Radical vaginal trachelectomy: long-term oncologic and fertility outcomes in patients with early cervical cancer.

OBJECTIVE: Radical vaginal trachelectomy is a fertility-preserving treatment for patients with early cervical cancer. Despite encouraging oncologic and fertility outcomes, large studies on radical vaginal trachelectomy are lacking. METHOD: Demographic, histological, fertility, and follow-up data of consecutive patients who underwent radical vaginal trachelectomy between March 1995 and August 2021 were prospectively recorded and retrospectively analyzed. RESULTS: A total of 471 patients of median age 33 years (range 21-44) were included. 83% (n=390) were nulliparous women. Indications were International Federation of Gynecology and Oncology (FIGO, 2009) stages IA1 with lymphvascular space involvement (LVSI) in 43 (9%) patients, IA1 multifocal in 8 (2%), IA2 in 92 (20%), IB1 in 321 (68%), and IB2/IIA in 7 (1%) patients, respectively. LVSI was detected in 31% (n=146). Lymph node staging was performed in 151 patients (32%) by the sentinel node technique with a median of 7 (range 2-14) lymph nodes and in 320 (68%) by systematic lymphadenectomy with a median of 19 (range 10-59) lymph nodes harvested. Residual tumor was histologically confirmed in 29% (n=136). In total, 270 patients (62%) were seeking pregnancy of which 196 (73%) succeeded. There were 205 live births with a median fetal weight of 2345 g (range 680-4010 g). Pre-term delivery occurred in 94 pregnancies (46%). After a median follow-up of 159 months (range 2-312), recurrences were detected in 16 patients (3.4%) of which 43% occurred later than 5 years after radical vaginal trachelectomy. Ten patients (2.1%) died of disease (five more than 5 years after radical vaginal trachelectomy). Overall survival, disease-free survival, and cancer-specific survival were 97.5%, 96.2%, and 97.9%, respectively. CONCLUSION: Our study confirms oncologic safety of radical vaginal trachelectomy associated with a high chance for childbearing. High rate of pre-term delivery may be due to cervical volume loss. Our long-term oncologic data can serve as a benchmark for future modifications of fertility-sparing surgery.

Oncologic and Fertility Outcomes After Simple Trachelectomy in Women With Early Cervical Cancer.

STUDY OBJECTIVE: This study aimed to present our case series of patients with early-stage cervical cancer undergoing simple trachelectomy (ST). Currently, radical trachelectomy is considered the most appropriate fertility-preserving procedure for the treatment of early-stage cervical cancer. However, there is increasing debate on the appropriate radicality of the surgery to preserve oncologic safety. DESIGN: Descriptive retrospective analysis of patient records and evaluation of questionnaires. SETTING: 2 gynecologic oncologic centers, surgeries performed by one surgical team. PATIENTS: 36 women with early-stage cervical cancer undergoing ST. INTERVENTIONS: Laparoscopic assisted simple vaginal trachelectomy. MEASUREMENTS: Demographic, histologic, fertility, and follow-up data of all patients who underwent ST between April 2007 and July 2021 were prospectively recorded and retrospectively analyzed. MAIN RESULTS: A total of 36 women (mean age: 28 years) underwent ST of whom 81% were nulliparous. Indications for ST were multifocal International Federation of Gynecology and Obstetrics stage IA1 (n = 30), stage IA1 L1 (n = 1), stage IA2 (n = 2), and stage IB1 (n = 3). Mandatory staging procedure was laparoscopic pelvic lymphadenectomy, including bilateral sentinel biopsy in 92% of the cases and systematic in 8%. Residual tumor was histologically confirmed in 8 specimens (22%); 18 women (50%) were seeking parenthood, and 13 succeeded (72%). There were 16 live births, all on term, with a median fetal weight of 3110 grams (2330-4420). One patient had a medical abortion owing to fetal congenital malformation. One pregnancy is ongoing. After a median follow-up of 91.5 months (9-174), all women are alive with no evidence of disease. CONCLUSION: ST represents a de-escalation compared with radical trachelectomy and provides excellent oncologic results with an outstanding fertility rate and obstetric outcome for patients with early cervical cancer. However, clear indications for this tailored fertility-preserving surgery have to be defined in well-designed trials.

Fertility sparing therapy in women with lymph node negative cervical cancer >2cm - oncologic and fertility outcomes of neoadjuvant chemotherapy followed by radical vaginal trachelectomy.

