Evaluation of Laparoscopy Virtual Reality Training on the Improvement of Trainees' Surgical Skills.

Background and objectives: The primary objective was to evaluate the benefit of training with virtual reality simulation. The secondary objective was to describe the short-term skill acquisition obtained by simulation training and to determine the factors affecting its magnitude. Materials and Methods: We prospectively performed a three-stage evaluation: face, constructive, and predictive to evaluate the training with a laparoscopic simulator with haptic feedback. The participants (n = 63) were divided according to their level of experience into three groups: 16% residents; 46% specialists and 38% were consultants. Results: Face evaluation demonstrates the acceptance of the design and realism of the tasks; it showed a median score of eight (IQR 3) on a Likert scale and 54% of participants (n = 34) gave the tissue feedback a moderate rating. Constructive evaluation demonstrates the improvement of the participants in the training session and the ability of the designed task to distinguish the experienced from the inexperienced surgeon based on the performance score, at task I (transfer of pegs) and II (laparoscopic salpingectomy). There was an improvement in both tasks with a significant increase in score and reduction in time. The study showed that those with a high score at the pre-test recorded a high score post-test, showing a significant pair-wise comparison (Z) and correlation (p) showing a significant statistical significance (p < 0.001). The predictive evaluation demonstrates the beneficiary effect of training four weeks afterward on the practice of surgeons addressed with five questions. It showed an improvement regarding implementation into daily routine, performance of procedure, suturing, shortening of the operative time, and complication management. Conclusions: Virtual reality simulation established high ratings for both realism and training capacity, including clinical relevance, critical relevance, and maintaining training enthusiasm.

Dasatinib prevents skeletal metastasis of osteotropic MDA-MB-231 cells in a xenograft mouse model.

PURPOSE: Bone metastasis in breast cancer has been linked to activity of c-Src kinase, one of the extensively explored tyrosine kinases in cell biology. The impact of TNF-related apoptosis inducing ligand (TRAIL) and TRAIL receptors has just recently been integrated into this conception. METHODS: An osteotropic clone of MDA-MB-231 cells simulated a model for bone metastasis of triple-negative breast cancer (TNBC). The effects of Dasatinib, a clinically established inhibitor of Src kinases family and Abl were evaluated in vitro and in vivo. In vivo effects of Dasatinib treatment on the occurrence of skeletal metastases were tested in a xenograft mouse model after intra-cardiac injection of osteotropic MDA-MB-231-cells. Ex vivo analyses of the bone sections confirmed intraosseous growth of metastases and allowed determination of osteoclastic activity. RESULTS: Treatment of osteotropic MDA-MB-231 cells with Dasatinib inhibited proliferation rates in vitro. A shift in TRAIL-receptor expression towards an induction of oncogenic TRAIL-R2 was observed. In vivo, 15 of 30 mice received an intra-peritoneal treatment with Dasatinib. These mice showed significantly less skeletal metastases in bioluminescence scans. Moreover, a pronounced increase in bone volume was observed in the treatment group, as detected by µ-Computed Tomography. Dasatinib treatment also led to a greater increase in bone density in tibiae without metastatic affection, which was accompanied by reduced recruitment of osteoclasts. CONCLUSION: Our observations support the concept of utilizing Dasatinib in targeting early-stage bone metastatic TNBC and sustaining bone health.

Early treatment modifications improve chemotherapy adherence in ovarian cancer patients ≥70 years.

