Early prediction of post-molar gestational trophoblastic neoplasia and resistance to methotrexate, based on a single serum human chorionic gonadotropin measurement.

BACKGROUND: Clinicians are unable to provide individualized counseling regarding risk of progression for patients with a complete hydatidiform mole (CHM). We developed nomograms enabling early prediction of post-molar gestational trophoblastic neoplasia (GTN) and resistance to methotrexate (MTX) based on a single serum human chorion gonadotropin (hCG) measurement. METHODS: We generated two nomograms with logistic regression: to predict post-molar GTN, and MTX resistance. For patients with high probability to progress to post-molar GTN or MTX resistance, we determined hCG cut-offs at 97.5% specificity to select patients for additional- or adjustments in current treatment. RESULTS: The nomograms had a good to excellent ability to distinguish either between patients with uneventful hCG regression versus progression to post molar GTN, or between patients cured by MTX versus patients in whom resistance would occur. At 97.5% specificity, we identified 66% (95%CI 56-75) of the 149 patients who would progress to post-molar GTN, four weeks after initial curettage. For patients treated with MTX, we identified 55% (95%CI 23-83) of the 43 patients who would become resistant, preceding their third course at 97.5% specificity. CONCLUSION: The nomograms and cut-off levels can be used to assist in counseling for patients diagnosed with CHM.

Salivary morning androstenedione and 17α-OH progesterone levels in childhood and puberty in patients with classic congenital adrenal hyperplasia.

BACKGROUND: Treatment of congenital adrenal hyperplasia due to 21-hydroxylase deficiency can be monitored by salivary androstenedione (A-dione) and 17α-hydroxyprogesterone (17OHP) levels. There are no objective criteria for setting relevant target values or data on changes of 17OHP and A-dione during monitoring. METHODS: We evaluated A-dione and 17OHP levels in nearly 2000 salivary samples collected during long-term treatment of 84 paediatric patients with classic 21-hydroxylase deficiency. RESULTS: A-dione and 17OHP levels and its ratio 17OHP/A-dione remained constant from 4 to 11 years with no sex-related differences. During puberty, A-dione and 17OHP levels both increased, starting at earlier age in girls than in boys. The ratio 17OHP/A-dione declined. Normalised A-dione concomitant with elevated 17OHP [1.43 nmol/L (0.46-4.41) during prepuberty; 2.36 nmol/L (0.63-8.89) for boys and 1.99 nmol/L (0.32-6.98) for girls during puberty] could be obtained with overall median glucocorticoid doses of 11-15 mg/m2/day. A-dione levels above the upper reference limit (URL), suggesting undertreatment, coincided with 17OHP levels ≥10 times URL. The percentage of A-dione levels above URL was 16% at ages 4-8 years, but increased to 31% for girls at 16 years and 46% for boys at 17 years. CONCLUSIONS: Normalised A-dione consistent with 17OHP three times URL during prepuberty and normalised A-dione consistent with 4-6 times URL during puberty could be obtained by moderate glucocorticoid dosages. A constant 17OHP/A-dione ratio during prepuberty suggested absence of adrenarche. During puberty, a higher percentage of samples met the criteria for undertreatment, especially of boys.

Identification of patients with persistent trophoblastic disease after complete hydatidiform mole by using a normal 24-hour urine hCG regression curve.

OBJECTIVE: The aim of this study was to establish a reference 24-hour urine human chorionic gonadotropin (hCG) regression curve in patients with complete hydatidiform mole (CHM) as diagnostic tool in the prediction of persistent trophoblastic disease (PTD). METHODS: From 2004 to 2011, 312 cases suitable for this study were registered at the Hydatidiform Mole Registry of the Royal Women's Hospital Melbourne, Australia. hCG levels of 61 patients diagnosed as having PTD according to FIGO 2000 criteria were compared with the 95th-percentile (p95) of the normal regression curve derived from hCG levels of 251 cases of uneventful CHM. RESULTS: In the test group of 61 patients PTD was diagnosed by FIGO 2000 criteria after a mean (±SD, min.-max.) of 7.6 (±3.4, 3.0-16.7) weeks after evacuation of the mole while in the same group hCG values for the first time exceeded the upper limit of the 95th percentile significantly earlier after 4.5 (±1.9, 2.0-9.9) weeks (P<0.001). However, hCG levels of 14% of the cases of uneventful CHM at least once exceeded the upper limit of p95, showing that one single value above p95 is not accurate enough for the diagnosis of PTD. CONCLUSIONS: The normal 24-hour urine hCG regression curve may be used as a tool in the follow-up of an individual case of CHM after evacuation. At least one hCG level exceeding the upper limit of p95 within 11weeks after evacuation could be added to the current FIGO criteria, in order to diagnose PTD early, but the lack of it may also prevent unnecessary treatment.