OBJECTIVE: Simple or radical trachelectomy are accepted fertility sparing therapies for patients diagnosed with cervical cancer ≤2 cm. In patients with larger tumors a fertility sparing concept is considered experimental. The aim of our study is to present oncological and fertility outcomes of laparoscopic pelvic lymphadenectomy followed by neoadjuvant chemotherapy and subsequent radical vaginal trachelectomy. These procedures were performed in two centers in patients diagnosed with cervical cancer of diameter >2 cm. METHOD: We retrospectively analyzed the demographic, histological, fertility and follow-up data of all patients with cervical cancer assessed as stage IB2, IB3 or IIA1 under the International Federation of Gynecology and Obstetrics (FIGO) 2018 system. These patients had undergone pelvic lymphadenectomy, followed by neoadjuvant chemotherapy and radical vaginal trachelectomy between February 2006 and June 2020 at Charité University Berlin and Asklepios Hospital, Hamburg. RESULTS: A total of 31 patients (mean age 29.5 years, range; 26-40) underwent neoadjuvant chemotherapy followed by radical vaginal trachelectomy in case of proven tumor-free lymph nodes. Twenty-six (84%) of these patients were nulliparous. Across all 31 patients, the initial tumor stages were FIGO 2018 stage IB2 (n=27), IB3 (n=3) and IIA1 (n=1).Lymphadenectomy was completed in all but one patient (sentinel) with a median of 33 (range; 11-47) pelvic lymph nodes. The neoadjuvant chemotherapy regimen was two cycles of paclitaxel, ifosfamide and cisplatin in 17 patients; three cycles of paclitaxel, ifosfamide and cisplatin in eight patients; two cycles of paclitaxel and cisplatin in four patients; two cylces cisplatin monoagent in one patient; and two cycles of paclitaxel and cisplatin followed by two cycles of paclitaxel, ifosfamide and cisplatin in one patient. Residual tumor was histologically confirmed in 17 specimens (55%). The median residual tumor size following neoadjuvant chemotherapy was 12 mm (range; 1-60). Fertility could be preserved in 27 patients (87%); two patients underwent adjuvant chemoradiation after radical vaginal trachelectomy due to high-risk histological features; two other patients underwent radical hysterectomy with adjuvant chemoradiation therapy following neoadjuvant chemotherapy. Of 18 (67%) patients seeking motherhood, 13 became pregnant (72%). There were 12 live births in 10 women, with a median fetal weight of 2490 grams (range; 1640-3560) and five miscarriages. After a median follow-up of 94.5 months (range; 6-183) three recurrences (11.1%) were detected, one patient (3.7%) died of the disease. CONCLUSION: Neoadjuvant chemotherapy followed by radical vaginal trachelectomy may be offered to patients seeking motherhood with cervical cancer >2 cm and histopathologically tumor-free lymph nodes, the rate of healthy baby pregnancy on discharge was 10/18 women (55%). This fertility-preserving strategy is associated with higher recurrence and death compared with what was published in the literature for women undergoing radical vaginal trachelectomy for tumors up to 2 cm.

Use of a microsurgical vascular clip system for temporary bilateral occlusion of the four main uterine vessels for laparoscopic enucleation of very large intramural uterine fibroids.

OBJECTIVES: The goal of this study was to examine the safety, feasibility, and effectiveness of the use of a microsurgical temporary vascular clip system to facilitate the laparoscopic enucleation of very large intramural uterine fibroids. METHODS: In this retrospective study, the surgical outcomes of 26 patients who underwent laparoscopic myomectomy with temporary uterine vessel clipping for very large (the largest measured diameter ≥ 9 cm) symptomatic intramural uterine fibroids in two tertiary referral hospitals between September 2017 and March 2020 were examined. Titan-made vascular clips (YASARGIL® Aneurysm Clip System) were used to temporarily occlude the bilateral uterine arteries and utero-ovarian vessels. Main outcomes included operating time, blood loss, number of leiomyomas and weight, conversion rate, intra- and postoperative complication rates, and length of hospital stay. RESULTS: Twenty six patients were included. Dominant intramural uterine fibroid diameters were 9-22 cm. The general characteristics of the patients were similar. The mean surgery duration and intraoperative blood loss were 175.3 ± 32.7 (range 120-250) min and 241.1 ± 103 (range 100-450) ml, respectively. The median postoperative drop in hemoglobin was 0.89 ± 0.75 g/dL. No patient required blood transfusion. No procedure was converted to laparotomy. No major intra- or postoperative complication occurred. CONCLUSIONS: Laparoscopic myomectomy for very large intramural uterine fibroids can be performed safely and effectively, with less intraoperative blood loss, using vascular clips for temporary clamping of the bilateral uterine vessels.

