Tumor-Free Resection Margin Distance in the Surgical Treatment of Node-Negative Squamous Cell Cancer of the Vulva Has No Impact on Survival: Analysis of a Large Patient Cohort in a Tertiary Care Center.

BACKGROUND: The aim of this study was to evaluate the impact of pathological tumor-free margin distance on survival in SCC patients treated with surgery alone. METHODS: This retrospective study included 128 patients with node-negative disease that received no adjuvant treatment. Disease-free and overall survival were analyzed according to pathological tumor-free margin distance. RESULTS: The patients were subclassified into three resection margin category groups: "1 to 3 mm" (n = 42), ">3 to 8 mm" (n = 47) or ">8 mm" (n = 39). Thirty-nine of the 128 patients (30.5%) developed recurrent disease. Median follow-up for disease-free survival (DFS) was 6.49 years (95% CI 5.16 years; 7.62 years), and median follow-up for overall survival (OS) was 6.29 years (95% CI 5.45 years; 7.33 years). The 5-year DFS rate was 0.70 (95% CI: 0.62-0.79), and the 5-year OS rate was 0.79 (95% CI: 0.71-0.87). Regarding the survival outcome, there were no independent significant differences in either disease-free survival (DFS) (p = 0.300) or overall survival (p = 1.000) among patients within the three tumor-free resection margin categories. Multivariate analyses did not show any statistically significant association between tumor-free resection margin distance and recurrent disease or death, either when analyzed as a categorical variable or when analyzed as a continuous variable. CONCLUSION: The present study did not show a significant impact of pathological tumor-free resection margin distance following surgery in patients with node-negative SCC of the vulva (that did not receive adjuvant treatment) on disease-free and overall survival.

Detection of circulating cell-free HPV DNA of 13 HPV types for patients with cervical cancer as potential biomarker to monitor therapy response and to detect relapse.

BACKGROUND: HPV-related cervical cancer (CC) is the fourth most frequent cancer in women worldwide. Cell-free tumour DNA is a potent biomarker to detect treatment response, residual disease, and relapse. We investigated the potential use of cell-free circulating HPV-DNA (cfHPV-DNA) in plasma of patients with CC. METHODS: cfHPV-DNA levels were measured using a highly sensitive next-generation sequencing-based approach targeting a panel of 13 high-risk HPV types. RESULTS: Sequencing was performed in 69 blood samples collected from 35 patients, of which 26 were treatment-naive when the first liquid biopsy sample was retrieved. cfHPV-DNA was successfully detected in 22/26 (85%) cases. A significant correlation between tumour burden and cfHPV-DNA levels was observed: cfHPV-DNA was detectable in all treatment-naive patients with advanced-stage disease (17/17, FIGO IB3-IVB) and in 5/9 patients with early-stage disease (FIGO IA-IB2). Sequential samples revealed a decrease of cfHPV-DNA levels in 7 patients corresponding treatment response and an increase in a patient with relapse. CONCLUSIONS: In this proof-of-concept study we demonstrated the potential of cfHPV-DNA as a biomarker for therapy monitoring in patients with primary and recurrent CC. Our findings facilitate the development of a sensitive and precise, non-invasive, inexpensive, and easily accessible tool in CC diagnosis, therapy monitoring and follow-up.

Improved preoperative risk stratification in endometrial carcinoma patients: external validation of the ENDORISK Bayesian network model in a large population-based case series.

PURPOSE: Preoperative risk stratification of newly diagnosed endometrial carcinoma (EC) patients has been hindered by only moderate prediction performance for many years. Recently ENDORISK, a Bayesian network model, showed high predictive performance. It was the aim of this study to validate ENDORISK by applying the model to a population-based case series of EC patients. METHODS: ENDORISK was applied to a retrospective cohort of women surgically treated for EC from 2003 to 2013. Prediction accuracy for LNM as well as 5-year DSS was investigated. The model's overall performance was quantified by the Brier score, discriminative performance by area under the curve (AUC). RESULTS: A complete dataset was evaluable from 247 patients. 78.1% cases were endometrioid histotype. The majority of patients (n = 156;63.2%) had stage IA disease. Overall, positive lymph nodes were found in 20 (8.1%) patients. Using ENDORISK predicted probabilities, most (n = 156;63.2%) patients have been assigned to low or very low risk group with a false-negative rate of 0.6%. AUC for LNM prediction was 0.851 [95% confidence interval (CI) 0.761-0.941] with a Brier score of 0.06. For 5-year DSS the AUC was 0.698 (95% CI 0.595-0.800) as Brier score has been calculated 0.09. CONCLUSIONS: We were able to successfully validate ENDORISK for prediction of LNM and 5-year DSS. Next steps will now have to focus on ENDORISK performance in daily clinical practice. In addition, incorporating TCGA-derived molecular subtypes will be of key importance for future extended use. This study may support further promoting of data-based decision-making tools for personalized treatment of EC.