Linear regression of postevacuation serum human chorionic gonadotropin concentrations predicts postmolar gestational trophoblastic neoplasia.

OBJECTIVE: Currently, human chorionic gonadotropin (hCG) follow-up after evacuation of hydatidiform moles is essential to identify patients requiring chemotherapeutic treatment for gestational trophoblastic neoplasia (GTN). We propose a model based on linear regression of postevacuation serum hCG concentrations for the prediction of GTN. METHODS: One hundred thirteen patients with at least 3 serum samples from days 7 to 28 after evacuation were selected from the Dutch Central Registry for Hydatidiform Moles (1994-2009). The slopes of the linear regression lines of the first 3 log-transformed serum hCG and free ß-hCG values were calculated. Receiver operating characteristic curves were constructed to calculate areas under curve (AUCs). RESULTS: The slope of the hCG regression line showed an AUC of 0.906 (95% confidence interval, 0.845-0.967). Gestational trophoblastic neoplasia could be predicted in 52% of patients with GTN at 97.5% specificity (cutoff, -0.020). Twenty-one percent of patients with GTN could be predicted before diagnosis according to the International Federation of Gynecology and Obstetrics 2000 criteria. The slope of free ß-hCG showed an AUC of 0.844 (95% confidence interval, 0.752-0.935), 69% sensitivity at 97.5% specificity, and 38% of patients with GTN could be predicted before diagnosis according to the International Federation of Gynecology and Obstetrics criteria. CONCLUSIONS: The slope of the linear regression line of hCG proved to be a good test to discriminate between patients who will achieve spontaneous disease remission and patients developing GTN. The slope of free ß-hCG seems to be a better predictor for GTN than the slope of hCG. Although this model needs further validation for different assays, it seems a promising way to predict the more aggressive cases of GTN.

Long-term outcome of placental site trophoblastic tumor in The Netherlands.

OBJECTIVE: To evaluate the outcome of 16 cases of placental site trophoblastic tumors (PSTTs) treated throughout The Netherlands. STUDY DESIGN: Patients with PSTT between 1991 and 2009 were identified using the nationwide network and registry of histopathology and cytopathology in The Netherlands (PALGA) and medical records. RESULTS: Data for 16 patients could be retrieved. The median age of the patients was 32 years. In 7 cases the antecedent pregnancy was a miscarriage and in 6, a term delivery. Clinical data on 3 patients could not be retrieved. Six patients were low-risk according to the International Federation of Gynecology and Obstetrics staging system. The median human chorionic gonadotropin (hCG) level was 46 IU/L, but in 4 patients the hCG level was not elevated. In the majority of patients a hysterectomy was performed, and 5 patients needed additional chemotherapy. There was only 1 recurrence and there were no fatalities. CONCLUSION: This study emphasizes the need for an international registration. No fatalities were registered. Because of the low incidence and limited experience of general gynecologists with this disease, there is a preference for centralization of all patients with PSTT regardless of their stage.

Predictors and risk model development for menopausal age in fragile X premutation carriers.