German evidence and consensus-based (S3) guideline: Vaccination recommendations for the prevention of HPV-associated lesions.

Anogenital and oropharyngeal infections with human papilloma viruses (HPV) are common. Clinically manifest disease may significantly impact quality of life; the treatment of HPV-associated lesions is associated with a high rate of recurrence and invasive neoplasms, such as cervical, anal, vulvar, penile, and oropharyngeal cancers, which are characterized by significant morbidity and mortality. Vaccination against HPV is an effective and safe measure for the primary prevention of HPV-associated lesions, but immunization rates are still low in Germany. The present publication is an abridged version of the German evidence and consensus-based guideline "Vaccination recommendations for the prevention of HPV-associated lesions", which is available on the website of the German Association of the Scientific Medical Societies (AWMF). On the basis of a systematic review with meta-analyses, a representative panel developed and agreed upon recommendations for the vaccination of different populations against HPV. In addition, consensus-based recommendations were developed for specific issues relevant to everyday practice. Based on current evidence and a representative expert consensus, these recommendations are intended to provide guidance in a field in which there is often uncertainty and in which both patients and health care providers are sometimes confronted with controversial and emotionally charged points of view.

Modification of Dargent's radical vaginal trachelectomy to facilitate ureteral dissection: description of technique.

OBJECTIVE: Radical vaginal trachelectomy is the fertility-preserving surgery for patients with early stage cervical cancer. However, it has not gained widespread approval by gynecologic oncologists because of difficulties in the dissection of the bladder pillars and identification of the ureter during the vaginal portion of the surgery. METHOD: We describe a modification of radical vaginal trachelectomy for easier dissection of the bladder pillar. Following pelvic lymphadenectomy, the vesicovaginal space is widely opened laparoscopically. After identification of the uterine arteries, one should proceed along the course of the arteries laterally and, thus, visualize the overcrossing of the artery with the ureter. The medial aspect of the supraureteric bladder pillar is transected and the ureter marked with vessel loops on both sides close to its entry into the bladder. The lateral portion of the supraureteric bladder pillar remains intact. During the vaginal part of radical vaginal trachelectomy, the ureter may be easily found by grasping the formerly placed vessel loop and dissection of the infraureteric bladder pillar may be done without risk of ureteral injury. RESULTS: Between October 2018 and August 2019 our group has performed radical vaginal trachelectomy using this modified ureteral dissection in 12 patients. Median operation time was 239 min (range 127-290) and median blood loss was 25 mL (range 10-100). No intra- or post-operative urologic complication occurred. Median time to normal bladder function was 4 days (range 3-13). CONCLUSION: The vaginal portion of radical vaginal trachelectomy may be simplified using this technique, especially when difficult circumstances such as endometriosis, prior operations, or unusual anatomy in nulliparous women are encountered.

Comparison of surgical and pathological parameters after laparoscopic transperitoneal pelvic/para-aortic lymphadenectomies.

OBJECTIVE: Lymphadenectomy is an integral part of surgical staging and treatment for patients with gynecologic malignancies. Since its introduction, laparoscopic lymphadenectomy has proved feasible, safe, and oncologically adequate compared with open surgery while morbidity is lower and hospital stay considerably shorter. The aim of this study was to examine if surgical outcomes may be improved after the initial learning curve is complete. METHODS: An analysis of 2535 laparoscopic pelvic and/or para-aortic lymphadenectomies was performed between July 1994 and March 2018 by one team of gynecologic oncology surgeons but with the consistent supervision of a consultant surgeon. Data were collected prospectively evaluating operative time, intra-operative and post-operative complications, number of lymph nodes, and body mass index (BMI). Previously published data of 650 patients treated after introduction of the method (period 1, 1994-2003) were compared with the latter 524 patients (period 2, 2014-2018). RESULTS: The median age of the 2535 patients was 43 years (IQR 34-57). The most common indication for pelvic and/or para-aortic lymphadenectomy was cervical cancer (n=1893). Operative time for para-aortic lymph node dissection was shorter in period 2 (68 vs 100 min, p<0.001). The number of harvested lymph nodes was increased for pelvic (19.2 (range 2-52) vs 21.9 (range 4-87)) and para-aortic lymphadenectomy (10.8 (range 1-52) vs 14.4 (range 4-64)), p<0.001. BMI did not have a significant influence on node count or operative time, with BMI ranging from 14.6 to 54.1 kg/m2. In contrast to period 1 (n=18, 2.9%), there were no intra-operative complications in period 2 (n=0, 0.0%, p<0.001) whereas post-operative complications were similar (n=35 (5.8%) in period 1; n=38 (7.6%) in period 2; p=0.32). CONCLUSION: In this large cohort of patients who underwent laparoscopic transperitoneal lymphadenectomy, lymph node count and peri-operative complications improved after the initial learning curve.

