Implications for surveillance for breast cancer patients based on the internally and externally validated BRENDA-metastatic recurrence score.

PURPOSE: Although the incidence of distant relapse is decreasing, 20-30% of patients with early breast cancer die of metastasis. The aim of this study is to characterize patients with metastasis-free survival(MFS) less than 5 years, to analyze the most probable site of metastases according to the internally and externally validated BRENDA-score. The BRENDA-score is a combination of the biological subtype and clinical staging. METHOD: 3832 patients with primary diagnosis of breast cancer and either distant metastatic recurrence within 5 years or MFS ≥ 5 years were assigned to this study. Patients were classified for metastatic recurrence according to the BRENDA-score. 1765 patients were in a validation set. Statistical methods were Kaplan-Meier curves, Cox regression analysis, Exhausted CHAID, likelihood-ratio tests and the Nearest Neighbor Estimation method. RESULTS: There was a significant(p < 0.001) difference between the Kaplan-Meier MFS-functions of M0-patients stratified by BRENDA-score. The BRENDA score outperforms intrinsic subtypes and the Nottingham prognostic score. It fits the original data and the validation set equally well (p = 0.179).There was a significant(p < 0.001) difference between mean BRENDA-Index for patients with MFS < 5y(21.0 ± 9.0) and patients with MFS ≥ 5y(mean BRENDA-Index 11.7 ± 8.2). 55.6% of the very high risk patients(BRENDA-Index ≥ 27) had metastases within 5 years. The most likely primary metastatic site was bone(30%) followed by liver(19%) and lung(18%). The discriminatory ability(areas under the time dependent ROC curve) of the BRENDA score is good to acceptable for the first 5 years. In the very low/low risk (intermediate, high/very high) risk group 50% of all metastases were diagnosed within 26 months. Guideline adherence had a highly significant influence on outcome independent of the risk group. CONCLUSION: The evaluation showed that the BRENDA-Score is a robust predictive tool for breast cancer recurrence and site of metastases in the first five years after diagnosis. It outperforms intrinsic subtypes and the Nottingham prognostic score. The BRENDA-score could be a tool for a risk orientated and targeted follow up.

Optimized process quality in certified breast centers through adherence to stringent diagnostic and therapeutic algorithms effects of structural as well as socio-demographic factors on start of therapy.

PURPOSE: An increasing incidence of breast cancer can be observed worldwide. Since a delay of therapy can have a negative impact on prognosis, timely cancer care is an important quality indicator. By receiving treatment at a certified breast cancer center, the patient has the best chance of treatment in accordance with guidelines and the best prognosis. The identification of risk factors for a delay of therapy is of central importance and should be the basis for a continuous optimization of treatment at breast cancer centers. METHODS: This retrospective study included women with breast cancer (primary diagnosis, relapse, or secondary malignancy) at the University Hospital Würzburg in 2019 and 2020. Data were retrieved from patients' records. Correlations and regression analyses were performed to detect potential risk factors for treatment delay. RESULTS: Patients who received the histological confirmation of breast cancer at an external institution experienced a later therapy start than those patients who received the histological confirmation at the University Hospital Würzburg itself. (35.7 vs. 32.2 days). The interval between histological confirmation and the first consultation at the University Hospital Würzburg correlated statistically significant with age, distress and distance to the hospital. CONCLUSION: Patients with an in-house diagnosis of breast cancer are treated more quickly than those whose diagnosis was confirmed in an external institution. We identified factors such as increased age, greater distance to the hospital as well as increased distress to prolong the time until start of oncological treatment. Intensified patient care should be offered to these subgroups.

Introducing a novel model for simulating large loop excision of the transformation zone (LLETZ) using 3D printing technique.