PURPOSE: Women who carry a fragile X mental retardation 1 premutation are at risk for fragile X-associated primary ovarian insufficiency and should be counseled for a potentially reduced fertility. Multiple factors can affect the age of onset and severity of fragile X-associated primary ovarian insufficiency. In this study, we assessed the predictive power of several factors with menopausal age, a surrogate measure of onset of fragile X-associated primary ovarian insufficiency. METHODS: Genetic, environmental, and reproductive factors were analyzed by Cox proportional hazard models in 1068 women, 385 of fragile X families ascertained through the Nijmegen study and 683 of fragile X families or general population families ascertained through the Atlanta study. RESULTS: The highest association with menopausal age among fragile X mental retardation 1 premutation carriers was found for risk index by CGG repeat size (hazard ratio, 1.43) and smoking (hazard ratio, 1.34). Women from the Nijmegen cohort showed an overall lower age at menopause onset, for which a correction was made. A prediction model based on these two parameters, mean menopausal age of first-degree relatives with the same mutation status and the correction for ascertainment site, estimated the probability of becoming postmenopausal for premutation carriers, with a margin of 7-10%. CONCLUSION: We conclude that this model serves as a first step toward clinical application of fragile X-associated primary ovarian insufficiency prediction.

Increase in the incidence of gestational trophoblastic disease in The Netherlands.

OBJECTIVE: The objective of this study is to determine the incidence and time trends of gestational trophoblastic disease (GTD) in The Netherlands using population-based data. METHODS: Data on patients with a pathologically confirmed diagnosis of GTD from 1995 to 2008 were obtained from PALGA, a national archive containing all histopathology reports in The Netherlands. Data on number of deliveries were obtained from the Database of Statistics Netherlands. RESULTS: During the study period, 4249 GTD patients were registered. Overall incidence rates of hydatidiform mole (HM), choriocarcinoma and placental site trophoblastic tumor (PSTT) were 1.34 per 1000 deliveries, 3.1 per 100,000 deliveries, and 1.0 per 100,000 deliveries, respectively. Incidence rates of HM increased from 1.02 per 1000 deliveries in 1995 to 1.56 per 1000 in 2001, an increase of 0.091 per year (95% CI 0.081-0.101). After 2001 incidence rates remained constant (increase per year -0.010, 95% CI -0.045-0.024). Maternal age and ethnicity are known to influence the risk of HM. Highest incidences were observed in women under 20 and over 40years of age. The proportion of deliveries accounted for by women over 40years of age increased from 1.5% to 2.9%, whereas women under 20 accounted for 1.5% of deliveries. The proportion of live births of Asian descent increased from 2.6% to 3.7%. CONCLUSION: The incidence of GTD in The Netherlands increased significantly from 1995 to 2008. This can partially be explained by increased maternal age and increased proportion of live births of Asian descent. Part of the increase might result from improved diagnostic techniques. However, these factors do not seem to account for the total observed increase and part of the increase therefore remains unexplained.

FSH isoform pattern in classic galactosemia.

Female classic galactosemia patients suffer from primary ovarian insufficiency (POI). The cause for this long-term complication is not fully understood. One of the proposed mechanisms is that hypoglycosylation of complex molecules, a known secondary phenomenon of galactosemia, leads to FSH dysfunction. An earlier study showed less acidic isoforms of FSH in serum samples of two classic galactosemia patients compared to controls, indicating hypoglycosylation. In this study, FSH isoform patterns of five classic galactosemia patients with POI were compared to the pattern obtained in two patients with a primary glycosylation disorder (phosphomannomutase-2-deficient congenital disorders of glycosylation, PMM2-CDG) and POI, and in five postmenopausal women as controls. We used FPLC chromatofocussing with measurement of FSH concentration per fraction, and discovered that there were no significant differences between galactosemia patients, PMM2-CDG patients and postmenopausal controls. Our results do not support that FSH dysfunction due to a less acidic isoform pattern because of hypoglycosylation is a key mechanism of POI in this disease.

The balance between extracellular cathepsins and cystatin C is of importance for ovarian cancer.