[Augmented Reality in Ophthalmology: Technical Innovation Complements Education for Medical Students]. / Augmented Reality in der Augenheilkunde: Technische Innovation ergänzt studentische Lehre.

BACKGROUND: At the Medical Faculty of the University of Ulm, the learning objectives of ophthalmology are taught to students in a one-week block course in the fourth year of study. According to the National Competency-based Learning Objective Catalogue Medicine (NKLM), one of these learning objectives is the clinical examination of the eye, including the eye fundus examination. In order to best train this expertise as defined in the NKLM, a novel, augmented reality-based training simulator (Eyesi Indirect, VRmagic Holding AG, Mannheim, Germany) was integrated into the teaching at the University Eye Hospital Ulm. During the block week, two key questions were examined: Does the one week block lesson increase interest in ophthalmology? How do students assess the use of an innovative e-learning technology compared to three other classical teaching methods for learning ophthalmoscopy? MATERIAL/METHODS: As part of the student teaching (block weeks July and October 2016), 292 students were questioned by questionnaire anonymously and on a voluntary basis regarding their assessment of the block week and the training simulator at the beginning and end of the one week event. The ophthalmoscopies were classically practiced on the ophthalmoscope trainer, head model and on fellow students and then performed on the new training simulator. RESULTS: Overall, there was little interest among the students in ophthalmology. However, the block week helped to increase interest (p < 0.001). The assessments of attractiveness before and after the block week of ophthalmology as a later professional goal and as an optional subject in the practical year were also significantly increased (p < 0.001 or p = 0.031). With regard to the use of e-learning technologies, it was shown that the handling of the simulator for learning ophthalmoscopy was rated more attractive by the students than the classical technology-based teaching methods (all p < 0.01). The joy of learning could only be further increased by practicing on a fellow student (p = 0.051). CONCLUSION: The results of the present study show a positive impact of the block week on the attractiveness assessment of the specialty by the participating students. Innovative e-learning methods can increase the enjoyment of learning. However, the training simulator cannot provide a complete replacement of the training on a real person.

Laparoscopic radical hysterectomy with transvaginal closure of vaginal cuff - a multicenter analysis.

OBJECTIVE: Laparoscopic/robotic radical hysterectomy has been historically considered oncologically equivalent to open radical hysterectomy for patients with early cervical cancer. However, a recent prospective randomized trial (Laparoscopic Approach to Cervical Cancer, LACC) has demonstrated significant inferiority of the minimally invasive approach. The aim of this study is to evaluate the oncologic outcomes of combined laparoscopic-vaginal radical hysterectomy. METHODS: Between August 1994 and December 2018, patients with invasive cervical cancer were treated using minimally-invasive surgery at the Universities of Jena, Charité Berlin (Campus CCM and CBF) and Cologne and Asklepios Clinic Hamburg. 389 patients with inclusion criteria identical to the LACC trial were identified. In contrast to the laparoscopic/robotic technique used in the LACC trial, all patients in our cohort underwent a combined transvaginal-laparoscopic approach without the use of any uterine manipulator. RESULTS: A total of 1952 consecutive patients with cervical cancer were included in the analysis. Initial International Federation of Gynecology and Obstetrics (FIGO) stage was IA1 lymphovascular space invasion (LVSI+), IA2 and IB1/IIA1 in 32 (8%), 43 (11%), and 314 (81%) patients, respectively, and histology was squamous cell in 263 (68%), adenocarcinoma in 117 (30%), and adenosquamous in 9 (2%) patients. Lymphovascular invasion was confirmed in 106 (27%) patients. The median number of lymph nodes was 24 (range 2-86). Lymph nodes were tumor-free in 379 (97%) patients. Following radical hysterectomy, 71 (18%) patients underwent adjuvant chemoradiation or radiation. After a median follow-up of 99 (range 1-288) months, the 3-, 4.5-, and 10-year disease-free survival rates were 96.8%, 95.8%, and 93.1 %, and the 3-, 4.5-, and 10-year overall survival rates were 98.5%, 97.8%, and 95.8%, respectively. Recurrence location was loco-regional in 50% of cases with recurrence (n=10). Interestingly, 9/20 recurrences occurred more than 39 months after surgery. CONCLUSION: The combined laparoscopic-vaginal technique for radical hysterectomy with avoidance of spillage and manipulation of tumor cells provides excellent oncologic outcome for patients with early cervical cancer. Our retrospective data suggest that laparoscopic-vaginal surgery may be oncologically safe and should be validated in further randomized trials.