Feasibility of Adjuvant Treatment with Abemaciclib-Real-World Data from a Large German Breast Center.

Abemaciclib significantly improves invasive disease-free survival when combined with endocrine therapy in clinical high-risk patients with HR+/Her2- early breast cancer (eBC). The objective of the following study was to model how many patients with eBC would be available for adjuvant treatment with abemaciclib in a real-world setting. Patients that underwent complete surgical treatment for eBC between January 2018 and December 2020 in a large single-center university hospital in Germany were eligible. Descriptive statistics were used to describe the patient population that could benefit from abemaciclib according to the inclusion criteria of monarchE. Of 1474 patients with eBC, 1121 (76.1%) had a HR+/Her2- subtype. Of these, 217 (19.4%) fulfilled the monarchE inclusion criteria. Within patients that fulfilled the monarchE inclusion criteria, 48.9% received no adjuvant or neoadjuvant chemotherapy. Thus, in a real-world situation, fewer patients will be pretreated with chemotherapy than was the case in monarchE. Breast care units are facing a significant patient burden, since the 2-year abemaciclib therapy requires regular monitoring of toxicities. Specific care concepts to strengthen therapy adherence as well as further studies to deescalate adjuvant systemic treatment and individualize CDK 4/6 inhibitor therapy are therefore needed.

Neoadjuvant Chemotherapy of Patients with Early Breast Cancer Is Associated with Increased Detection of Disseminated Tumor Cells in the Bone Marrow.

Preclinical data suggest that neoadjuvant chemotherapy (NAT) may promote micrometastatic spread. We aimed to compare the detection rate and prognostic relevance of disseminated tumor cells (DTCs) from the bone marrow (BM) of patients with early-stage breast cancer (EBC) after NAT with that of therapy-naive EBC patients. DTCs were identified from BM samples, collected during primary surgery. Patients who received NAT were compared to patients who received chemotherapy after surgery. In total, 809 patients were analyzed. After NAT, 45.4% of patients were DTC-positive as compared to 19.9% of patients in the adjuvant chemotherapy group (p < 0.001). When sampled in patients who had undergone NAT, the detection of DTCs in the BM was significantly increased (OR: 3.1; 95% confidence interval (CI): 2.1-4.4; p < 0.001). After NAT, DTC-positive patients with ≥2 DTCs per 1.5 × 106 mononuclear cells in their BM had an impaired disease-free survival (HR: 4.8, 95% CI: 0.9-26.6; p = 0.050) and overall survival (HR: 4.2; 95% CI: 1.4-12.7; p = 0.005). The higher rate of DTC-positive patients after NAT as compared to a treatment-naive comparable control cohort suggests that NAT supports tumor cell dissemination into the bone marrow. DTC positivity in BM predicted relapse in various distant organs, implying that tumor cell dissemination was not restricted to the bone marrow.

Evaluation of sonographic detectability of different markers within an in vitro simulation model of the axilla.