PURPOSE: Electrosurgery is the gold-standard procedure for the treatment of cervical dysplasia. The quality of the outcome depends on the accuracy of performance, which underlines the role of adequate training of surgeons, especially, as this procedure is often performed by novice surgeons. According to our knowledge, medical simulation has up until now lacked a model, which focuses on realistically simulating the treatment of cervical dysplasia with the concerning anatomy. METHODS AND RESULT: In our work, we present a model created using 3D printing for holistically simulating diagnostic, as well as surgical interventions of the cervix, as realistically as possible. CONCLUSION: This novel simulator is compared to an existing model and both are evaluated. By doing so, we aim to provide novice gynecologists with standardized and high-quality simulation models for practicing to improve their proficiency.

Analysis of microRNAs in Exosomes of Breast Cancer Patients in Search of Molecular Prognostic Factors in Brain Metastases.

Brain metastases are the most severe tumorous spread during breast cancer disease. They are associated with a limited quality of life and a very poor overall survival. A subtype of extracellular vesicles, exosomes, are sequestered by all kinds of cells, including tumor cells, and play a role in cell-cell communication. Exosomes contain, among others, microRNAs (miRs). Exosomes can be taken up by other cells in the body, and their active molecules can affect the cellular process in target cells. Tumor-secreted exosomes can affect the integrity of the blood-brain barrier (BBB) and have an impact on brain metastases forming. Serum samples from healthy donors, breast cancer patients with primary tumors, or with brain, bone, or visceral metastases were used to isolate exosomes and exosomal miRs. Exosomes expressed exosomal markers CD63 and CD9, and their amount did not vary significantly between groups, as shown by Western blot and ELISA. The selected 48 miRs were detected using real-time PCR. Area under the receiver-operating characteristic curve (AUC) was used to evaluate the diagnostic accuracy. We identified two miRs with the potential to serve as prognostic markers for brain metastases. Hsa-miR-576-3p was significantly upregulated, and hsa-miR-130a-3p was significantly downregulated in exosomes from breast cancer patients with cerebral metastases with AUC: 0.705 and 0.699, respectively. Furthermore, correlation of miR levels with tumor markers revealed that hsa-miR-340-5p levels were significantly correlated with the percentage of Ki67-positive tumor cells, while hsa-miR-342-3p levels were inversely correlated with tumor staging. Analysis of the expression levels of miRs in serum exosomes from breast cancer patients has the potential to identify new, non-invasive, blood-borne prognostic molecular markers to predict the potential for brain metastasis in breast cancer. Additional functional analyzes and careful validation of the identified markers are required before their potential future diagnostic use.

Laparoscopic Management of a Heterotopic Pregnancy in the Tubal Stump.

STUDY OBJECTIVE: To demonstrate how a heterotopic tubal stump pregnancy can be safely managed with laparoscopy, preserving the intrauterine pregnancy. DESIGN: Stepwise demonstration of the technique by means of a video tutorial. SETTING: The management of pregnancies in the tubal stump after salpingectomy involves either a surgical intervention or systemic therapy. In case of a simultaneous intrauterine pregnancy, although the prognosis for the fetus remains good with live births in approximately 70% of the cases, the surgical management of the tubal stump pregnancy is challenging owing to the risk of bleeding from the uterine horn [1-5]. We present an effective and reproducible laparoscopic technique on the basis of a 31-year-old patient with 2 prior right fallopian tube pregnancies, which were later treated with salpingectomy. The patient is now presenting in the sixth week of gestation after transfer from 2 oocytes with a pregnancy in the tubal stump and a concomitant vital intrauterine pregnancy. INTERVENTIONS: The key steps of laparoscopic surgery include (1) continuous absorbable monofilament suture on the uterine horn around the tubal stump to achieve hemostasis and exposure of the proximal part of the tube, (2) removal of ectopic pregnancy, and (3) closure of the excision site with continuous absorbable polyfilament suture. The instillation of vasoconstrictive substances and the use of electrical coagulation should be avoided. CONCLUSION: The demonstrated laparoscopic technique is a feasible method of removal of a tubal stump pregnancy without interfering with the vital intrauterine pregnancy. The blood loss can be minimized, and laparotomy can be avoided.

Combining Molecular Dynamics and Machine Learning to Predict Self-Solvation Free Energies and Limiting Activity Coefficients.