Utilizing research findings in medical education: The testing effect within a flipped/inverted biochemistry classroom.

Purpose: Basic research about test-enhanced learning points towards its effectiveness to improve students' learning and is still underutilized in educational practice. Therefore, we developed an evidence-based instructional design to investigate the usefulness of test-enhanced learning within a flipped/inverted classroom approach. Materials and Methods: We developed two modes of learning material for the self-study phase of a flipped classroom for 139 students: in addition to educational films, one group of students received a reader and another group received multiple-choice questions that corresponded to the reader in content and length. An assessment of the content of the learning material was conducted at the subsequent on-site phase. Also, ratings about students' perceptions of the additional learning material were gathered. Results: At the assessment, students that prepared with films and multiple-choice questions outperformed students that prepared with films and the reader. Furthermore, students perceived the multiple-choice questions as more helpful, more motivating and felt better prepared for the assessment than students that used the reader. Conclusions: This study shows that test-enhanced learning can be utilized to promote students' learning within the self-study phase of a flipped classroom. Not only assessment scores are positively affected but also the motivation to learn and preparedness towards an assessment.

Investigating the self-study phase of an inverted biochemistry classroom - collaborative dyadic learning makes the difference.

BACKGROUND: The inverted classroom approach is characterized by a primary self-study phase for students followed by an on-site, face-to-face teaching phase that is used to deepen the prior acquired knowledge. Obviously, this teaching approach relies on the students preparing before the on-site phase, which in turn requires optimized preparatory material as well as defined working instructions. The major aim of this study, therefore, was to investigate the effect of different preparatory materials and working instructions for the self-study phase of an e-learning-based inverted classroom on the knowledge gained by medical students in biochemistry. Furthermore, we analyzed whether collaborative dyadic learning during the self-study phase is more effective than individual learning with respect to knowledge gain. METHODS: The study was performed in a biochemistry seminar for second semester medical students at Ulm University in Germany. This seminar was held using an e-learning-based inverted classroom. A total of 196 students were divided into three homogeneous study groups that differed in terms of the working material and instructions provided for the self-study phase. Knowledge gain was measured by formative tests at the beginning of the on-site phases. Questionnaires were also handed out asking about motivation, interest and learning time in the self-study phases. RESULTS: Students who were told to prepare in collaborating dyads during the self-study phase performed better in formative tests taken at the beginning of on-site phases than learners who were told to prepare individually. The study material that was provided was of minor importance for the differences in formative testing since almost all students prepared for the on-site phases. With the dyadic learning approach, both students benefited from this collaboration, characterized by a higher motivation and interest in the topic, as well as a longer time spent on task. CONCLUSION: Our study provides strong evidence that the study material, but more importantly the instructions provided for the self-study phase, affect students` knowledge gain in an e-learning-based inverted classroom. The instructed collaboratively working group was the most successful.

How do German medical students perceive role models during clinical placements ("Famulatur")? An empirical study.

BACKGROUND: Studies have demonstrated the importance of role models in medical education. Medical students in Germany participate in clinical placements ("Famulatur") that last 4 months in total and represent the first real-world setting where students encounter possible role models in their clinical education. These placements are an extracurricular activity, however, and regarded as the "black box" of medical education. This study aimed to evaluate whether and how students experience role models during clinical placements, the qualities associated with potential role models and whether role model-related learning gains are relevant. METHODS: We recruited 96 students (mean age: 23.83 years; 75% female) in their 5th to 9th semesters at the Faculty of Medicine at the University of Ulm, Germany, who were participating in a clinical placement between July and October 2015. Participants completed a questionnaire at the beginning of a 5-day working week to record sociodemographic and other information and another one at the end of the week to assess various aspects of their experiences. On each of the 5 days, they completed a structured questionnaire to record their perceived role models and self-assessed learning gains. RESULTS: Role models and role modelling play an important role in clinical placements. The positive function of medical staff as role models predominated (88.4%) across all specialties. Junior doctors were the most frequently perceived role models (28.5%), followed by consultants (25.1%) and nursing staff (22.4%). The most commonly perceived positive quality was the interaction with students (16.5%), followed by team behaviour (13.6%), interaction with patients (13.6%) and professional expertise (13.4%). Students also had various kinds of learning gains such as knowledge or skills. CONCLUSIONS: Although these clinical placements are extracurricular activities in Germany and their content is not regulated, they are home to a relevant amount of role modelling. Students experience the various medical professions in different roles and in a range of tasks and interactions. Defining basic learning objectives could help to increase the relevance of these placements for the medical curriculum in Germany and transfer the associated learning gains from the hidden to the open curriculum.

