Study Protocol of a Prospective, Monocentric, Single-Arm Study Investigating the Safety and Efficacy of Local Ablation of Symptomatic Uterine Fibroids with US-Guided High-Intensity Focused Ultrasound (HIFU).

Uterine fibroids are the most common benign tumors of the uterus. Approximately 20-50% of women with myomas experience a variety of symptoms such as vaginal bleeding, abdominal pain, pelvic pain and pressure, and urological problems, possibly interfering with fertility and pregnancy. Although surgery remains the standard treatment option for fibroids, non-invasive therapeutic options, such as high-intensity focused ultrasound (HIFU), have emerged over the last dec ade. During HIFU, ultrasound is focused on the target tissue causing coagulation necrosis. HIFU has, meanwhile, become an established method for treating uterine fibroids in many countries. Clinical data have shown that it effectively alleviates fibroid-related symptoms and reduces fibroid size with a very low rate of side effects. However, there is a lack of data on how this treatment affects laboratory parameters and structural features of uterine tissue. As our center is the only one in German-speaking countries where ultrasound-guided HIFU technology is currently established, the aim of this prospective, monocentric, single-arm trial is not only to evaluate the safety and efficacy of local US-guided HIFU in symptomatic uterine fibroid patients according to GCP standards but also to explore its effects on blood parameters and the structural integrity of uterine tissue using elastographic methods.

Treatment strategies in patients with gynecological sarcoma: Results of the prospective intergroup real-world registry for gynecological sarcoma in Germany (REGSA-NOGGO RU1).

OBJECTIVE: Gynecological sarcomas account for 3% of all gynecological malignancies and are associated with a poor prognosis. Due to the rarity and heterogeneity of gynecological sarcomas there is still no consensus on optimal therapeutic strategies. This study's objective was to describe the treatment strategies used in patients with gynecological sarcomas in the primary course of disease. METHODS: The German prospective registry for gynecological sarcoma (REGSA) is the largest registry for gynecological sarcomas in Germany, Austria and Switzerland. Primary inclusion criteria for REGSA are histological diagnosis of sarcoma of the female genital tract, sarcoma of the breast or uterine smooth muscle tumors of uncertain malignant potential (STUMP). We evaluated data of the REGSA registry on therapeutic strategies used for primary treatment from August 2015 to February 2021. RESULTS: A total of 723 patients from 120 centers were included. Data on therapeutic strategies for primary treatment were available in 605 cases. Overall, 580 (95.9%) patients underwent primary surgery, 472 (81.4%) of whom underwent only hysterectomy. Morcellation was reported in 11.4% (n=54) of all hysterectomies. A total of 42.8% (n=202) had no further surgical interventions, whereas an additional salpingo-ophorectomy was performed in 54% (n=255) of patients. An additional lymphadenectomy was performed in 12.7% (n=60), an omentectomy in 9.5% (n=45) and intestinal resection in 6.1% (n=29) of all patients. Among 448 patients with available information, 21.4% (n=96) received chemo- or targeted therapies, more commonly as single-agent treatment than as drug combinations. Information about anti-hormonal treatment was available for 423 patients, among which 42 (9.9%) received anti-hormonal treatment, 23 (54.8%) of whom with low-grade endometrial stroma sarcomas. For radiotherapy, data of 437 patients were available, among which 29 (6.6%) patients underwent radiotherapy. CONCLUSION: Our study showed that treatment of patients with gynecologic sarcomas is heterogeneous. Further trials are needed along with more information on treatment modalities, therapy response and patient-reported outcomes to implement new treatment strategies.

Evaluation of an OSCE's implementation and a two-step approach for a theoretical and practical training program in Obstetrics and Gynecology.

Objective structured clinical examination (OSCE) is a well-known assessment method to evaluate clinical skills and competence in healthcare. Following the recently reformed National Competence-Based Catalog of Learning Objectives in Medicine, the implementation of this assessment method in the training program for medical students is now obligatory in Germany. This major change requires a reorganization not only of the training programs but also of the students themselves and the way they learn. We performed a poll evaluating the students' opinions regarding these major changes and the implementation of the OSCE with a new training program. To implement this assessment method and to evaluate the OSCE, Kern's six-step approach comprising (1) problem identification and general needs assessment, (2) needs assessment of the targeted learners, (3) goals and objectives, (4) educational strategies, (5) implementation, and (6) evaluation and feedback was applied. To evaluate and gather feedback, a poll was used to analyze the student's opinions regarding OSCE in gynecology and obstetrics and OSCE in general, in addition to the regular analysis of the students' results. To reform the educational strategy, a two-step approach was developed: First, the students completed the regular training program and a written examination, and second, they participated in a 1-week clerkship, in small group teaching, and in the OSCE. The OSCE stations were developed primarily based on the National Competence-Based Catalog and the German Catalog of Learning Objectives in Medicine, as well as on the feedback of experts reflecting their expectations for physicians beginning their careers. The students performed well in the OSCE and gave positive feedback regarding this examination method. Furthermore, they welcomed the upcoming changes by considering OSCE a valuable assessment tool, and they showed appreciation for the two-step approach by supporting the combination of an OSCE and a written examination. Thus, this article presents the implementation of an OSCE and a strategy for the adaptation of the curriculum to fulfill the new OSCE requirements and-to our knowledge-reveals students' primary opinions regarding the changes in their medical training program for the first time.