Computational prediction of limiting activity coefficients is of great relevance for process design. For highly nonideal mixtures including molecules with directed interactions, methods that maintain the molecular character of the solvent are most promising. Computational expense and force-field deficiencies are the main limiting factors that prevent the use of high-throughput molecular dynamics (MD) simulations in a predictive setup. The combination of MD simulations and machine learning used in this work accounts for both issues. Comparison to published data including free-energy simulations, COSMO-RS and UNIFAC models, reveals competitive prediction accuracy.

Preliminary Experience with Virtual Monoenergetic Imaging and Iodine Mapping in the Primary Staging of Endometrial Cancer.

This study investigated whether virtual monoenergetic images (VMIs) and iodine mapping based on dual-energy CT (DECT) provide advantages in the assessment of endometrial cancer. A dual-source DECT was performed for primary staging of histologically proven endometrioid adenocarcinoma in 21 women (66.8 ± 12.0 years). In addition to iodine maps, VMIs at 40, 50, 60, 70, and 80 keV were reconstructed from polyenergetic images (PEIs). Objective analysis comprised the measurement of tumor contrast, contrast-to-noise ratio, and normalized iodine concentration (NIC). In addition, three radiologists independently rated tumor conspicuity. The highest tumor contrast (106.6 ± 45.0 HU) and contrast-to-noise ratio (4.4 ± 2.0) was established for VMIs at 40 keV. Tumor contrast in all VMIs ≤ 60 keV was higher than in PEIs (p < 0.001). The NIC of malignant tissue measured in iodine maps was substantially lower compared with a healthy myometrium (0.3 ± 0.1 versus 0.6 ± 0.1 mg/mL; p < 0.001). Tumor conspicuity was highest in 40 keV datasets, whereas no difference was found among PEIs and VMIs at 60 and 70 keV (p ≥ 0.334). Interobserver agreement was good, indicated by an intraclass correlation coefficient of 0.824 (0.772-0.876; p < 0.001). In conclusion, computation of VMIs at 40 keV and color-coded iodine maps aids the assessment of endometroid adenocarcinoma in primary staging.

Evaluating the value of individualized 3D printed models for examination, diagnosis and treatment planning of cervical cancer.

BACKGROUND: 3D printing holds great potential of improving examination, diagnosis and treatment planning as well as interprofessional communication in the field of gynecological oncology. In the current manuscript we evaluated five individualized, patient-specific models of cervical cancer FIGO Stage I-III, created with 3D printing, concerning their value for translational oncology. METHODS: Magnetic resonance imaging (MRI) of the pelvis was performed on a 3.0 Tesla MRI, including a T2-weighted isotropic 3D sequence. The MRI images were segmented and transferred to virtual 3D models via a custom-built 3D-model generation pipeline and printed by material extrusion. The 3D models were evaluated by all medical specialties involved in patient care of cervical cancer, namely surgeons, radiologists, pathologists and radiation oncologists. Information was obtained from evaluated profession-specific questionnaires which were filled out after inspecting all five models. The questionnaires included multiple-select questions, questions based on Likert scales (1 = "strongly disagree " or "not at all useful " up to 5 = "strongly agree " or "extremely useful ") and dichotomous questions ("Yes" or "No"). RESULTS: Surgeons rated the models as useful during surgery (4.0 out of 5) and for patient communication (4.7 out of 5). Furthermore, they believed that the models had the potential to revise the patients' treatment plan (3.7 out of 5). Pathologists evaluated with mean ratings of 3.0 out of 5 for the usefulness of the models in diagnostic reporting and macroscopic evaluation. Radiologist acknowledged the possibility of providing additional information compared to imaging alone (3.7 out of 5). Radiation oncologists strongly supported the concept by rating the models highly for understanding patient-specific pathological characteristics (4.3 out of 5), assisting interprofessional communication (mean 4.3 out of 5) and communication with patients (4.7 out of 5). They also found the models useful for improving radiotherapy treatment planning (4.3 out of 5). CONCLUSION: The study revealed that the 3D printed models were generally well-received by all medical disciplines, with radiation oncologists showing particularly strong support. Addressing the concerns and tailoring the use of 3D models to the specific needs of each medical speciality will be essential for realizing their full potential in clinical practice.