OBJECTIVE: Elderly ovarian cancer patients are underrepresented in clinical trials and disadvantaged with regard to therapeutic standards compared to other age groups. We explored the specific performance of a subset of patients aged ≥70 years in a large meta-data set of 3 phase III trials. METHODS: 3333 patients with advanced ovarian cancer recruited into 3 clinical phase III trials of the AGO & GINECO study groups were retrospectively analysed for age-specific prognostic and toxicity parameters. RESULTS: Only 10% (359/3333) of the patients were aged ≥70 years. This subgroup presented with impaired performance statuses (ECOG 2 14.8 vs 10.1%) and higher FIGO-stages (FIGO IIIC-IV 78.5 vs 73.6%) compared to younger patients. Complete operative tumor resection was achieved less frequently (postoperative tumor burden >10 mm 46.7 vs 33.9%) and elderly received less cycles of platinum/taxane-based chemotherapies (>4 cycles 81.9 vs 90.7%). FIGO-stage, histology, postoperative tumor burden and number of chemotherapy cycles were independent prognostic factors in elderly patients. Elderly patients with ≤4 cycles of chemotherapy showed a median OS of 18.4 months compared to 30.9 months in elderly with 5-6 cycles (p < 0.001). This effect was accentuated in elderly patients after complete tumor resection (cumulative survival benefit of 33.8 months). Analyses of chemotherapeutic delivery revealed that elderly patients with at least one cycle delay had higher chances to complete >4 cycles of chemotherapy. CONCLUSIONS: Protocol defined treatment modifications might support completion of >4 cycles of standard chemotherapy in fit elderly OC patients.

Accuracy of tumor size measurement: comparison of B-mode ultrasound, strain elastography, and 2D and 3D shear wave elastography with histopathological lesion size.

BACKGROUND: Predicting the exact extent of a breast tumor is of great importance for oncologic treatment strategies. Different types of elastography can be used as new tools for measuring lesion size. PURPOSE: To provide evidence regarding the accuracy of tumor size measurement of strain elastography (SE), two-dimensional (2D) and three-dimensional (3D) shear wave elastography (SWE), and conventional B-image ultrasound. MATERIAL AND METHODS: In this prospective study, the diameter of 105 malignant breast lesions was measured by SE, 2D and 3D SWE, and B-mode ultrasound. The histopathological lesion size was compared to all imaging-based measuring methods. RESULTS: The mean lesion size of all breast carcinomas was 1.54 cm. B-mode ultrasound underestimates breast cancer size in 65.7 % of all cases in this study ( P < 0.0001). Mean lesion size was more accurately determined by SE, 2D and 3D SWE compared to B-mode ultrasound. Absolute differences between measured and actual lesion are smaller for B-mode ultrasound (0.26 cm) than for SE (0.41 cm) and 2D and 3D SWE (0.41 cm and 0.44 cm, respectively). CONCLUSION: B-mode ultrasound allows more accurate lesion size measurement than SE and 2D or 3D SWE but has a significantly higher risk of underestimating tumor size which could lead to incomplete margins during surgery. 3D SWE was not superior to 2D SWE or SE but by trend more precise in predicting the size of invasive lobular carcinoma.

Validation of psychomotor tasks by Simbionix LAP Mentor simulator and identifying the target group.

BACKGROUND: This study addresses target group reliability and task validity for training on a laparoscopic simulator. MATERIAL AND METHODS: Data were collected on 64 participants prospectively at the Department of OB/GYN, University Hospitals Schleswig-Holstein, Campus Kiel. The Simbionix LAP Mentor for laparoscopic simulation was used to test trainees. Each participant received a questionnaire to clarify his/her medical position, surgical experience, and previous virtual reality (VR) experience, including video gaming experience. Pre- and post-tests were performed. Performances were analyzed for task completion and total time. RESULTS: All participants revealed a significant improvement in the post-test compared with the pre-test (p < .005), independent of their previous level of experience. Regarding accomplishment of the assigned task, the experts revealed in the pre-test an advantage in tasks 1-4 and 6-8. The beginners revealed wide-ranging improvements in tasks 3, 5, 8, and 9 between the pre-test and the post-test compared with novices in laparoscopic surgery (residents), and a wide range of improvements relative to experts. VR experience and video gaming exposure revealed an advantage in the pre-test; however, participants without previous exposure were able to narrow the gap, revealing extensive improvements in the post-test. CONCLUSION: The trainer could be beneficial for medical students and surgical novices.

Head-to-head comparison of the impact of Aurora A, Aurora B, Repp86, CDK1, CDK2 and Ki67 expression in two of the most relevant gynaecological tumor entities.