PURPOSE: Clip-marking of axillary lymph nodes with initial biopsy-confirmed metastasis is required for targeted axillary dissection (TAD), which includes sentinel lymph node dissection (SLND) and selective localization and removal of the clipped targeted lymph node. There have been several studies which examined the feasibility of TAD in routine clinical use. In this context, the optimal clip visualisation was noted as one of the crucial limiting factors. We, therefore, evaluated the sonographic detectability of 10 different commercially available markers within an in vitro model simulating the anatomical composition of the axilla. METHODS: In this standardised model consisting of porcine fat with 30 mm thickness, the visibility of a total of ten markers was analysed in all 3 planes (parallel, diagonal, orthograde) with wire guidance and then classified into either "visibility good", "visibility moderate" or "visibility poor" with regard to the alignment of the transducer. Additionally, "real-life conditions" were simulated, in which the markers were searched without any wires guidance. RESULTS: It was observed that, while not all markers are detectable in fatty tissue, markers with spherical shape (non-embedded Inconel or Nitinol) or rectangular-shaped Titanium markers with embedded material have a clear advantage. 3D-shaped markers can always be detected in all three axes, which is of particular importance in the axilla with its pyramid shape and fatty tissue. CONCLUSION: The shape and the embedding of the material play a crucial role for visibility and efficacy of the marker, as reliable marking of suspicious and pathological axillary lymph nodes is essential for TAD.

Living-Donor Uterus Transplantation: Pre-, Intra-, and Postoperative Parameters Relevant to Surgical Success, Pregnancy, and Obstetrics with Live Births.

Uterus transplantation (UTx) can provide a route to motherhood for women with Mayer-Rokitansky-Küster-Hauser syndrome (MRKHS), a congenital disorder characterized by uterovaginal aplasia, but with functional ovaries. Based on our four successful living-donor transplantations and two resulting births, this analysis presents parameters relevant to standardizing recipient/donor selection, UTx surgery, and postoperative treatment, and their implementation in routine settings. We descriptively analyzed prospectively collected observational data from our four uterus recipients, all with MRKHS, their living donors, and the two newborns born to two recipients, including 1-year postnatal follow-ups. Analysis included only living-donor/recipient pairs with completed donor/recipient surgery. Two recipients, both requiring ovarian restimulation under immunosuppression after missed pregnancy loss in one case and no pregnancy in the other, each delivered a healthy boy by cesarean section. We conclude that parameters crucial to successful transplantation, pregnancy, and childbirth include careful selection of donor/recipient pairs, donor organ quality, meticulous surgical technique, a multidisciplinary team approach, and comprehensive follow-up. Surgery duration and blood vessel selection await further optimization, as do the choice and duration of immunosuppression, which are crucial to timing the first embryo transfer. Data need to be collected in an international registry due to the low prevalence of MRKHS.

Percutaneous Ultrasound-Guided Core Needle Biopsy: Comparison of 16-Gauge versus 14-Gauge Needle and the Effect of Coaxial Guidance in 1065 Breast Biopsies - A Prospective Randomized Clinical Noninferiority Trial.

PURPOSE: Ultrasound-guided core needle biopsy (CNB) is considered the standard assessment to diagnose sonographically visible suspicious breast mass lesions. Based on nonrandomized trials, the current German guidelines recommend at least three cylinders with ≤ 14-gauge needle biopsy. However, no recommendation is made as to how many specimens are needed with a smaller needle size, such as 16-gauge, or if biopsy with coaxial guidance improves diagnostic accuracy and quality. Therefore, in a prospective monocentric unblinded randomized controlled clinical noninferiority trial, the diagnostic accuracy of 16-gauge versus 14-gauge core needle biopsy, with and without coaxial guidance, was evaluated. MATERIALS AND METHODS: 1065 breast biopsies were included in order to analyze the number of core samples necessary to obtain an appropriate rate of diagnostic quality adequate for histological evaluation, and to achieve high diagnostic accuracy and diagnostic yield. Histological results were verified by surgery or long-term follow-up of at least two years up to five years. RESULTS: In order to obtain an additive diagnostic accuracy of > 99 %, a minimum of two cylinders with 14-gauge biopsy were required. The diagnostic accuracy and the diagnostic quality of 14-gauge biopsy were not affected by the coaxial technique. When performing a 16-gauge biopsy, five cylinders were required to achieve an additive diagnostic accuracy of > 99 %. Without coaxial guidance, 16-gauge CNB required at least three samples, whereas five needle passes with coaxial-guided 16-gauge biopsy were needed. CONCLUSION: The diagnostic accuracy and quality of ultrasound-guided 16-gauge core needle biopsy were inferior to the 14-gauge needle size, regardless of the use of a coaxial technique.

Difficulties in diagnosis of a minimal deviation adenocarcinoma of uterine cervix diagnosed postoperatively: brief communication and literature review.