Evaluation of different imaging modalities for axillary lymph node staging in breast cancer patients to provide a personalized and optimized therapy algorithm.

PURPOSE: The reliable detection of tumor-infiltrated axillary lymph nodes for breast cancer [BC] patients plays a decisive role in further therapy. We aimed to find out whether cross-sectional imaging techniques could improve sensitivity for pretherapeutic axillary staging in nodal-positive BC patients compared to conventional imaging such as mammography and sonography. METHODS: Data for breast cancer patients with tumor-infiltrated axillary lymph nodes having received surgery between 2014 and 2020 were included in this study. All examinations (sonography, mammography, computed tomography [CT] and magnetic resonance imaging [MRI]) were interpreted by board-certified specialists in radiology. The sensitivity of different imaging modalities was calculated, and binary logistic regression analyses were performed to detect variables influencing the detection of positive lymph nodes. RESULTS: All included 382 breast cancer patients had received conventional imaging, while 52.61% of the patients had received cross-sectional imaging. The sensitivity of the combination of all imaging modalities was 68.89%. The combination of MRI and CT showed 63.83% and the combination of sonography and mammography showed 36.11% sensitivity. CONCLUSION: We could demonstrate that cross-sectional imaging can improve the sensitivity of the detection of tumor-infiltrated axillary lymph nodes in breast cancer patients. Only the safe detection of these lymph nodes at the time of diagnosis enables the evaluation of the response to neoadjuvant therapy, thereby allowing access to prognosis and improving new post-neoadjuvant therapies.

Prognostic effect of HER2 evolution from primary breast cancer to breast cancer metastases.

PURPOSE: Therapeutic options for breast cancer (BC) treatment are constantly evolving. The Human Epidermal Growth Factor 2 (HER2)-low BC entity is a new subgroup, representing about 55% of all BC patients. New antibody-drug conjugates demonstrated promising results for this BC subgroup. Currently, there is limited information about the conversion of HER2 subtypes between primary tumor and recurrent disease. METHODS: This retrospective study included women with BC at the University Medical Centre Wuerzburg from 1998 to 2021. Data were retrieved from patients' records. HER2 evolution from primary diagnosis to the first relapse and the development of secondary metastases was investigated. RESULTS: In the HR-positive subgroup without HER2 overexpression, HER2-low expression in primary BC was 56.7 vs. 14.6% in the triple-negative subgroup (p < 0.000). In the cohort of the first relapse, HER2-low represented 64.1% of HR-positive vs. 48.2% of the triple-negative cohort (p = 0.03). In patients with secondary metastases, HER2-low was 75.6% vs. 50% in the triple negative subgroup (p = 0.10). The subgroup of HER2-positive breast cancer patients numerically increased in the course of disease; the HER2-negative overall cohort decreased. A loss of HER2 expression from primary BC to the first relapse correlated with a better OS (p = 0.018). No clinicopathological or therapeutic features could be identified as potential risk factors for HER2 conversion. CONCLUSION: HER2 expression is rising during the progression of BC disease. In view of upcoming therapeutical options, the re-analysis of newly developed metastasis will become increasingly important.

Psycho-Oncological Care Provision in Highly Distressed Breast Cancer Patients.

Objective To evaluate the proportion of breast cancer (BC) patients with distress or psychological comorbidity as well as offer and use of psychological support in subgroups of BC patients with different extents of distress. Methods 456 patients with BC were evaluated at baseline (t1) and until 5 years after diagnosis (t4) at the BRENDA certified BC centers. Logistic regression was used to analyze if patients with distress at t1 received offers and actual psychological support more often than patients without distress at t1. Regression analyses were used to examine if acute, emerging or chronic disease was associated with higher rates of offer and use of psychotherapy as well as intake of psychotropic drugs. Results In 45% of BC patients psychological affection was detected at t4. The majority of patients with moderate or severe distress at t1 (77%) received the offer for psychological service, while 71% of those received the offer for support at t4. Patients, who were psychologically affected at t1, have not been offered psychological services more often than those without, but they significantly more often used services if offered. Especially patients with acute comorbidity received significantly more often an offer for psychotherapy compared to unimpaired patients, while those patients with emerging or chronic disease did not. 14% of BC patients took psychopharmaceuticals. This mainly concerns patients with chronic comorbidity. Conclusion Psychological services were offered to and used by a fair amount of BC patients. All subgroups of BC patients should be addressed, in order to improve the comprehensive supply with psychological services.