BACKGROUND: A major step in cancer formation involves the degradation of the extracellular matrix, mediated by multiple degradative actions of (lysosomal) proteases. Extracellular release of lysosomal proteases (cathepsins) and their inhibitors has been associated with the development and progression of several types of cancer. We investigated whether cathepsins in ovarian cyst fluid (oCF) were associated with disease outcome in patients with epithelial ovarian cancer (EOC). MATERIALS AND METHODS: The levels of cathepsin B (CatB), H (CatH), L (CatL) and X (CatX) and their most abundant extracellular inhibitor cystatin C (CysC) were determined in oCF of 50 EOC patients by quantitative ELISAs. The cathepsin levels and ratios between cathepsins and CysC were related to clinicopathological parameters (Mann-Whitney U and Kruskal-Wallis tests) and survival (Cox Regression analysis). RESULTS: Median (25th-75th percentile) levels of cathepsin B, H, L, X and CysC in oCF were 97 (42-203), 18 (12-32), 61 (37-108), 20 (13-47) and 657 (501-805) ng mL(-1) respectively. Ratio of CysC/CatB was significantly lower for patients with metastatic compared with localised EOC (P = 0.025). Ratios of CysC/CatH and CysC/CatX differed significantly between histological subtypes (P = 0.012 and P = 0.035 respectively) and were significantly higher for high-grade tumours compared with low-grade tumours (P = 0.031 and P = 0.039 respectively). Neither cathepsins nor their ratios were significant predictors of survival for EOC patients. CONCLUSIONS: Ratios between CysC and cathepsins in oCF differed significantly between important clinicopathological subgroups. We believe that a complex cascade of proteolytic events, in which cathepsins play different roles, might be responsible for progression and metastasis in EOC.

Pre-evacuation hCG glycoforms in uneventful complete hydatidiform mole and persistent trophoblastic disease.

OBJECTIVE: To investigate whether the glycoform distribution patterns of human chorionic gonadotropin (hCG) obtained by chromatofocusing in pre-evacuation serum are different for patients who will eventually develop into persistent trophoblastic disease in case of complete hydatidiform mole pregnancy as compared to those patients for whom trophoblastic tissue will regress uneventfully. METHODS: Pre-evacuation blood samples were collected from women with complete hydatidiform mole with uneventful spontaneous regression after molar evacuation (n=32), from women with complete hydatidiform mole who developed persistent trophoblastic disease after evacuation of their mole (n=28) and, as a control group, from women during the first trimester of normal pregnancy (n=22). The serum specimens were subjected to chromatofocusing, and hCG was determined in the fractions collected in the pH range 7.0-3.0. RESULTS: Receiver operating characteristics (ROC) analysis revealed that 36% of complete hydatidiform mole patients with post-molar persistent trophoblastic disease development had different hCG glycoform profiles at 97% specificity (pH interval 6.3-5.1, hCG cutoff 9.9%). There was a significant difference between complete hydatidiform mole with and without persistent trophoblastic disease for the cumulative percent amounts of hCG in the pH interval 6.3-5.1 (p<0.0003). CONCLUSION: In 36% of the patients with complete hydatidiform mole with subsequent development of persistent trophoblastic disease, typical glycoform profiles for hCG are observed in pre-evacuation serum samples. This result suggests that hCG glycoform profiles are of potential use in the prediction of persistent trophoblastic disease.

Earlier diagnosis and serum human chorionic gonadotropin regression in complete hydatidiform moles.

OBJECTIVE: To estimate serum human chorionic gonadotropin (hCG) regression in uneventful complete hydatidiform moles before and after the introduction of routine first-trimester ultrasonography. METHODS: Gestational age, maternal age, preevacuation hCG concentrations, serum hCG regression, and hCG disappearance time among a recent group of 137 women with uneventful complete hydatidiform moles that were found between 1994 and 2006 were evaluated retrospectively and compared with a historical cohort of 106 patients with complete moles that were found between 1977 and 1989. RESULTS: Gestational age, preevacuation hCG concentration, and hCG disappearance time were significantly lower in the recent complete hydatidiform mole cohort compared with the historic series. Ninety-nine percent of the recent cohort achieved hCG normalization within 19 weeks after uterine evacuation compared with 25 weeks in the historic group. CONCLUSION: Earlier serum hCG regression in the recent cohort of complete hydatidiform moles probably is a result of widely used first-trimester ultrasonography leading to detection and evacuation of complete moles at younger gestational ages, resulting in lower hCG levels at time of evacuation. LEVEL OF EVIDENCE: : II.

Preoperative CA-125 levels in 123 patients with borderline ovarian tumors: a retrospective analysis and review of the literature.