PURPOSE: Rare minimal deviation adenocarcinoma (MDA) diagnosed postoperatively as incidental finding of a suspicious cervical lesion at laparoscopy, emphasizing it represents a diagnostic challenge mimicking both benign and malignant cervical lesions with often overlapping imaging characteristics-case report and literature review. CASE PRESENTATION: 35-year-old Gravida with primary infertility presented with a suspicious cervical lesion and complained about menorrhagia, hyper-/dysmenorrhea. Clinical examination was unremarkable, transvaginal scan presented a 42 × 38 × 28 mm sized cervical lesion (i.e. fibroid) without hypervascularization. Unexpectedly, the diagnosis of minimal deviation adenocarcinoma in tissue sample taken from suspicious cervical lesion at laparoscopy was revealed in final pathological report. According to suspected early stage of MDA a radical abdominal hysterectomy (PIVER III/IV), bilateral salpingo-oophorectomy, omentectomy, pelvic and para-aortic lymphadenectomy was scheduled. Final histology report confirmed: "MDA", G2, FIGO pT1b1, pN0 (0/23 LN) L0 V0 Pn0 R0. RESULTS: Ultrasonography may indicate MDA throughout the examination of vascularization/echogenicity with possibility of mimicking benign lesions with similar characteristics. Magnetic resonance imaging shows no pathognomonic signs for MDA. Subsequently, a review of literature was conducted and main factors affecting the prognosis of MDA considering diagnostic tools, clinical stage, histopathological results and surgical protocols were analyzed. CONCLUSIONS: Minimal deviation adenocarcinoma represents one of rare cervical adenocarcinomas without HPV-association. While it is crucial to differentiate benign from malignant lesions in this subtype, imaging characteristics often overlap and may not provide a specific diagnosis. Therefore, it should be considered in suspicious multicystic cervical lesions and inconclusive PAP-smear. Definitive diagnosis of this subtype should be based on cervical biopsy.

Ultrasound-Assisted Tumor Surgery in Breast Cancer - A Prospective, Randomized, Single-Center Study (MAC 001).

PURPOSE: Breast-conserving therapy is associated with a risk of tumor-involved margins. For intraoperative orientation, non- palpable or indistinctly palpable lesions are wire-marked prior to surgery. Ultrasound-guided surgery has the potential to reduce the number of tumor-involved margins. In the MAC 001 trial we evaluated ultrasound-guided breast-conserving surgery compared to wire-guided surgery with regard to free tumor margins, duration of surgery and resection volume. MATERIALS AND METHODS: In this randomized, prospective, single-center controlled trial, patients with ductal invasive breast cancer were recruited for either ultrasound-guided or wire localization surgery. Primary outcomes were tumor-free resection margins, the reoperation rate and the resection volume in each group. The results were analyzed by intention to treat. The trial was registered under ClinicalTrials.gov NCT02222675. RESULTS: 56 patients were assessed, and 47 patients were evaluated in the trial. 93 % (25/27) of the patients in the ultrasound arm had an R0 reoperation compared to 65 % (13/20) in the wire localization control arm. This result was statistically significant (p = 0.026). No statistical difference was found for the resection volume or the duration of surgery between the two arms. No major complication was seen in either arm. CONCLUSION: Ultrasound-assisted breast surgery significantly increases the possibility of tumor-free margins and therefore reduces the risk of reoperations. Breast surgeons should be trained in ultrasound and ultrasound should be available in every breast surgery operating room.

Prediction of Non-sentinel Lymph Node Metastases After Positive Sentinel Lymph Nodes Using Nomograms.