Predictors of Decreased Quality of Life in Breast Cancer Survivors Five Years After Diagnosis.

PURPOSE: Due to improved therapy, early diagnosis, and growing incidence rates, the number of long-term breast cancer survivors is increasing. Survivors can still be affected by aftercare, resulting in reduced quality of life (QoL). Thus, in this study, we investigated possible predictors of decreased physical and social functioning in breast cancer survivors. METHODS: In a German multicenter prospective study, we enrolled 759 female patients with breast cancer before surgery (t1), and contacted them again 5 years after surgery (t4). Data on QoL were assessed at t4 using the European Organization for Research and Treatment of Cancer QoL Core Questionnaire (EORTC QLQ-C30) and its breast cancer module EORTC QLQ-BR23. Predictors of decreased physical and social functioning were analyzed using logistic regression with odds ratios as effect estimates and 95% confidence intervals. Thresholds for the clinical importance of detrimental effects on QoL were defined according to Giesinger. RESULTS: Questionnaires from 759 patients were retrieved at t1. Of these, 456 participated in the study at t4. Poor QoL 5 years after diagnosis was reported by 20%-50% of the participants. Age, mastectomy, chemotherapy, education, employment, cohabitation, psychiatric comorbidities at t1, anxiety, depression, and intensity of physical activity emerged as predictors of decreased physical and social functioning 5 years after diagnosis. CONCLUSION: Relief of symptoms and improvement in the QoL should be priorities in aftercare. Detecting patients with a decreased QoL is a rising challenge. Healthcare providers should take special care of patients aged 50-59 years, patients with psychiatric comorbidities and depression, and patients who have undergone mastectomy.

Evaluating a novel 3D printed model for simulating Large Loop Excision of the Transformation Zone (LLETZ).

BACKGROUND: Electrosurgical excisions are common procedures for treating cervical dysplasia and are often seen as minor surgeries. Yet, thorough training of this intervention is required, as there are considerable consequences of inadequate resections, e.g. preterm birth, the risk of recurrence, injuries and many more. Unfortunately, there is a lack of sufficiently validated possibilities of simulating electrosurgeries, which focus on high fidelity and patient safety. METHODS: A novel 3D printed simulator for examination and electrosurgical treatment of dysplastic areas of the cervix was compared with a conventional simulator. Sixty medical students experienced a seminar about cervical dysplasia. Group A underwent the seminar with the conventional and Group B with the novel simulator. After a theoretical introduction, the students were randomly assigned by picking a ticket from a box and went on to perform the hands-on training with their respective simulator. Each student first obtained colposcopic examination training. Then he or she performed five electrosurgical excisions (each). This was assessed with a validated score, to visualize their learning curve. Furthermore, adequate and inadequate resections and contacts between electrosurgical loop and vagina or speculum were counted. Both groups also assessed the seminar and their simulator with 18 questions (Likert-scales, 1-10, 1 = strongly agree / very good, 10 = strongly disagree / very bad). Group B additionally assessed the novel simulator with four questions (similar Likert-scales, 1-10). RESULTS: Nine of 18 questions showed statistically significant differences favoring Group B (p < 0.05). Group B also achieved more adequate R0-resections and less contacts between electrosurgical loop and vagina or speculum. The learning curves of the performed resections favored the novel simulator of Group B without statistically significant differences. The four questions focusing on certain aspects of the novel simulator indicate high appreciation of the students with a mean score of 1.6 points. CONCLUSION: The presented novel simulator shows several advantages compared to the existing model. Thus, novice gynecologists can be supported with a higher quality of simulation to improve their training and thereby patient safety.