We studied preoperative CA-125 levels of 123 patients with borderline ovarian tumors (BOTs) and performed an analysis with data of earlier published studies. CA-125 levels were compared according to histology and stage of disease. Preoperative serum CA-125 levels were significantly higher for patients with advanced stage (median, 181 U/mL; range, 413 U/mL) compared with patients with stage I (median, 28 U/mL; range, 1123 U/mL) BOTs and for patients with serous (median, 59 U/mL; range, 1119 U/mL) compared with patients with mucinous (median, 25 U/mL; range, 371 U/mL) BOTs (both P < 0.001, Mann-Whitney U test). A pooled analysis of 3 studies and the present study showed positive rates of CA-125 (value >35 U/mL) in 171 (53%) of 325 patients with BOTs. Positive rates were more often found in patients with serous (67%) compared with patients with mucinous BOTs (39%) and in patients with advanced stage (83%) compared with patients with stage I BOTs (47%) (both P < 0.001, Pearson chi(2) test). This main effect was also found for each individual study of the pooled analysis. From a clinical perspective, we believe, on base of the results of this study and the literature, that preoperative discrimination using CA-125 level is especially difficult between patients with stage I ovarian cancer and the group of patients with serous and/or advanced-stage BOTs.

Secondary ovarian malignancies: frequency, origin, and characteristics.

OBJECTIVE: To evaluate the frequency of metastatic tumors among malignant ovarian neoplasms, the site distribution of the primary malignancies that give rise to ovarian metastasis and the clinicopathologic features of metastatic tumors. METHODS: We analyzed a total number of 116 patients diagnosed with metastasis to the ovary between 1985 and 2007 at the Radboud University Nijmegen Medical Centre. The medical records of the patients were reviewed for age at diagnosis, medical history, menopausal state, clinical manifestation, primary tumor, intraoperative findings, and prognosis. The pathology reports were reviewed for macroscopic appearances and histopathologic features. RESULTS: Metastasis to the ovary accounted for 15% of all ovarian malignancies identified in the 22-year period at the Radboud University Nijmegen Medical Centre. The gastrointestinal tract was the most common primary site (39%), followed by breast (28%) and endometrium (20%). There were 22 metastases to the ovary that mimicked a primary ovarian tumor at first clinical presentation, of which the single greatest number of cases (36%) originated from a primary tumor of the large intestine. Ovarian cysts were present in 71% of patients, and most ovaries with metastatic disease were 10 cm in diameter or less. Bilateral ovarian involvement was present in 69% of the patients, including all patients with tumors of the stomach. CONCLUSION: In case of an ovarian tumor, metastatic disease should always be considered to avoid pitfalls in diagnosis and therapy. The gastrointestinal tract is the most likely location of the primary tumor, followed by breast and endometrium.

Long-term follow-up of children with classic congenital adrenal hyperplasia: suggestions for age dependent treatment in childhood and puberty.

Background In congenital adrenal hyperplasia (CAH), achieving the balance between overtreatment and undertreatment remains challenging. Final height (FH) can serve as a long-term outcome measure. We aimed to identify age-dependent factors that influence FH in CAH patients, resulting in age-specific treatment goals. Methods We retrospectively evaluated longitudinal data of 39 pediatric CAH patients born between 1980 and 1997 from the Radboudumc CAH database. We analyzed height and bone age (BA) at diagnosis or 4 years of age, at the start of puberty and at FH. Height data were corrected for parental height and secular trend. Hydrocortisone (HC) use and salivary steroid concentrations were studied longitudinally throughout childhood and puberty. Results Median FH standard deviation scores (SDSs) corrected for target height SDSs (THSDSs) was -1.63. Median height SDS corrected for THSDS (HSDS-THSDS) decreased from diagnosis/age 4 years to FH in both salt wasting (SW) CAH and simple virilizing (SV) CAH, and in both male and female patients. However, when height was corrected for BA, no height loss occurred from diagnosis/age 4 years to FH in any of the subgroups, while a height gain was seen in SV males. In the combined model analyzing both HC dose and salivary steroid concentrations, in childhood the androstenedione (A) concentration was negatively associated with FH, while in puberty the HC dose was negatively associated with FH. Conclusions In CAH, loss of growth potential already occurs in early childhood. In prepubertal children, exposure to elevated androgens is associated with decreased FH. In puberty, the growth suppressing effects of HC outweigh the negative effects of elevated androgens. Therefore, we suggest different treatment approaches in prepubertal and pubertal patients.

Induction of IgG antibodies to MUC1 and survival in patients with epithelial ovarian cancer.