PURPOSE: The dysregulation of cell cycle kinases plays a crucial role in carcinogenesis and the expression of various kinases has been attributed to aggressive tumor growth and an unfavourable prognosis in oncological patients. We, therefore, aimed to evaluate the expression of Ki67 among five additional cell cycle kinases in a collective of mammary and ovarian tumor specimens and to find a correlation with clinicopathological parameters. METHODS: 76 mammary and 93 ovarian benign and malignant tumor samples were immunohistochemically stained and evaluated for the expression of Aurora A and B, Repp86, CDK1 and 2 (only breast specimens) and Ki67. The expression patterns of these cell cycle kinases were matched with retrospectively collected clinicopathological parameters. RESULTS: All examined cell cycle kinases accurately discriminated benign from malignant breast and ovarian tissues. In breast cancer, Aurora A and B-, Repp86-, CDK2- and Ki67-expression was inversely associated with ER expression. No correlation with the HER2-status was found in our collective. Importantly, we found a significant correlation between the expression of Aurora A and CDK1 and axillary lymph node metastasis in breast cancer. Furthermore, a shortened disease free survival (DFS) upon expression of Aurora B and CDK2 was shown in breast cancer patients. None of the cell cycle kinases was associated with predictive or prognostic factors in epithelial ovarian cancer. CONCLUSION: The prognostic value of the expression of Ki67 is overtrumped by alternative cell cycle kinases when it comes to prediction of axillary tumor spread and a shortened DFS, which might allow a further risk stratification in breast cancer patients.

Diagnosis and management of an unilateral giant fibroadenoma of the breast in pregnancy.

BACKGROUND: Fibroadenomas represent the vast majority of breast pathologies in young women. 2-4% of the fibroadenomas exceed 5 cm in size or 500 g in weight and are called "giant fibroadenomas". Due to their excessive growth they are usually enucleated to clarify a malignant origin, to differentiate from phyllodes tumor and to prevent persisting deformities of the breast. CASE: We present a case of a 17-year-old female who was pregnant in the 24th week and suffered from a giant fibroadenoma in the right breast. Besides the massive swelling no other illnesses were found. The patient was clinically asymptomatic and had noticed the tumor just 8 weeks ago. On clinical examination we found a tumor of more than 10 cm in size which fulfilled the criteria of a benign process. A prior performed biopsy and an ultrasound investigation could not definitely differentiate the mass from phyllodes tumor. Because of the rapid growth and the progressive deformation of the breast a lumpectomy was indicated and performed without complications in consideration of the gestational stage. CONCLUSION: We present a rare case of giant fibroadenoma in pregnant young women. Because of the progressive structural damage of the breast immediate surgical enucleation was indicated. Safety of the fetus was provided by perioperative monitoring. The pre-operative differentiation from phyllodes tumor is still challenging.

Mucinous Cystic Neoplasm of Pancreas in a Pregnant Woman Presenting with Severe Anemia and Gastric Bleeding: Case Report and Review of the Literature.

Mucinous cystic neoplasms of the pancreas are uncommon and especially their occurrence during pregnancy is an extremely rare event which necessitates an individualized and interdisciplinary management. A 33-year old woman was referred to our department during her third trimester of pregnancy (34th week of gestation) with severe anemia and tarry stools. Based on gastroscopic findings, our interdisciplinary team suspected a gastrointestinal stromal tumor and therefore indicated a prompt delivery via cesarean section completed with an oncological resection of the neoplasm. Histological examination subsequently showed a mucinous cystic neoplasm of the pancreas with no evidence of malignancy. To review the prevalence of mucinous cystic neoplasms and to discuss diagnosis and treatment during pregnancy. Moreover, we critically value the indication of preterm delivery and the oncological procedure in the perspective of outcome for mother and infant. A bleeding gastrointestinal tumor during pregnancy represents a life-threatening risk for mother and infant and requires an immediate interdisciplinary treatment. The urgency and radicality of the therapy should be adapted according to individual findings. As our patient's tumor was suspected of having a malignant progression, an extensive surgical intervention was necessary.