Evaluating the value of a 3D printed model for hands-on training of gynecological pelvic examination.

BACKGROUND: Simulation in the field of gynecological pelvic examination with educational purposes holds great potential. In the current manuscript we evaluate a 3D printed model of the female pelvis, which improves practical teaching of the gynecological pelvic examination for medical staff. METHODS: We evaluated the benefit of a 3D printed model of the female pelvis (Pelvisio®) as part of a seminar ("skills training") for teaching gynecological examination to medical students. Each student was randomly assigned to Group A or B by picking a ticket from a box. Group A underwent the skills training without the 3D printed model. Group B experienced the same seminar with integration of the model. Both groups evaluated the seminar by answering five questions on Likert scales (1-10, 1 = "very little" or "very poor", 10 equals "very much" or "very good"). Additionally, both groups answered three multiple-choice questions concerning pelvic anatomy (Question 6 to 8). Finally, Group B evaluated the 3D printed model with ten questions (Question 9 to 18, Likert scales, 1-10). RESULTS: Two of five questions concerning the students' satisfaction with the seminar and their gained knowledge showed statistically significant better ratings in Group B (6.7 vs. 8.2 points and 8.1 vs. 8.9 points (p < 0.001 and p < 0.009). The other three questions showed no statistically significant differences between the traditional teaching setting vs. the 3D printed model (p < 0.411, p < 0.344 and p < 0.215, respectively). The overall mean score of Question 1 to 5 showed 8.4 points for Group B and 7.8 points for Group A (p < 0.001). All three multiple-choice questions, asking about female pelvic anatomy, were answered more often correctly by Group B (p < 0.001, p < 0.008 and p < 0.001, respectively). The mean score from the answers to Questions 9 to 18, only answered by Group B, showed a mean of 8.6 points, indicating, that the students approved of the model. CONCLUSION: The presented 3D printed model Pelvisio® improves the education of female pelvic anatomy and examination for medical students. Hence, training this pivotal examination can be supported by a custom designed anatomical model tailored for interactive and explorative learning.

A 3D printed model of the female pelvis for practical education of gynecological pelvic examination.

BACKGROUND: Pelvic palpation is a core component of every Gynecologic examination. It requires vigorous training, which is difficult due to its intimate nature, leading to a need of simulation. Up until now, there are mainly models available for mere palpation which do not offer adequate visualization of the concerning anatomical structures. In this study we present a 3D printed model of the female pelvis. It can improve both the practical teaching of gynecological pelvic examination for health care professionals and the spatial understanding of the relevant anatomy. METHODS: We developed a virtual, simplified model showing selected parts of the female pelvis. 3D printing was used to create a physical model. RESULTS: The life-size 3D printed model has the ability of being physically assembled step by step by its users. Consequently, it improves teaching especially when combining it with commercial phantoms, which are built solely for palpation training. This is achieved by correlating haptic and visual sensations with the resulting feedback received. CONCLUSION: The presented 3D printed model of the female pelvis can be of aid for visualizing and teaching pelvic anatomy and examination to medical staff. 3D printing provides the possibility of creating, multiplying, adapting and sharing such data worldwide with little investment of resources. Thus, an important contribution to the international medical community can be made for training this challenging examination.

Treatment of Vulvovaginal Atrophy with Fractional CO2 Laser: Evaluating Real-World Data.