We investigated whether epithelial ovarian cancer patients participating in a randomized phase III trial comparing single intraperitoneal (IP) administration of yttrium-90-labeled murine HMFG1 ((90)Y-muHMFG1) plus standard treatment (AT) vs. standard treatment (ST) alone developed IgG ab to MUC1 that had an impact on disease outcome. Serial serum samples from 208 patients in the AT and 199 patients in the ST arm were tested for IgG ab to MUC1 (anti-MUC1 IgG). Anti-MUC1 IgG at weeks 4, 8 and 12 ranked higher in the AT than in the ST arm (p < 0.001). The median (range) area under the curve (AUC) of anti-MUC1 IgG for weeks 1 to 12 was 5.53 (1.51-39.51) and 3.92 (1.17-68.74) for the AT and ST arm, respectively (p < 0.001). An anti-MUC1 IgG AUC > 13 was associated with a benefit in overall survival (OS) and disease-free survival (DFS) in the AT arm in univariate (p = 0.043 and 0.036, respectively), but not in multivariate analysis (Cox proportional hazards regression model). Kaplan-Meier analysis showed a benefit in OS and DFS in patients with an anti-MUC1 IgG AUC > 13 in the AT arm (p = 0.043 and 0.036, respectively), but not in the ST arm. A single IP injection with muHMFG1 did not lead to a survival benefit in the randomized trial, but it induced ab to MUC1 that were associated with an improved disease outcome in patients with highest levels of anti-MUC1 IgG. Immunotherapy against MUC1 could be effective in the treatment of epithelial ovarian cancer.

The use of monoclonal antibodies for the treatment of epithelial ovarian cancer (review).

The prognosis for patients with ovarian cancer is still poor and more effective therapeutic modalities are needed. (Radio)immunotherapy using monoclonal antibodies (Mabs) could be one of these approaches. Here, we review the status of (radio)immunotherapy using Mabs for the treatment of ovarian cancer. The Pubmed database was searched for clinical trials investigating the effect of (radio)immunotherapy in ovarian cancer published until October 1, 2007. Keywords for the search were: ovarian cancer, monoclonal antibodies, CA 125, gp38, HER2, HMFG, MUC1, TAG 72 and VEGF. A total of 44 trials on immunotherapy with unconjugated Mabs, Mab vaccination and (radio)immunotherapy directed towards the antigens CA 125, gp38, HER2, MUC1, TAG 72 or VEGF in patients with ovarian cancer were found, reviewed and discussed. Out of these trials, 23 studied immunotherapy with unconjugated Mabs, 5 vaccination with Mabs and 16 trials studied (radio)immunotherapy. The lack of large randomized prospective trials with Mabs directed to tumor-associated antigens expressed on ovarian cancer cells preclude any firm conclusion on the potential of Mabs use in the treatment of ovarian cancer. Oregovomab, directed against CA 125, and bevacizumab, targeting VEGF, are two unconjugated Mabs closest to clinical introduction for the treatment of ovarian cancer. Vaccination with Mab ACA 125 seems promising but these findings need to be confirmed in controlled randomized trials. Sole RIT should be investigated with the appropriate radionuclide and a Mab with high affinity for the specific tumor-associated antigen in the appropriate patient group to determine whether it may have a therapeutic effect. Additionally, appending (radio)immunotherapy with anti-TAG 72 or anti-MUC1 to other treatment strategies such as chemotherapy could also be a strategy worthwhile investigating. The potential of Mabs to complement current treatment paradigms, is encouraging and may bring a significant improvement to the overall therapeutic outcomes currently being achieved in ovarian cancer.

Transient human anti-mouse antibodies (HAMA) interference in CA 125 measurements during monitoring of ovarian cancer patients treated with murine monoclonal antibody.

