Carina G. J. M. Hilders

Successful human ovarian autotransplantation to the upper arm

In young patients with cervical carcinoma, the standard surgical treatment is often followed by postoperative radiotherapy. This treatment strategy, although resulting in a significant increase in cure rates, often causes infertility and premature ovarian failure. Ovarian autotransplantation outside the field of radiotherapy is a new technique to preserve gonadal function.One ovary was transplanted to the left upper arm during the surgical treatment for cervical carcinoma. Vascular anastomoses were performed by microsurgery. After transplantation, the ovary showed adequate arterial and venous blood flow. By clinical examination and ultrasound monitoring, the ovarian cycles remained regular and follicle growth occurred normally for > 1 year. Heterotopic autotransplantation of the ovary to the upper arm is a promising surgical technique to maintain the ovarian function in women who become menopausal due to cancer treatment regimens. Cancer 2004.

Development of the follicular basement membrane during human gametogenesis and early folliculogenesis

BackgroundIn society, there is a clear need to improve the success rate of techniques to restore fertility. Therefore a deeper knowledge of the dynamics of the complex molecular environment that regulates human gametogenesis and (early) folliculogenesis in vivo is necessary. Here, we have studied these processes focusing on the formation of the follicular basement membrane (BM) in vivo.ResultsThe distribution of the main components of the extracellular matrix (ECM) collagen IV, laminin and fibronectin by week 10 of gestation (W10) in the ovarian cortex revealed the existence of ovarian cords and of a distinct mesenchymal compartment, resembling the organization in the male gonads. By W17, the first primordial follicles were assembled individually in that (cortical) mesenchymal compartment and were already encapsulated by a BM of collagen IV and laminin, but not fibronectin. In adults, in the primary and secondary follicles, collagen IV, laminin and to a lesser extent fibronectin were prominent in the follicular BM.ConclusionsThe ECM-molecular niche compartimentalizes the female gonads from the time of germ cell colonization until adulthood. This knowledge may contribute to improve methods to recreate the environment needed for successful folliculogenesis in vitro and that would benefit a large number of infertility patients.

Searching for metastases in ovarian tissue before autotransplantation: a tailor-made approach

OBJECTIVE To exclude minimal residual disease in remaining ovarian tissue after harvesting the ovarian cortex for cryopreservation, by means of a tailor-made approach. DESIGN Retrospective case series. SETTING Hospital laboratory. PATIENT(S) We evaluated the ovarian and tubal tissue from 47 cancer patients (breast cancer, [non-]Hodgkin lymphoma; osteo-, Ewing, myxoid lipo-, and oropharyngeal synovial sarcoma; cervical, rectal, and esophageal cancer), who had stored ovarian tissue for fertility preservation. INTERVENTION(S) Immunohistochemistry (IHC) with tumor-related antibodies and genetic mutation analysis were performed to detect micrometastases by multiple sectioning at three levels of the paraffin-embedded formalin-fixed material. Molecular assays were performed with the use of tissue between these three levels of sectioning. MAIN OUTCOME MEASURE(S) Detection of micrometastases in ovaries. RESULT(S) We analyzed 847 ovarian slides to detect isolated tumor cells (ITCs) or micrometastases by IHC. In only one case (1/47) were ITCs detected in the fallopian tube. That patient had an intra-abdominal metastatic esophageal carcinoma. Additional DNA analyses of breast and rectal cancer, Ewing sarcoma, and human papilloma virus in cervical patients did not show evidence of micrometastases in the ovarian tissue. CONCLUSION(S) The tailor-made approach consisted of patient-specific tumor markers which were used to search for ovarian micrometastases. We found evidence of metastatic disease within the fallopian tube of a patient with intraperitoneal metastatic esophageal adenocarcinoma.

Non-invasive detection of metastases and follicle density in ovarian tissue using full-field optical coherence tomography

Purpose: Autotransplantation of ovarian tissue can be used to restore fertility in patients with cancer following gonadotoxic treatment. Whether this procedure is safe remains unclear, as current tumor detection methods render the ovarian tissue unsuitable for transplantation. Full-field optical coherence tomography (FF-OCT) is an imaging modality that rapidly produces high-resolution histology-like images without the need to fix, freeze, or stain the tissue. In this proof-of-concept study, we investigated whether FF-OCT can be used to detect metastases in ovarian tissue, thereby increasing the safety of ovarian tissue autotransplantation. We also evaluated whether cortical ovarian tissue and follicles remain viable following FF-OCT imaging. Experimental Design: Formalin-fixed, paraffin-embedded tissue samples were obtained from seven normal ovaries and fourteen ovaries containing metastases and/or micrometastases. These samples were deparaffinized and imaged using FF-OCT. The FF-OCT images were then compared with corresponding hematoxylin and eosin–stained tissue sections. Finally, we examined the effect of FF-OCT imaging on the viability of ovarian tissues and follicles in fresh bovine ovarian tissue using a glucose uptake and neutral red staining, respectively. Results: FF-OCT illustrated both normal structures and metastases in ovarian tissue within minutes. Primordial follicles were readily identifiable. Finally, tissues and follicles remained viable following FF-OCT imaging for up to 180 and 60 minutes, respectively. Conclusions: FF-OCT imaging is a promising method for the noninvasive detection of metastases, including micrometastases, in ovarian tissue. Moreover, this method facilitates the selection of cortical ovarian tissue with the highest density of primordial follicles, potentially increasing the likelihood of restoring ovarian function following ovarian tissue autotransplantation. Clin Cancer Res; 22(22); 5506–13. ©2016 AACR.