[Innovative Teaching Methods: Wet Lab-based Ophthalmosurgical Education for Medical Students]. / Innovative Lehrmethoden: Einsatz eines ophthalmochirurgischen Wetlabs im Studentenunterricht.

BACKGROUND: An increased demand for young physicians in Germany is causing increased competition to attract the best minds, even during their undergraduate studies. Therefore, it is the task of the university hospitals to offer their students the best possible courses in order to arouse interest in the relevant subject area. We therefore examined the impact of an ophthalmosurgical wet lab on teaching undergraduate medical students. MATERIAL/METHODS: Undergraduate medical students were offered voluntary participation in the ophthalmosurgical wet lab during an ophthalmology block week. At the beginning and at the end of the week, as well as at the end of the wet lab, the students answered questionnaires with questions about the interest in the field of ophthalmology and the specific assessment of the wet lab. RESULTS: The interest of the students in ophthalmology was increased by the block week and additionally by the wet lab. The wet lab enriched the block week and was rated as very good by the participants. The overall rating of the block week was significantly better among participants in the wet lab than in the group without wet lab participation. The wet lab gave the students great pleasure, enabled them to apply the acquired knowledge, gain valuable insights into ophthalmology, and was easily implemented. CONCLUSION: The integration of a wet lab into the block week was evaluated very positively by the students and gives them a valuable insight into the field of ophthalmology.

Incidence of Histologically Proven Pelvic and Para-Aortic Lymph Node Metastases and Rate of Upstaging in Patients with Locally Advanced Cervical Cancer: Results of a Prospective Randomized Trial.

BACKGROUND: Surgical staging is associated with a significant rate of upstaging compared to clinical/radiological staging in patients with locally advanced cervical cancer. OBJECTIVE: To analyze the stage-specific percentage of pelvic and para-aortic lymph node metastases and the upstaging ratio in a prospective randomized trial (Uterus-11). METHODS: FIGO stage IIB-IVA cervical cancer patients were randomized to surgical staging (arm A) or to clinical staging and primary chemoradiation (arm B). Arm B patients underwent CT-guided biopsy of suspicious para-aortic lymph nodes. Confirmed para-aortic metastasis patients received extended-field radiation therapy. RESULTS: A total of 234 patients were enrolled, including 120 (arm A) and 114 (arm B) treated per protocol. The groups were well balanced. Pelvic and para-aortic lymph node metastases were identified after surgical staging in 51 and 24% of patients, respectively (p < 0.001). Pelvic and para-aortic lymph node metastases were confirmed in 45 and 20% of IIB patients and in 71 and 37% of IIIB patients, respectively. Upstaging occurred in 39/120 (33%) in arm A and in 9/114 (8%) in arm B (p < 0.001). CONCLUSION: The histological results in both groups led to a considerable rate of upstaging. Oncological data from the Uterus-11 study may reveal whether modified therapy translates into a survival benefit.

Online or face-to-face instruction? A qualitative study on the electrocardiogram course at the University of Ulm to examine why students choose a particular format.