A Giant Mammary Hamartoma in a Young Breast Cancer Patient.

BACKGROUND: Hamartomas of the breast are rare benign tumors. Pre- and also postoperative differentiation from other benign or even malignant tumors is challenging. CASE PRESENTATION: A 36-year-old female presented with a giant tumor of the left breast. The patient had suffered from an early breast cancer of the contralateral right breast the year before, which was treated with breast-conserving therapy, radiation, and endocrine therapy ever since. The hamartoma was classified as BI-RADS 2 in mammography and BI-RADS 4 in ultrasound. On clinical examination, a tumor of nearly 15 cm in size led to an abstruse deformity of the breast and the nipple-areola complex. We found an indolent, grand bulging tumor with an elastic texture directly beneath the skin. A biopsy that had been performed before was compatible with the suspected hamartoma. Because of the remaining diagnostic uncertainties after contralateral breast cancer and the progressive malformation of the left breast, a tumor extirpation utilizing a reduction mammaplasty was performed without complications. Subsequent genetic analyses excluded a loss of PTEN in this patient. CONCLUSION: We presented the rare case of a 36-year-old woman with a history of breast cancer and a 700-g breast hamartoma. The preoperative and even the postoperative specification of a hamartoma remains challenging, and associations with genetic alterations should be considered.

Cytoplasmic levels of high mobility group A2 determine survival prognoses in breast cancer patients.

BACKGROUND: High mobility group A proteins are involved in chromatin remodeling, thereby influencing multiple fundamental biological processes. HMGA2 has been linked to oncogenic traits among a variety of malignancies. OBJECTIVE: To determine the prognostic implications of subcellular distribution patterns of HMGA2 in breast cancer. METHODS: Nuclear and cytoplasmic HMGA2 was evaluated in 342 breast cancer specimens and matched with clinico-pathological parameters. RESULTS: Overall and cytoplasmic, but not nuclear, levels of HMGA2 correlated with better survival prognoses in our collective (hazard ratio (HR) 0.34, P = 0.001 and HR 0.34, P < 0.001, respectively). The protective effect of cytoplasmic HMGA2 persisted in the Luminal A and triple negative breast cancer subgroups. Evaluating Luminal A and B subgroups jointly, only cytoplasmic, but not overall or nuclear HMGA2 levels were associated with better survival (HR 0.42, 95% confidence interval 0.21, 0.86, P = 0.017), irrespective of tumor size and node status. The addition of HMGA2 overall and cytoplasmic scores strengthened the prognostic selectivity in a model of conventional breast cancer risk factors. No predictive significance with regard to endocrine or chemoendocrine therapies was observed. CONCLUSION: Unexpectedly, we found a favorable survival probability upon overall levels of HMGA2 in our breast cancer collective, which was predominantly determined by the presence of HMGA2 in the cytoplasm.

Heterogeneous intracellular TRAIL-receptor distribution predicts poor outcome in breast cancer patients.

Upon ligand binding, plasma membrane-located TNF-related apoptosis-inducing ligand (TRAIL)-receptors 1 and 2 induce apoptosis as well as cancer-promoting signaling in cancer cells. TRAIL-R3 and TRAIL-R4 are believed to negatively regulate TRAIL-mediated apoptosis. Intracellular localization of TRAIL-receptors, as observed in many tumor cells, has been associated with oncogenic features, which are distinct from membrane-associated TRAIL-R signaling. Here, analyzing a panel of 354 breast cancer specimens, we found that an unfavorable outcome correlating with cancer-promoting properties of TRAIL-R1, TRAIL-R2, and TRAIL-R4 was most significantly defined by their intracellular distribution and mutual co-expression. A nuclear or cytoplasmic heterogeneous expression pattern correlated with markedly decreased overall survival and discriminated high-risk breast cancer patients from low-risk patients with a homogeneous distribution of expression, i.e., nuclear and cytoplasmic expression. The homogeneous TRAIL-R expression was associated with favorable breast cancer surrogate markers corresponding with excellent survival prognoses at 5 years after diagnosis (hazard ratio, 0.043) and over the complete course of follow-up (hazard ratio, 0.098; both p < 0.001). No associations with specific intrinsic breast cancer subtypes were found. Our data suggest that the determination of intracellular co-expression patterns of TRAIL-R1, TRAIL-R2, and TRAIL-R4 provides an innovative and robust method for risk stratification in breast cancer patients beyond conventional prognostic markers. KEY MESSAGES: A total of 70% of breast cancer specimens show comparably high levels of intracellular TRAIL-Rs. Nuclear or cytoplasmic TRAIL-R co-expression occurs in the majority of tumors. A total of 25% of tumors show a heterogeneous expression of cytoplasmic or nuclear TRAIL-Rs. Patients with a heterogeneous TRAIL-R expression present with poor prognoses. Additive TRAIL-R-based risk stratification comprises different breast cancer subtypes.