BACKGROUND/AIM: Only 30-50% of patients with sentinel lymph node (SLN) metastases present with further axillary lymph node metastases. Therefore, up to 70% of patients with positive SLN are overtreated by axillary dissection (AD) and may suffer from complications such as sensory disturbances or lymphedema. According to the current S3 guidelines, AD can be avoided in patients with a T1/T2 tumor if breast-conserving surgery with subsequent tangential irradiation is performed and no more than two SLNs are affected. Additionally, use of nomograms, that predict the probability of non-sentinel lymph node (NSLN) metastases, is recommended. Therefore, models for the prediction of NSLN metastases in our defined population were constructed and compared with the published nomograms. PATIENTS AND METHODS: In a retrospective study, 2,146 primary breast cancer patients, who underwent SLN biopsy at the University Women's Hospital in Tuebingen, were evaluated by dividing the patient group in a training and validation collective (TC or VC). Using the SLN-positive TC patients, three models for the prediction of the likelihood of NSLN metastases were adapted and were then validated using the SLN-positive VC patients. In addition, the predictive power of nomograms from Memorial Sloan Kettering Cancer Center (MSKCC), Stanford, and the Cambridge model were compared with regard to our patient collective. RESULTS: A total of 2,146 patients were included in the study. Of these, 470 patients had positive SLN, 295 consisted the training collective and 175 consisted the validation collective. In a regression model, three variants - with 11, 6 and 2 variables - were developed for the prediction of NSLN metastases in our defined population and compared to the most frequently used nomograms. Our variants with 11 and with 6 variables were proven to be a particularly suitable model and showed similarly good results as the published MSKCC nomogram. CONCLUSION: Our developed nomograms may be used as a prediction tool for NSLN metastases after positive SLN.

Modified LeFort colpocleisis: clinical outcome and patient satisfaction.

OBJECTIVES: The purpose of this study was to determine the anatomical and functional outcomes, as well as patients' satisfaction and morbidity associated with modified LeFort colpocleisis. STUDY DESIGN: Between 7/2007 and 6/2011 58 patients underwent a modified LeFort colpocleisis. Thirty-eight were available for follow-up visit. Records were reviewed for patients' characteristics, operative data and incidence of complications. The follow-up visit comprised a medical history and a gynecological examination. A visual-analog-scale to assess patients' quality of life after surgery was used. The patients were asked: "Would you again choose to have this surgery performed?" and "Do you regret choosing to have a vaginal closure procedure?" Statistical analysis was performed using R version 2.12.1, R Foundation for Statistical Computing, Vienna, Austria. RESULTS: There were no treatment failures within a mean follow-up of 14 months (range 3-41 months). 89% of patients reported an improved quality of life postoperatively. No complications occurred intraoperatively and none of the patients regretted the loss of sexual function. All patients stated that they would choose to have the colpocleisis procedure again. Postoperatively 8 urinary tract infections, 2 hematomas and 1 pyometra occurred. Two patients complained about stress urinary incontinence and another one about an overactive bladder. CONCLUSION: The study highlights an additional safe and effective option for an individualized treatment of pelvic organ prolapse.

Improvement of survival in sex cord stromal tumors - an observational study with more than 25 years follow-up.

OBJECTIVE: To highlight aspects of malignant ovarian sex cord stromal tumors, effects of treatment, and developments over the past 28 years. DESIGN: Population-based cohort study. SETTING: Gynecological departments within the catchment-area of the Munich Cancer Registry and associated with the project group 'Malignant Ovarian Tumors' of the Munich Cancer Center. SAMPLE: One hundred and forty-five women with an invasive single sex cord stromal tumor diagnosed between 1978 and 2005. METHODS: Overall survival was estimated with the Kaplan-Meier method, relative survival was computed by the ratio of observed to expected survival rate. The impact of age, International Federation of Gynecology and Obstetrics (FIGO)-stage, residual tumor, and chemotherapy was examined by multivariate analysis (Cox regression model). MAIN OUTCOME MEASURES: Overall and relative survival and multivariate adjusted overall survival. RESULTS: Survival data showed a five-/10-year overall survival of 55.8%/42.8% (relative survival 58.6%/49.2%) for women diagnosed before 1988 and 89.1%/78.3% (relative survival 92.7%/85.2%) for women diagnosed after 1988. After adjustment for age and FIGO-stage, the following hazard ratios and 95% confidence intervals (95% CI) for treatment methods resulted: 3.3 (95% CI 1.5-7.0) for women with compared to women without residual tumor and 2.2 (95% CI 1.2-4.2) for women with chemotherapy compared to women where no chemotherapy was given. CONCLUSIONS: Improvements in survival may be attributed to a stage-shift toward more favorable stages at diagnosis and to advances in treatment such as improved surgery without residual tumor. There is no evidence for any benefit of adjuvant chemotherapy. Surgery remains the cornerstone of treatment, yet the benefit of postoperative therapy is still under debate.