BACKGROUND: Since the introduction of the e-learning electrocardiogram (ECG) course 'ECG Online' into the curriculum at the University of Ulm, a small but relatively constant number of students have decided not to participate in the online course but to attend the face-to-face course, although the content of both courses is identical. The present study examined why students prefer one format or the other. METHODS: In a qualitative research approach, ten medical students were questioned in a guided interview. At the time of the survey the interviewees were enrolled in the 7th to 10th semesters. Among the respondents, 2 had participated only in the face-to-face ECG course, 4 only in the online version and 4 in both the face-to-face and the online course. RESULTS: Interestingly, the very factors associated with e-learning - and always praised as advantages of it - are viewed critically by the students. Thus, although the 24-h access to learning content was consistently evaluated positively, the unlimited availability (lack of expiry date) was not seen as conducive to learning. The lack of fixed time constraints and the attendant lack of pressure were important reasons why some of the students had discontinued the online course prematurely. A similar distinction was seen in the flexibility of location for e-learning, because the very obligation to be physically present on a particular day at a fixed time led to a higher degree of commitment to courses and a willingness to actually attend the course until the end. In addition, if the content has a high degree of perceived professional relevance face-to-face courses are preferred because they offer the possibility of direct interaction. CONCLUSIONS: Even though the small sample size limits the generalisability of the results, our findings indicate that when developing online courses students' needs could be better met if measures were included to strengthen extrinsic and intrinsic motivation and formats were favoured that enable students to have a minimum level of personal interaction with the lecturer.

Epigenetic inactivation of TRAIL decoy receptors at 8p12-21.3 commonly deleted region confers sensitivity to Apo2L/trail-Cisplatin combination therapy in cervical cancer.

Multiple chromosomal regions are affected by deletions in cervical cancer (CC) genomes, but their consequence and target gene involvement remains unknown. Our single nucleotide polymorphism (SNP) array identified 8p copy number losses localized to an 8.4 Mb minimal deleted region (MDR) in 36% of CC. The 8p MDR was associated with tumor size, treatment outcome, and with multiple HPV infections. Genetic, epigenetic, and expression analyses of candidate genes at MDR identified promoter hypermethylation and/or inactivation of decoy receptors TNFRSF10C and TNFRSF10D in the majority of CC patients. TNFRSF10C methylation was also detected in precancerous lesions suggesting that this change is an early event in cervical tumorigenesis. We further demonstrate here that CC cell lines exhibiting downregulated expression of TNFRSF10C and/or TNFRSF10D effectively respond to TRAIL-induced apoptosis and this affect was synergistic in combination with DNA damaging chemotherapeutic drugs. We show that the CC cell lines harboring epigenetic inactivation of TRAIL decoy receptors effectively activate downstream caspases suggesting a critical role of inactivation of these genes in efficient execution of extrinsic apoptotic pathway and therapy response. Therefore, these findings shed new light on the role of genetic/epigenetic defects in TRAIL decoy receptor genes in the pathogenesis of CC and provide an opportunity to explore strategies to test decoy receptor gene inactivation as a biomarker of response to Apo2L/TRAIL-combination therapy.

A phase 1/2a study to test the safety and immunogenicity of a p16(INK4a) peptide vaccine in patients with advanced human papillomavirus-associated cancers.

BACKGROUND: The cyclin-dependent kinase inhibitor p16(INK4a) is strongly and consistently overexpressed in all human papillomavirus (HPV)-associated cancers. Therefore, the authors hypothesized that p16(INK4a) may be a vaccine target antigen for HPV-associated cancers. To test this hypothesis, the authors performed a phase 1/2a first-in-human trial to evaluate the safety and immunogenicity of a p16(INK4a) -based peptide vaccine. METHODS: A total of 26 patients with different, advanced, p16(INK4a) -overexpressing, HPV DNA-positive cancers were included after the completion of standard treatment. According to protocol, 12 subcutaneous injections of a p16(INK4) peptide (P16_37-63) mixed in a water-in-oil emulsion with immunoadjuvant activity (Montanide ISA-51 VG) were administered over a 6-month period. RESULTS: A total of 20 patients received at least 4 injections and were evaluable for immune responses against P16_37-63. Clusters of differentiation (CD) 4 T cells were detected in 14 of 20 patients (3 of whom had preexisting CD4 T cells before vaccination), CD8 T cells were detected in 5 of 20 patients, and antibodies were detected in 14 of 20 patients (1 of whom had preexisting antibodies). No suspected unexpected serious adverse reaction or serious adverse drug reaction was documented. All reported serious adverse events were expected and not considered to be related to study therapy. None of the patients discontinued trial participation due to unacceptable toxicities and no dose-limiting toxicities occurred. Tumor response could be assessed in 14 patients. Of these, 9 patients (64%) had stable disease as their best overall response and 5 patients (36%) developed progressive disease. CONCLUSIONS: Vaccination with the p16(INK4a) -derived peptide P16_37-63 appears to induce cellular and humoral immune responses and does not cause severe toxicities. The results of the current study pave the way for the further clinical development of p16(INK4a) -based cancer immunotherapeutics. Cancer 2016;122:1425-1433. © 2016 American Cancer Society.