Postoperative Femoral Nerve Palsy and Meralgia Paresthetica after Gynecologic Oncologic Surgery.

Femoral nerve palsy and meralgia paresthetica following gynecologic cancer surgery are rare, but severe and long lasting. Here, we aimed to study their incidence, severity, possible risk factors and its time to remission. Between January 2008 and December 2017 976 gynecologic cancer patients were identified in our institutional database receiving surgery. Complete patient charts were reviewed retrospectively. Possible risk factors were analyzed by Fisher's exact test. 441 (45.18%) out 976 were treated for Ovarian cancer. In total 23 patients were identified with a postoperative neurological leg disorder. A femoral nerve palsy was present in 15 patients (1.5%) and a meralgia paresthetica in 8 patients (0.82%). Three patients showed both disorders. Duration of surgery (p = 0.0000), positioning during surgery (p = 0.0040), femoral artery catheter (p = 0.0051), prior chemotherapy (p = 0.0007), nicotine abuse (p = 0.00456) and prior polyneuropathy (p = 0.0181) showed a significant association with a postoperative femoral nerve palsy. Nicotine abuse (p = 0.0335) and prior chemotherapy (p = 0.0151) were significant for the development of a meralgia paresthetica. Long lasting surgery, patient positioning and femoral arterial catheter placement are risk factors for a postoperative femoral nerve palsy in gynecologic cancer surgery. Polyneuropathy, nicotine abuse, and prior chemotherapy are predisposing risk factors for a femoral nerve palsy and a meralgia paresthetica. A resolution of symptoms is the rule for both disorders within different time schedules.

Clinical value of pre-operative scoring systems to predict leiomyosarcoma: results of a validation study in 177 patients from the NOGGO-REGSA Registry.

OBJECTIVES: Benign leiomyomas are the most common uterine tumors. In contrast, uterine leiomyosarcomas are malignancies with a poor prognosis due to difficulties in early diagnosis and inappropriate surgical treatment. Most often they are diagnosed incidentally after surgery performed for treatment of leiomyoma. As the appropriate surgical treatment is crucial for survival of the patient, there is a high demand to predict leiomyosarcoma pre-operatively. Available scoring systems to discriminate leiomyoma from leiomyosarcoma are based on retrospective studies with limited numbers of patients and are not implemented in routine clinical practice. METHODS: The aim of our study was to evaluate a recently published score-the pre-operative leiomyosarcoma (pLMS) score-to determine whether it would have been predictive of leiomyosarcoma in 177 patients from the NOGGO-REGSA study, a German register of histologically proven gynecological sarcoma detected during routine clinical investigation. RESULTS: The threshold of the pLMS score for 'leiomyosarcoma not probable' (< -3) failed for 7.5% of the patients and the threshold 'indicator for leiomyosarcoma' (>+1) was true for 39.1% of the patients. 53.4% of the patients were attributed to the group 'additional investigations are recommended' (-3 to +1). The most relevant parameters in our analysis were suspicious sonography and rapid growth, but neither have been quantitatively defined. CONCLUSION: In our validation cohort, the pLMS score seems not to be a reliable tool to predict leiomyosarcoma and therefore we do not recommend its clinical implementation to identify leiomyosarcoma.

Diagnostic and Therapeutic Approach in a Metastatic Vaginal Adenocarcinoma: A Case Report.