Medical leaders or masters? - A systematic review of medical leadership in hospital settings

Medical leadership is increasingly considered as crucial for improving the quality of care and the sustainability of healthcare. However, conceptual clarity is lacking in the literature and in practice. Therefore, a systematic review of the scientific literature was conducted to reveal the different conceptualizations of medical leadership in terms of definitions, roles and activities, and personal–and context-specific features. Eight databases were systematically searched for eligible studies, including empirical studies published in peer-reviewed journals that included physicians carrying out a manager or leadership role in a hospital setting. Finally, 34 articles were included and their findings were synthesized and analyzed narratively. Medical leadership is conceptualized in literature either as physicians with formal managerial roles or physicians who act as informal ‘leaders’ in daily practices. In both forms, medical leaders must carry out general management and leadership activities and acts to balance between management and medicine, because these physicians must accomplish both organizational and medical staff objectives. To perform effectively, credibility among medical peers appeared to be the most important factor, followed by a scattered list of fields of knowledge, skills and attitudes. Competing logics, role ambiguity and a lack of time and support were perceived as barriers. However, the extent to which physicians must master all elicited features, remains ambiguous. Furthermore, the extent to which medical leadership entails a shift or a reallocation of tasks that are at the core of medical professional work remains unclear. Future studies should implement stronger research designs in which more theory is used to study the effect of medical leadership on professional work, medical staff governance, and subsequently, the quality and efficiency of care.

Prevalence and Risk Factors of Ovarian Metastases in Breast Cancer Patients < 41 Years of Age in the Netherlands: A Nationwide Retrospective Cohort Study.

Purpose Breast cancer is one of the primary indications for cryopreservation and subsequent autotransplantation of ovarian tissue. The safety of this fertility preservation method remains questionable, as the presence of disseminated breast tumor cells cannot yet be excluded in the ovarian autografts. We explored the prevalence of ovarian metastases among young breast cancer patients and determined risk factors for the development of ovarian metastases. Methods Using the nationwide database of the Dutch Pathology Registry (PALGA), we identified a cohort of 2648 women with primary invasive breast cancer at age < 41 years in the period 2000–2010 in the Netherlands who subsequently underwent an oophorectomy. From this source population, all cases who had histologically confirmed ovarian metastases were included. For each case of whom clinical data were available, one control without ovarian metastases who matched the time interval between breast cancer diagnosis and oophorectomy was selected. Data were collected on patient characteristics, diagnosis, treatment and follow-up. Results Ovarian metastases were found in 63 out of 2648 patients who met the inclusion criteria. The risk of developing ovarian metastases increased with time passed since breast cancer diagnosis. Multivariate logistic regression analyses showed significant association between tumor stage and the development of ovarian metastases (p = 0.024). Conclusions The prevalence of ovarian metastases was 2.4% among young breast cancer patients. Early ovary removal may reduce the risk of developing ovarian metastases. In breast cancer patients with tumors > 5 cm and/or inflammatory carcinoma, we recommend a cautious approach to ovarian tissue autotransplantation.

Morphological and phenotypical features of ovarian metastases in breast cancer patients

BackgroundAutotransplantation of frozen-thawed ovarian tissue is a method to preserve ovarian function and fertility in patients undergoing gonadotoxic therapy. In oncology patients, the safety cannot yet be guaranteed, since current tumor detection methods can only exclude the presence of malignant cells in ovarian fragments that are not transplanted. We determined the need for a novel detection method by studying the distribution of tumor cells in ovaries from patients with breast cancer. Furthermore, we examined which cell-surface proteins are suitable as a target for non-invasive tumor-specific imaging of ovarian metastases from invasive breast cancer.MethodsUsing the nationwide database of the Dutch Pathology Registry (PALGA), we identified a cohort of 46 women with primary invasive breast cancer and ovarian metastases. The localization and morphology of ovarian metastases were determined on hematoxylin-and-eosin-stained sections. The following cell-surface markers were immunohistochemically analyzed: E-cadherin, epithelial membrane antigen (EMA), human epidermal growth receptor type 2 (Her2/neu), carcinoembryonic antigen (CEA), αvβ6 integrin and epithelial cell adhesion molecule (EpCAM).ResultsThe majority of ovarian metastases (71%) consisted of a solitary metastasis or multiple distinct nodules separated by uninvolved ovarian tissue, suggesting that ovarian metastases might be overlooked by the current detection approach. Combining the targets E-cadherin, EMA and Her2/neu resulted in nearly 100% detection of ductal ovarian metastases, whereas the combination of EMA, Her2/neu and EpCAM was most suitable to detect lobular ovarian metastases.ConclusionsExamination of the actual ovarian transplants is recommended. A combination of targets is most appropriate to detect ovarian metastases by tumor-specific imaging.