First step in implementation of opportunistic salpingectomy for prevention of ovarian cancer: Current care and its determinants.

INTRODUCTION: Opportunistic salpingectomy (OS) refers to additional removal of the fallopian tubes during abdominal surgery performed for another medical indication, as prevention for ovarian cancer. As OS has been inconsistently implemented, its clinical practice varies worldwide. To reduce this variation, insight is required into current clinical practice and its determinants. Therefore, the study aim was to determine the implementation of counseling and performance of OS between 2015 and 2018, and its patient, surgical, physician, and hospital characteristics. MATERIAL AND METHODS: Retrospective study using electronic medical records from six different Dutch hospitals: two academic, two large teaching, and two non-teaching hospitals. Patients were considered eligible for OS if they underwent elective non-obstetric abdominal surgery for a gynecological indication from January 2015 through December 2018. Primary outcomes were uptake of counseling and performance of OS. Multilevel multivariable logistic regression analyses were conducted to identify characteristics associated with OS. RESULTS: A total of 3214 patients underwent elective non-obstetric abdominal surgery for a gynecological indication and were eligible for OS. Counseling on OS increased significantly from 2.9% in 2015 to 29.4% in 2018. In this period, 440 patients were counseled on OS, of which 95.9% chose OS. Performance of OS increased significantly from 6.9% in 2015 to 44.5% in 2018. Counseling for and performance of OS were more likely in patients who had surgery by laparoscopic approach, were counseled by a gynecological resident, or had more than three contact moments before surgery. Additionally, OS was less likely in patients who had vaginal surgery. CONCLUSIONS: Although the uptake of OS increased from 2015 to 2018, the majority of patients who were eligible for OS were not counseled and did not undergo OS. Its clinical practice varies on patient, surgery, and physician characteristics. Therefore, an implementation strategy tailored to associated determinants is recommended.

Peritoneal lesions caused by Enterobius vermicularis suspected to be metastases of ovarian malignancy.

Enterobius vermicularis, also known as pinworm, is a helminth that commonly causes intestinal parasitic infestation. E. vermicularis can also cause extraintestinal infestations. We report a case of lower abdominal pain and intermittent vaginal bleeding in a 45-year-old woman who was referred to our gynaecology department. On investigation, a transvaginal ultrasound showed a multilocular cyst in the left ovary, along with elevated levels of cancer antigen 125. Consequently, a laparoscopic salpingo-oophorectomy was performed. A biopsy of atypical peritoneal lesions revealed remains of E. vermicularis Peritoneal lesions are a rare complication of enterobiasis, and the diagnosis of this complication is usually delayed by limitations in diagnostic options. Although extraintestinal enterobiasis does not require treatment because it is the last stage of the parasitic cycle, primary intestinal infestation requires treatment with mebendazole.

[A neonate with a vaginal cyst]. / Een neonaat met een vaginale cyste.

During the physical examination of a full-term neonate we noticed a stalked, fluid-filled appendix, attached to the posterior vagina wall. A 'hymenal tag' was diagnosed: an innocent, self-limiting phenomenon caused by maternal oestrogens.

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.

Improvement of endometrial biopsy over transvaginal ultrasound alone for endometrial surveillance in women with Lynch syndrome.

In women with hereditary non polyposis colorectal carcinoma (HNPCC) an annual gynaecological surveillance has been recommended because of an increased lifetime risk of developing endometrial and ovarian carcinoma. The aim of this study was to assess the efficacy of gynaecological surveillance with regard to endometrial and ovarian carcinoma. Included were women from families that fulfilled the revised Amsterdam criteria for HNPCC or who showed a proven mutation in one of the mismatch repair genes. An annual gynaecological surveillance was performed (transvaginal ultrasound (TVU) and CA 125 assessment). From January 2006 on, routine endometrial sampling was included. In a total number of 100 women 285 surveillance visits were performed. Among these, in 64 visits routine endometrial samplings were performed: three atypical hyperplasias and one endometrial carcinoma were diagnosed. This was significantly more than the atypical hyperplasia and two endometrial carcinomas that were detected after 28 samples performed because of abnormal surveillance results in 221 visits. There were no interval carcinomas. One invasive ovarian carcinoma stage IIIC was diagnosed at ovarian surveillance. Endometrial surveillance with routine endometrial sampling in women with HNPCC is more efficient in diagnosing endometrial (pre)malignancies than TVU only. Ovarian surveillance is not capable of diagnosing early stage ovarian carcinoma. Prophylactic hysterectomy in HNPCC should be restricted to women in whom abdominal surgery for other reasons is performed and to those with particularly increased risk such as MSH6 mutation carriers and/or women with multiple relatives with endometrial carcinoma.

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.

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.

Extraperitoneal leakage as a possible explanation for failure of one-time intraperitoneal treatment in ovarian cancer.

We conducted a single-arm study to determine the biodistribution of intraperitoneally (i.p.) administered 90yttrium-labeled murine monoclonal antibody HMFG1 (90Y-muHMFG1) in patients with advanced stage ovarian cancer. Seventeen (17) patients in complete clinical remission for epithelial ovarian cancer were included. After completion of chemotherapy, a mixture of 111indium-labeled muHMFG1 (imaging) and 90Y-muHMFG1 (therapy) was i.p. administered by a surgically placed, indwelling i.p. catheter. Planar and single-photon emission computed tomography images were recorded to determine the distribution of the study medication during the first 6 days postinjection. Of the first 3 patients, 2 patients had extraperitoneal leakage of up to 50% of the injected dose within 24 hours after injection of the study medication. Extraperitoneal leakage was mainly seen in the retroperitoneal spaces covering the upper and lower quadrant of the abdomen. After adjustments in the procedure, leakage was observed in 2 of the remaining 14 patients. Extraperitoneal leakage of i.p. administered therapy does occur. Such leakage would reduce the locally delivered dose of a drug and could potentially have a negative impact on therapeutic efficacy. Given the potential attraction of developing i.p. treatments for intra-abdominal cancer, the observations in this study need to be taken into consideration.

Decreased intraperitoneal disease recurrence in epithelial ovarian cancer patients receiving intraperitoneal consolidation treatment with yttrium-90-labeled murine HMFG1 without improvement in overall survival.

This study analyzes the site of disease recurrence in ovarian cancer patients to assess the influence of a single intraperitoneal (IP) administration of yttrium-90-labeled murine monoclonal antibody HMFG1 ((90)Y-muHMFG1) on the pattern of disease recurrence. In a large phase III trial ovarian cancer patients in complete clinical remission with FIGO stage Ic-IV were randomized between standard treatment plus a single IP (90)Y-labeled muHMFG1 versus standard treatment alone after negative second-look laparoscopy. Case report forms of all patients with disease recurrence were reviewed to determine site and date of recurrent disease. In total 447 patients were included in the study with a median follow-up of 3.5 years. Relapse was seen in 104/224 in the active and 98/223 in the control arm. Significantly fewer IP (p < 0.05) and more extraperitoneal (p < 0.05) relapses occurred in the active treatment arm. Time to IP recurrence was significantly longer (p = 0.0019) and time to extraperitoneal recurrence was significantly shorter for the active treatment arm (p < 0.001). The impact of IP radioimmunotherapy on IP relapse-free survival could only be seen in the subgroup of patients with residual disease after primary surgery (HR, 0.31; 95% CI, 0.18 to 0.53; p = 0.002). Although, there is no survival benefit for IP radioimmunotherapy as consolidation treatment for epithelial ovarian cancer, we found an improved control of IP disease, that was offset by increased extraperitoneal recurrences.