Background: Vaginal adenocarcinomas (VAC) are most often reported after intrauterine exposition to diethylstilbestrol (DES). Rarely, VACs are reported as a malignant transformation of vaginal adenosis or endometriosis, in the context of chromosomal abnormalities or malformations of the uterus or the vagina. VACs without DES exposition have a poor prognosis and a significantly worse outcome compared to vaginal squamous cell carcinomas or DES-associated VACs. Objective: Here, we report the case of a primarily metastatic VAC, treated successfully with different lines of chemo-, antiangiogenic, antibody, and immunotherapy. Case: The 49-year-old patient presented in 5/2018 with a primarily pulmonary metastatic VAC. Significant tumor reduction was seen after six cycles of carboplatin AUC5/paclitaxel 175 mg/m²/bevacizumab 15 mg/kg q3w. Bevacizumab maintenance therapy and later cisplatin mono 50 mg/m² q2w led to local and distant tumor progression. To identify a potential targeted therapy, new tumor biopsies were obtained. Immunohistochemistry revealed ERBB2 expression, and paclitaxel 80 mg/m² weekly plus trastuzumab 4 mg/m² respectively 2 mg/m² q3w was administered. Due to local and pulmonal tumor progression after 6 months and persistent ERBB2 positivity, the therapy was adjusted to trastuzumab emtansine (T-DM1) 3.6 mg/kg q3w; however, the patient remained locally progressive after three cycles of T-DM1 and additionally showed a new bone metastasis. The new tumor biopsies revealed a combined positive score (CPS) of 2 regarding PD-L1, and pembrolizumab 200 mg q3w was initiated. The bone metastasis was radiated and treated with denosumab 120 mg q4w. Extreme tumor regression followed by stable disease was maintained for 9 months. Due to a slow locoregional progress only with new inguinal lymph node and pararectal lymph node metastases, a new tumor biopsy was taken. Molecular profiling showed an ARID1A mutation, a mutational burden of 5.1 mutations per megabase, and no genfusions. Based on these findings, therapy with PD-L1 antibodies, PD-1 antibodies, gemcitabine, or dasatinib was suggested. Therefore, administration of pembrolizumab was continued and local radiation therapy was performed. This led to a decrease in local tumor manifestations and a stable systemic disease. Conclusion: Our case demonstrates the diagnostic and therapeutic approach in a patient with primary metastatic vaginal adenocarcinoma. By tumorgenetic profiling, different lines of systemic therapy, namely, antiangiogenic therapy, monoclonal antibody therapy, immunotherapy, and local radiation therapy, were identified and successfully administered.

[Incidental finding of an intestinally differentiated adenocarcinoma in a tailgut cyst after robotic-assisted resection]. / Zufallsbefund eines intestinal differenzierten Adenokarzinoms in einer Tailgut Zyste nach robotisch-assistierter Resektion.

Due to pelvic symptoms, a diagnostic sectional imaging was initiated in a 52-year-old female patient. This revealed a cystic, retrorectal mass, suspected to be a tailgut cyst. Due to the symptoms and the unclear dignity after several frustrating endosonographic punctures, a robotic-assisted resection of the cystic Tumor was performed after careful interdisciplinary consultation.The histological examination confirmed the diagnosis of a tailgut cyst but also revealed parts of an intestinally differentiated adenocarcinoma.Due to the unclear metastatic behaviour, robotic-assisted low anterior resection with total mesorectal excision was performed as oncological resection, similar to rectal carcinomas. No residuals or lymph node metastases were detectable in the histological examination, so that follow- up monitoring was recommended.Retrorectal tumours are an extremely rare entity, worldwide only 28 cases of an intestinally differentiated carcinoma in a tailgut cyst have been described so far. Since there are no clear recommendations in the literature regarding the diagnostic or therapeutic procedure, we would like to discuss a possible algorithm in case of a proven retrorectal mass in our case study.

Pelvic Exenteration in Advanced Gynecologic Malignancies - Who Will Benefit?

BACKGROUND/AIM: In selected patients, pelvic exenteration (PE) is curative, but morbidity and mortality are feared. Unfortunately, prerequisites for indicating PE are not generally defined. The aim of the study was to identify prognostic factors for survival after PE in advanced pelvic gynecological malignancies for finding possible prerequisites for the indication of PE. PATIENTS AND METHODS: Between 2002 and 2016, 49 patients underwent pelvic exenteration for advanced pelvic malignancies apart from ovarian cancer. Progression-free survival (PFS) and overall survival (OS) were calculated based on the Kaplan-Meier method. Factors significantly affecting 5-year overall survival were identified using multivariate regression analysis. Survival distributions between the best and the worst group were compared by the log rank test. RESULTS: Forty-nine patients with recurrent or primary pelvic gynecological malignancy (20 recurrent disease, 29 primary disease) were included. Seventeen patients had oligometastatic disease at surgical intervention. Resection margin, age, primary versus secondary exenteration and metastatic disease were independent prognostic factors in multivariate regression analysis. A significant difference was observed in 5-year overall survival regarding the best group (57.14%) and the worst group (10%) (p=0.009). Cervical cancer was the only identified risk factor for increased morbidity. CONCLUSION: Pelvic exenteration is a valuable therapeutic option with most long-term survivors in the group of patients below 63 years, as primary treatment, with clear microscopic margins and no distant metastases. These four factors may serve as valuable prerequisites for the indication of pelvic exenteration as survival and morbidity in this group of patients compares favorably to alternative therapeutic options.