Molecular Diagnosis for Nodal Metastasis in Endoscopically Managed Cervical Cancer: The Accuracy of the APTIMA Test to Detect High-risk Human Papillomavirus Messenger RNA in Sentinel Lymph Nodes.

STUDY OBJECTIVE: To evaluate the feasibility and accuracy of a commercially available test to detect E6/E7 mRNA of 14 subtypes of high-risk HPVs (APTIMA; Hologic, Bedford, MA) in the sentinel lymph nodes of CC patients laparoscopically operated. DESIGN: Prospective pilot study. SETTING: The study was conducted in the Department of Advanced Operative and Oncologic Gynecology, Asklepios Hospital, Hamburg, Germany. PATIENTS: 54 women with HPV-positive CC submitted to laparoscopic sentinel node biopsy alone or sentinel node biopsy followed by systematic pelvic and/or para-aortic endoscopic lymphadenectomy. INTERVENTIONS: All removed sentinel lymph nodes (SLNs) underwent sample collection by cytobrush for the APTIMA assay before frozen section. MEASUREMENTS: Results obtained with the HPV mRNA test were compared with the definitive histopathological analysis of the SLNs and additional lymph nodes removed. RESULTS: A total of 125 SLNs (119 pelvic and 6 paraaortic) were excised with a mean number of 2.3 SLNs per patient. Final histopathologic analysis confirmed nodal metastases in 10 SLNs from 10 different patients (18%). All the histologically confirmed metastatic lymph nodes were also HPV E6/E7 mRNA positive, resulting in a sensitivity of 100%. Four histologically free sentinel nodes were positive for HPV E6/E7 mRNA, resulting in a specificity of 96.4%. CONCLUSION: The HPV E6/E7 mRNA assay in the SLNs of patients with CC is feasible and highly accurate. The detection of HPV mRNA in 4 women with negative SLNs might denote a shift from microscopic identification of metastasis to the molecular level. The prognostic value of this findings awaits further verification.

Potential Surgical and Oncologic Consequences Related to Skin Tattoos in the Treatment of Cervical Cancer.

STUDY OBJECTIVE: Skin tattoos on the feet, legs, and lower abdominal wall are progressively gaining popularity. Consequently, the number of tattooed women with cervical cancer has significantly increased in the last decade. However, pigments of tattoo ink can be transported to regional lymph nodes and potentially clog lymphatic pathways that might also be used by sentinel labeling substances. Therefore, here we report whether the presence of tattoo ink affected pelvic lymph nodes in women with early cervical cancer and discuss its potential oncologic and surgical consequences. DESIGN: Prospective observational study. SETTING: University Hospital in Hamburg, Germany (Canadian Task Force classification II2). PATIENTS: Women affected by cervical cancer. INTERVENTIONS: Between January 2014 and May 2016, 267 laparoscopic oncologic operations, including at least a pelvic sentinel or complete lymphadenectomy, were performed in the Department of Advanced Surgical and Oncologic Gynecology, Asklepios Hospital, Hamburg, Germany. Among these, 191 patients were affected by cervical cancer. MEASUREMENTS AND MAIN RESULTS: Data of patients in whom dyed lymph nodes without the use of patent blue as a sentinel marker or different from blue-colored pelvic lymph nodes in the case of sentinel procedure were identified and prospectively collected. RESULTS: In 9 patients, skin tattoos localized in the lower extremities caused discoloration of at least 1 pelvic lymph node. This effect was observed in 40% of women (9/23) with tattoos in this area of the body. Mean patient age was 34 years (range, 27-56). All women had cutaneous tattoos on their feet or legs, and in 1 woman an additional tattoo situated on the inferior abdominal wall was observed. The stage of cervical cancer was FIGO IB1 in all cases. One woman was at the 16th week of gestation at the time of cancer diagnosis. On average, 26 pelvic lymph nodes (range, 11-51) were harvested from both pelvic basin sides. None of the removed lymph nodes was tumor involved. Three patients (33%) developed postoperatively infected lymphoceles on the side of the tattooed lymph nodes, and 1 woman had multiple episodes of fever without a clear origin. CONCLUSION: In women affected by cervical cancer with skin tattoos located in the lower limbs, the pelvic lymph nodes can be partially or totally occupied by the ink. This must be taken into consideration, especially for women scheduled exclusively for sentinel node biopsy. Infectious complications related to nodal dissection, in particular infected lymphoceles, may be more frequent in this population.