OBJECTIVE: To investigate the influence of human anti-mouse antibodies (HAMA) on serial CA 125 measurements in serum of patients with epithelial ovarian cancer following single intraperitoneal (IP) therapy with Yttrium-90-labeled human milk fat globule 1 murine monoclonal antibody ((90)Y-muHMFG1) as part of a large international randomized phase III trial. METHODS: We monitored CA 125 concentrations in longitudinally collected serum samples from 224 patients after IP (90)Y-muHMFG1 (study group) and from 223 patients who received standard treatment (control group). Serum samples of 22 study patients with increased CA 125 concentrations were selected and subjected to affinity chromatography to study HAMA interference in CA 125 measurements. RESULTS: CA 125 serum concentrations at weeks 1, 4 and 8 were significantly higher in the study group than in the control group. In the first 8 weeks after IP (90)Y-muHMFG1 administration significantly more patients of the study group (144/224) demonstrated CA 125 concentrations above the upper limit of normal of 23 U/mL, as compared to those of the control group (37/223). Affinity chromatography of serum with high CA 125 values in the first 8 weeks confirmed HAMA interference in CA 125 measurements while after 24 weeks this HAMA interference could no longer be detected. CONCLUSIONS: This is the first study to demonstrate that clinical trials applying murine monoclonal antibodies may be flawed by a transient HAMA effect, which should be considered when monitoring ovarian cancer patients with CA 125 measurements.

Human anti-mouse IgM and IgG responses in ovarian cancer patients after radioimmunotherapy with 90Y-muHMFG1.

BACKGROUND: Human anti-mouse antibody (HAMA)-IgM and IgG in ovarian cancer patients treated with intraperitoneal (i.p.) 90Y-muHMFG1 as consolidating therapy were analyzed for a relationship with outcome of disease. PATIENTS AND METHODS: Serial serum samples from 208 ovarian cancer patients participating in a phase III trial of i.p. 90Y-muHMFG1 and 25 controls were analyzed for HAMA-IgM and HAMA-IgG. Results were correlated with time to, and location of, disease recurrence. RESULTS: Patients receiving i.p. 90Y-muHMFG1 developed a rapid HAMA-IgM peak (week 4 to 8), followed by a HAMA-IgG peak 2-4 weeks later. HAMA levels in the control group remained unchanged. Early maximum HAMA-IgG peaks were associated with early relapse [hazard ratio (HR), 0.975; 95% confidence interval (CI) 0.956 to 0.995; p=0.012]. Patients with a HAMA-IgG maximum before or at 8 weeks were at significantly higher risk for disease recurrence (HR, 1.6; 95% CI 1.1 to 25;p=0.021) as compared to patients with a HAMA-IgG maximum after 8 weeks. CONCLUSION: Besides time point of maximum HAMA-IgG, no evident relation could be found between HAMA-IgM or HAMA-IgG development and time to relapse or location of recurrence.

Pesticide exposure: the hormonal function of the female reproductive system disrupted?

Some pesticides may interfere with the female hormonal function, which may lead to negative effects on the reproductive system through disruption of the hormonal balance necessary for proper functioning. Previous studies primarily focused on interference with the estrogen and/or androgen receptor, but the hormonal function may be disrupted in many more ways through pesticide exposure. The aim of this review is to give an overview of the various ways in which pesticides may disrupt the hormonal function of the female reproductive system and in particular the ovarian cycle. Disruption can occur in all stages of hormonal regulation: 1. hormone synthesis; 2. hormone release and storage; 3. hormone transport and clearance; 4. hormone receptor recognition and binding; 5. hormone postreceptor activation; 6. the thyroid function; and 7. the central nervous system. These mechanisms are described for effects of pesticide exposure in vitro and on experimental animals in vivo. For the latter, potential effects of endocrine disrupting pesticides on the female reproductive system, i.e. modulation of hormone concentrations, ovarian cycle irregularities, and impaired fertility, are also reviewed. In epidemiological studies, exposure to pesticides has been associated with menstrual cycle disturbances, reduced fertility, prolonged time-to-pregnancy, spontaneous abortion, stillbirths, and developmental defects, which may or may not be due to disruption of the female hormonal function. Because pesticides comprise a large number of distinct substances with dissimilar structures and diverse toxicity, it is most likely that several of the above-mentioned mechanisms are involved in the pathophysiological pathways explaining the role of pesticide exposure in ovarian cycle disturbances, ultimately leading to fertility problems and other reproductive effects. In future research, information on the ways in which pesticides may disrupt the hormonal function as described in this review, can be used to generate specific hypotheses for studies on the effects of pesticides on the ovarian cycle, both in toxicological and epidemiological settings.