Gene expression in the Angiopoietin/TIE axis is altered in peripheral tissue of ovarian cancer patients: A prospective observational study.

AIMS: Clinical studies suggest altered systemic vascular biology in cancer patients. We assessed expression patterns of endothelial activation- and vascular leakage-related genes in tumor as well as in tumor-free peripheral tissues from patients with and without ovarian cancer (OC). MAIN METHODS: Patients being scheduled for laparotomy for either gynecologic benign diagnosis (n = 10) or for advanced-stage OC (n = 22) were prospectively recruited to this observational study. Serum samples were taken preoperatively, and tissue samples were taken from peripheral abdominal wall musculature, tumor-free peritoneum and the tumor itself. KEY FINDINGS: Patients in OC group received significantly more fluid per time intraoperatively (p = 0.01). IL-8 and MCP-1/CCL2, VCAM-1 (CD 106) and ICAM-1 (CD 54) as well as Thrombomodulin were significantly increased in cancer patients' serum at baseline (p = 0.03). Expression of distinct vascular leakage-related genes (Angiopoietin-1 (ANG-1), ANG-2, TIE2, VEGFR1, VEGFR2) was significantly altered in tumor tissue of OC patients (p = 0.003), while in tumor-free peritoneal tissue, ANG-2/1 expression ratio was more than doubled in OC group (p = 0.03). In peripheral musculature, particularly genes from the ANG/TIE axis were significantly changed in OC patients (p = 0.005), suggesting a distinct vascular leakage-related genotype. Gene expression changes in OC patients were significantly associated with the postoperative fluid balance (p = 0.03). SIGNIFICANCE: Altered expression of barrier dysfunction- and angiogenesis-associated genes from the ANG/TIE axis was detected not only in tumor but also in peripheral tissues of cancer patients. This may contribute to a systemic vascular leakage-related genotype.

Lower Genital Tract Melanomas: Staging, Predictors of Outcome, and New Therapeutic Options.

BACKGROUND/AIM: Identification of predictors of survival of patients with lower genital tract melanoma (LGTM) and evaluation of the effectiveness of immunotherapy. PATIENTS AND METHODS: Data of twenty women with LGTM were retrospectively collected. Survival outcomes were evaluated using the Kaplan-Meier method. Survival distributions were analyzed using the Log rank test. RESULTS: Twenty patients with LGTM (6 vaginal/14 vulvar) were evaluated. Factors significantly affecting Five-year OS was the stage of the American Joint Committee on Cancer (AJCC 2017) (I+II: 55.6% vs. III+IV: 25.9%; p=0.030) and the T-Stage (I+II: 100% vs. III+IV: 7.5%; p=0.280). Factors negatively affecting Five-year PFS was T-Stage >II (p=0.005), AJCC stage >II (p<0.001), depth of tumor infiltration >3 mm (p=0.008), nodal involvement (p=0.013), distant disease (p=0.002), and resection margins <10 mm (p=0.024). Nine patients received immunotherapy [median duration of response (DOR)=4 months]. Three patients received immuno- and radiation therapy (median DOR of 5 months). Two patients received T-VEC, only one responded. CONCLUSION: Surgery has a therapeutic effect in early stage LGTM. Advanced stages may be treated with immunotherapy, radiation therapy, a combination of both, and oncolytic viral immunotherapy.

Risk Factors for Severe Complications in Ovarian Cancer Surgery.

Backround: Due to extensive surgical intervention for macroscopic complete cytoreduction in epithelial ovarian cancer (EOC) patients, severe complications in the postoperative course are possible. PATIENTS AND METHODS: A total of 345 EOC patients who underwent cytoreductive surgery were retrospectively evaluated regarding risk factors for an unfavorable postoperative course. Possible pre-, intra- and postoperative risk factors were statistically analyzed performing multivariate ordinal logistic regression. RESULTS: A total of 345 EOC patients underwent cytoreductive surgery. There were no complications in 114 patients, mild complications in 114 patients and severe complications in 117 patients. The risk factor evaluation identified age (p=0.049), smoking (p=0.032) and duration of surgery (p<0.0001) as significant factors for severe postoperative morbidity. CONCLUSION: In EOC patients age, smoking and the duration of surgery have significant impact on the postoperative course. Only the duration of surgery can be positively influenced by a well-trained EOC team.