Physical Exercise During Pregnancy - How Active Are Pregnant Women in Germany and How Well Informed?

INTRODUCTION: There is sufficient evidence showing the positive effects of physical exercise on various aspects of pregnancy. This study evaluates knowledge and status of physical exercise among pregnant women. METHODS: The standardised paper-pencil questionnaire "Pregnancy Physical Activity Questionnaire" (PPAQ) as well as general demographic questions were used to assess the exercise behaviour of study participants. 83 questionnaires completed by women presenting to the Kiel University Hospital for antenatal assessment were included in the analysis. RESULTS: At the time of questionnaire completion 10 women were in the first trimester of pregnancy, 64 in the second, and 9 in the third. Just less than 90% of participants felt they had been informed "sufficiently" on the topic physical exercise during pregnancy, over 50% felt they were "well" or "very well" informed. Just less than half of participants received their information from a doctor (either their gynaecologist or general practitioner) and none of these felt "insufficiently" informed. Almost 80% of participants reported still doing no sport or less exercise than before falling pregnant. The maximum proportional energy expenditure for recreational activity - just under 20% - was in the third trimester. Women who felt they had been well counselled tended to have higher activity levels. CONCLUSION: Study participants demonstrated a clear decline in physical exercise during pregnancy despite clear evidence of the benefits of regular exercise for pregnant women, and despite participants feeling they were well informed. Detailed information on the recommendations for physical exertion in pregnancy should form an integral part of antenatal counselling.

Pharmacologically Inactive Bisphosphonates as an Alternative Strategy for Targeting Osteoclasts: In Vivo Assessment of 5-Fluorodeoxyuridine-Alendronate in a Preclinical Model of Breast Cancer Bone Metastases.

Bisphosphonates have effects that are antiresorptive, antitumor, and antiapoptotic to osteoblasts and osteocytes, but an effective means of eliciting these multiple activities in the treatment of bone metastases has not been identified. Antimetabolite-bisphosphonate conjugates have potential for improved performance as a class of bone-specific antineoplastic drugs. The primary objective of the study was to determine whether an antimetabolite-bisphosphonate conjugate will preserve bone formation concomitant with antiresorptive and antitumor activity. 5-FdU-ale, a highly stable conjugate between the antimetabolite 5-fluoro-2'-deoxyuridine and the bisphosphonate alendronate, was tested for its therapeutic efficacy in a mouse model of MDA-MB231 breast cancer bone metastases. In vitro testing revealed osteoclasts to be highly sensitive to 5-FdU-ale. In contrast, osteoblasts had significantly reduced sensitivity. Tumor cells were resistant in vitro but in vivo tumor burden was nevertheless significantly reduced compared with untreated mice. Sensitivity to 5-FdU-ale was not mediated through inhibition of farnesyl diphosphate synthase activity, but cell cycle arrest was observed. Although serum tartrate-resistant acid phosphatase (TRAP) levels were greatly reduced by both drugs, there was no significant decrease in the serum bone formation marker osteocalcin with 5-FdU-ale treatment. In contrast, there was more than a fivefold decrease in serum osteocalcin levels with alendronate treatment (p < 0.001). This finding is supported by time-lapse micro-computed tomography analyses, which revealed bone formation volume to be on average 1.6-fold higher with 5-FdU-ale treatment compared with alendronate (p < 0.001). We conclude that 5-FdU-ale, which is a poor prenylation inhibitor but maintains potent antiresorptive activity, does not reduce bone formation and has cytostatic antitumor efficacy. These results document that conjugation of an antimetabolite with bisphosphonates offers flexibility in creating potent bone-targeting drugs with cytostatic, bone protection properties that show limited nephrotoxicity. This unique class of drugs may offer distinct advantages in the setting of targeted adjuvant therapy and chemoprevention of bone diseases. © 2016 American Society for Bone and Mineral Research.

