRI compared with clinical staging (n = 42) was correct in 91% (38/42) and to histopathology in 85% (22/26). Comparison of clinical staging with histopathology was 85% (22/26). In conclusion, fast dynamic MR imaging is superior to post-contrast and pre-contrast MR imaging and is at least as good as clinical staging in the evaluation of cervical carcinoma.

Adult↗

Borderline ovarian malignancy: ultrasound and fast dynamic MR findings.

Ovarian tumors of borderline malignancy are low-grade malignant neoplasms, and have a rather good prognosis. They account for approximately 10-20% of all ovarian tumors. Very few reports available in literature that analyses ultrasound and MR findings in establishing the diagnosis. The purpose of this study is to describe eight cases of ovarian tumors of borderline malignancy with dynamic gadolinium-enhanced MR imaging. Comparison is made with CA 125 serum levels and ultrasound findings. Early enhancing endocystic vegetations, local cystic masses in, and (irregular) thickened walls of large multicystic tumors were important findings in borderline malignant tumors. The accuracy to detect a malignant tumor of borderline malignancy with CA 125, ultrasound and MRI in these eight cases was 50, 63 and 75%, respectively. MRI is a valuable imaging modality to characterize adnexal tumors and might play a role in preoperative evaluation of borderline malignancies.

Female↗

Quantitation of IgG and IgM human anti-mouse antibodies (HAMA) interference in CA 125 measurements using affinity chromatography.

Currently no available immunoassay system offers complete protection against spuriously elevated or lowered results due to interference by Human Anti-Mouse Antibodies (HAMA). Although routine use of chromatography procedures is not an acceptable option because of the extra cost and workload involved, such a procedure would be highly desirable to ensure accurate immunoassay results. The present report describes a relatively simple affinity chromatography procedure using a HiTrap Protein G column to isolate immunoglobulin G (IgG) HAMA, followed by a HiTrap N-hydroxy-succinimide (NHS)-activated column coupled to goat-anti human immunoglobulin M (IgM) to bind IgM HAMA. To examine the usefulness of this purification procedure we determined CA 125 in forty serum samples prior to and following chromatography. Pre- and post-injection samples were obtained from 20 patients injected with 1 mg of 111In-labelled murine OC 125 F(ab')2 fragments in an immunoscintigraphy study. It is shown that this analytical procedure provides a technique to determine the extent and the nature of the existing HAMA interference in samples of patients after in vivo use of monoclonal antibodies for diagnostic or therapeutic purposes. The procedure can also contribute to the clarification of clinically discordant CA 125 results. Finally, the availability of such a procedure in the clinical laboratory provides an opportunity to test the robustness of newly developed immunoassay systems towards HAMA interference.

Animals↗