Objective: We aimed to evaluate real-world data for the use of fractional CO2 laser therapy for treating symptoms of vulvovaginal atrophy (VVA). Background: VVA is widespread and can reduce the patients' quality of life. There is a lack of data regarding its therapy with laser, especially for daily practice (i.e., real-world data). Methods: Thirty-six patients were treated in a single medical center. They consisted of pre- and postmenopausal women and received three fractional CO2 laser therapy treatments with 3-6 weeks between each treatment. Each patient financed the treatment privately. The symptoms pain, pruritus, dyspareunia, burning, dryness, and dysuria were recorded with a visual analog scale (1-10) before the first, second, and third laser treatment. The data were examined retrospectively. Results: Pain was reduced from a mean of 2.5 points (minimum 0, maximum 9 points) to 1.1 (minimum 0, maximum 8 points) before the third laser treatment. Pruritus showed a mean score of 3.8 (minimum 0, maximum 10 points). This decreased to 1.4 (minimum 0, maximum 8 points). Dyspareunia scored a mean of 6.8 (minimum 0, maximum 10 points). After two laser therapies, the score was 3.3 (minimum 0, maximum 8 points). Burning showed 4.2 points (minimum 0, maximum 10 points). Having experienced two laser therapy sessions, the patients scored 1.5 (minimum 0, maximum 9 points) points. The severity of dryness dropped from 6.5 (minimum 0, maximum 10 points) to 3.3 (minimum 0, maximum 9 points). Dysuria was stated with 1.8 points (minimum 0, maximum 10 points) before the first and 0.5 points (minimum 0, maximum 6 points) before the third laser therapy. All changes showed statistical significance (p < 0.002). Conclusions: This real-world data propose fractional CO2 laser to reduce VVA-associated genital discomfort, thus being a valuable therapy option for pre- and postmenopausal women.

Total Mesometrial Resection With (Neo)Adjuvant Chemotherapy in Locally Advanced Cervical Cancer: A Tumor Response Score.

BACKGROUND/AIM: There is a lack of data concerning the surgical treatment of locally advanced squamous cell carcinoma of the uterine cervix (LACC) with neoadjuvant and adjuvant chemotherapy (NACT, ACT) as well as total mesometrial resection (TMMR). The aim of the study was to present a novel approach for treating LACC using a tumor response score for NACT. PATIENTS AND METHODS: A total of 12 patients with LACC were treated with NACT [cisplatin, ifosfamide, paclitaxel (TIP)], TMMR and ACT containing TIP. To measure the response during NACT, we scored i) the maximum tumor diameter (maxTD) in gynecological examination, ii) the MRI for radiologic maxTD, iii) the tumor volume and iv) the squamous cell carcinoma antigen before and after two applications of TIP. RESULTS: TIP reduced all score-parameters in 10 of 12 patients (p<0.005). We found a possible reduction of lymph node metastasis in 72.7%. The proposed score detected sufficient and insufficient tumor response. CONCLUSION: TIP followed by TMMR with ACT could be a possibility for patients denying radiochemotherapy. The tumor response score can detect patients with inadequate benefit from NACT.

High Prevalence of Genital Human Papillomavirus Infection in Patients With Primary Immunodeficiencies.

Background: Genital human papillomavirus (HPV)-infections are common in the general population and are responsible for relevant numbers of epithelial malignancies. Much data on the HPV-prevalence is available for secondary immunodeficiencies, especially for patients with human immunodeficiency virus (HIV)-infection. Little is known about the genital HPV-prevalence in patients with primary immunodeficiencies (PIDs). Methods: We performed a cross-sectional study of patients with PIDs and took genital swabs from male and female patients, which were analyzed with polymerase chain reaction for the presence of HPV-DNA. Clinical and laboratory data was collected to identify risk factors. Results: 28 PID patients were included in this study. 10 of 28 (35.7%) had HPV-DNA in their genital swabs. 6 patients had high-risk HPV-types (21.4%). Most patients had asymptomatic HPV-infections, as genital warts were rare (2 of 28 patients) and HPV-associated malignancy was absent. Differences in the HPV-positivity regarding clinical PID-diagnosis, duration of PID, age, sex, immunosuppression, immunoglobulin replacement, or circumcision in males were not present. HPV-positive PID patients had higher numbers of T cells (CD3+), of cytotoxic T cells (CD3+/CD8+), of transitional B cells (CD19+/CD38++/CD10+/IgD+), and of plasmablasts (CD19+/CD38+/CD27++/IgD-) compared to HPV-negative. Conclusion: PID patients exhibit a high rate of genital HPV-infections with a high rate of high-risk HPV-types. Regular screening for symptomatic genital HPV-infection and HPV-associated malignancy in PID patients seems recommendable.