TRAIL-R2 promotes skeletal metastasis in a breast cancer xenograft mouse model.

Despite improvements in detection, surgical approaches and systemic therapies, breast cancer remains typically incurable once distant metastases occur. High expression of TRAIL-R2 was found to be associated with poor prognostic parameters in breast cancer patients, suggesting an oncogenic function of this receptor. In the present study, we aimed to determine the impact of TRAIL-R2 on breast cancer metastasis. Using an osteotropic variant of MDA-MB-231 breast cancer cells, we examine the effects of TRAIL-R2 knockdown in vitro and in vivo. Strikingly, in addition to the reduced levels of the proliferation-promoting factor HMGA2 and corresponding inhibition of cell proliferation, knockdown of TRAIL-R2 increased the levels of E-Cadherin and decreased migration. In vivo, these cells were strongly impaired in their ability to form bone metastases after intracardiac injection. Evaluating possible underlying mechanisms revealed a strong downregulation of CXCR4, the receptor for the chemokine SDF-1 important for homing of cancers cells to the bone. In accordance, cell migration towards SDF-1 was significantly impaired by TRAIL-R2 knockdown. Conversely, overexpression of TRAIL-R2 upregulated CXCR4 levels and enhanced SDF-1-directed migration. We therefore postulate that inhibition of TRAIL-R2 expression could represent a promising therapeutic strategy leading to an effective impairment of breast cancer cell capability to form skeletal metastases.

Intra-operative use of one-step nucleic acid amplification (OSNA) for detection of the tumor load of sentinel lymph nodes in breast cancer patients.

BACKGROUND: The purpose of this single-center study was to determine the practicability of the intra-operative use of one-step nucleic acid amplification (OSNA) as the only method for detection of SLN. The OSNA system has been well described and is supposed to be as accurate as conventional histology. METHODS: Three hundred and thirty SLNs from 143 breast cancer patients were analyzed in an intra-operative setting. The CK19-copy number was determined by OSNA and divided into 3 results ("-" no metastasis; "+" micrometastasis; "++" marcometastasis). If OSNA gave a positive result, an axillary lymph node dissection was carried out during the same session. The central 1-mm slice of each node was obtained for permanent histology. Additionally, the results were correlated to clinicopathological factors, and the time for the intra-operative use was evaluated. RESULTS: Thirty-nine of the 143 patients were OSNA positive, 22 with macrometastatic and 17 with micrometastatic spread. The mean time for the OSNA run with one SLN was 34.4 min. We could show a correlation between the tumor size and OSNA positivity as well as between the numbers of OSNA positive SLNs with the tumor load of associated non-SLNs. Furthermore, we found that a cutoff CK19 copy number of 7,900/µL indicates a positive non-SLN result with the highest sensitivity (91 %) and specificity (61 %). CONCLUSION: We found OSNA to be very helpful for the intra-operative determination of the tumor load of a SLN as a basis for decision-making concerning further surgical axillary intervention. OSNA allows precise differentiation of micro- from macrometastasis, and the CK19 copy number predicts the probability of tumor load in other axillary lymph nodes and might help to find adequate adjuvant treatment options. This objective method is well suitable for everyday use and may reduce the pathologic workload and the risk of secondary operative interventions with all associated costs and stress for the patients.