BRENDA-Score, a Highly Significant, Internally and Externally Validated Prognostic Marker for Metastatic Recurrence: Analysis of 10,449 Primary Breast Cancer Patients.

Background Current research in breast cancer focuses on individualization of local and systemic therapies with adequate escalation or de-escalation strategies. As a result, about two-thirds of breast cancer patients can be cured, but up to one-third eventually develop metastatic disease, which is considered incurable with currently available treatment options. This underscores the importance to develop a metastatic recurrence score to escalate or de-escalate treatment strategies. Patients and methods Data from 10,499 patients were available from 17 clinical cancer registries (BRENDA-project [1]. In total, 8566 were used to develop the BRENDA-Index. This index was calculated from the regression coefficients of a Cox regression model for metastasis-free survival (MFS). Based on this index, patients were categorized into very high, high, intermediate, low, and very low risk groups forming the BRENDA-Score. Bootstrapping was used for internal validation and an independent dataset of 1883 patients for external validation. The predictive accuracy was checked by Harrell's c-index. In addition, the BRENDA-Score was analyzed as a marker for overall survival (OS) and compared to the Nottingham prognostic score (NPS). Results: Intrinsic subtypes, tumour size, grading, and nodal status were identified as statistically significant prognostic factors in the multivariate analysis. The five prognostic groups of the BRENDA-Score showed highly significant (p < 0.001) differences regarding MFS:low risk: hazard ratio (HR) = 2.4, 95%CI (1.7-3.3); intermediate risk: HR = 5.0, 95%CI.(3.6-6.9); high risk: HR = 10.3, 95%CI (7.4-14.3) and very high risk: HR = 18.1, 95%CI (13.2-24.9). The external validation showed congruent results. A multivariate Cox regression model for OS with BRENDA-Score and NPS as covariates showed that of these two scores only the BRENDA-Score is significant (BRENDA-Score p < 0.001; NPS p = 0.447). Therefore, the BRENDA-Score is also a good prognostic marker for OS. Conclusion: The BRENDA-Score is an internally and externally validated robust predictive tool for metastatic recurrence in breast cancer patients. It is based on routine parameters easily accessible in daily clinical care. In addition, the BRENDA-Score is a good prognostic marker for overall survival. Highlights: The BRENDA-Score is a highly significant predictive tool for metastatic recurrence of breast cancer patients. The BRENDA-Score is stable for at least the first five years after primary diagnosis, i.e., the sensitivities and specificities of this predicting system is rather similar to the NPI with AUCs between 0.76 and 0.81 the BRENDA-Score is a good prognostic marker for overall survival.

The Role of Deconstructive Teaching in the Training of Laparoscopy.

BACKGROUND AND OBJECTIVES: Skills-lab training is crucial for the development of advanced laparoscopic skills. In this study, we examined whether a systematic deconstructive and comprehensive tutoring approach improves training results in laparoscopic suturing and intracorporeal knot tying. METHODS: Sixteen residents in obstetrics and gynecology participating in structured skills-lab laparoscopy training were randomized in 2 equal-sized groups receiving 1-on-1 tutoring either in the traditional method or according to the Peyton's 4-step approach, involving an additional training step, with the trainees instructing the tutor to perform the exercises. A validated assessment tool (revised Objective Structured Assessment of Technical Skills) and the number of completed square knots per training session and the mean time per knot were used to assess the efficacy of training in both groups. RESULTS: Trainees in Peyton's group achieved significantly higher revised Objective Structured Assessment of Technical Skills scores (28.6 vs 23.9 points; P = .05) and were able to improve their scores during autonomous training repetitions, in contrast to the trainees not in Peyton's group (difference +4.75 vs -4.29 points, P = .02). Additionally, they seemed to be able to perform a greater number of successful knots during the exercise and to complete each knot quicker with the later observations failing to reach the threshold of statistical significance. CONCLUSION: Peyton's 4-step approach seemed to be superior for teaching laparoscopic skills to obstetrics and gynecology residents in the skills-lab setting and can be therefore proposed for training curricula.