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Currently, the effect of prenatal ultrasound on foetal development is intensively discussed and the guidelines for prenatal diagnostics have been changed. However, data supporting these concerns are scarce. Therefore, we used an established in ovo model of the chicken embryo to investigate cell proliferation and apoptosis within the retina. A total of 21 chicken eggs were fenestrated on Day 5 and allocated to either the control (n = 8) or exposition group (n = 13). The exposition group was treated with pulsed‐wave Doppler ultrasound (PWD) for 10 min while controls remained without treatment. After subsequent incubation (6–48 h), the eggs were sacrificed, and chicken embryos were examined morphologically (HE‐staining) and immunohistochemically. Counting of apoptotic and proliferating cells per retina was performed using antibodies specific for phospho‐histone‐H3 and active caspase‐3 in combination with a biotin‐labelled secondary antibody and peroxidase conjugated avidin–biotin complex for chromogenic detection. Due to a rather low number of specimens at each time point after ultrasound exposition, we neglected the effects of incubation time and focused on treatment effects. This approach revealed that the median number of proliferating cells is reduced after 10 min of exposure to PWD (569 vs. 766), while the number of apoptotic cells is fairly comparable between groups (5 vs. 6). Our data contribute to a better understanding of prenatal US on foetal development by suggesting that PWD could have an impact on the number of proliferating cells in the developing chicken retina and therefore justify further investigations. [ABSTRACT FROM AUTHOR]

Simple Summary: The study's purpose was to determine whether neurotoxic signs in breast cancer patients receiving taxane (paclitaxel) chemotherapy correlate with retinal or corneal nerve changes in a longitudinal study combining oncological examinations with advanced biophotonic imaging techniques. Recruited breast cancer patients underwent regular monitoring sessions including the clinical assessment of their quality of life and neurological scores, ophthalmological status, retinal optical coherence tomography, and large area confocal laser scanning microscopy of their corneal subbasal nerve plexus (SNP). The study revealed two key breakthroughs: an observable increase in retinal thickness and the examination of identical corneal SNP large-area mosaics over time. Consequently, advanced biophotonic imaging techniques could represent a powerful diagnostic tool for the objective assessment of the severity of adverse events, wherein oncologists and ophthalmologists could benefit from each other, leading to a better outcome for the patient. A common severe neurotoxic side effect of breast cancer (BC) therapy is chemotherapy-induced peripheral neuropathy (CIPN) and intervention is highly needed for the detection, prevention, and treatment of CIPN at an early stage. As the eye is susceptible to neurotoxic stimuli, the present study aims to determine whether CIPN signs in paclitaxel-treated BC patients correlate with ocular changes by applying advanced non-invasive biophotonic in vivo imaging. Patients (n = 14, 10 controls) underwent monitoring sessions after diagnosis, during, and after therapy (T0-T3). Monitoring sessions included general anamnesis, assessment of their quality of life, neurological scores, ophthalmological status, macular optical coherence tomography (OCT), and imaging of their subbasal nerve plexus (SNP) by large-area confocal laser-scanning microscopy (CLSM). At T0, no significant differences were detected between patients and controls. During treatment, patients' scores significantly changed while the greatest differences were found between T0 and T3. None of the patients developed severe CIPN but retinal thickenings could be detected. CLSM revealed large SNP mosaics with identical areas while corneal nerves remained stable. The study represents the first longitudinal study combining oncological examinations with advanced biophotonic imaging techniques, demonstrating a powerful tool for the objective assessment of the severity of neurotoxic events with ocular structures acting as potential biomarkers. [ABSTRACT FROM AUTHOR]

Background: Reduction of positive margin rate (PMR) in breast-conserving surgery (BCS) of non-palpable breast cancer remains a challenge. The efficacy of intraoperative specimen radiography (SR) is unclear. This randomized trial evaluated whether the PMR was reduced by the use of devices that allow precise localization of the affected margins. Methods: Patients with microcalcification-associated breast cancer undergoing planned BCS were enrolled. Study participants were randomized to receive either SR with radiopaque tissue transfer and X-ray system (KliniTray™) or the institutional standard procedure (ISO). In all patients with a radiological margin less than 5 mm, an immediate re-excision was conducted. The primary outcome was the PMR. Risk factors for positive margins and the effect of immediate re-excision on final surgery were secondary analyses. Results: Among 122 randomized patients, 5 patients were excluded due to the extent of primary surgery and 117 were available for analysis. Final histopathology revealed a PMR of 31.7 per cent for the KliniTray™ group and 26.3 per cent for the ISO group (P = 0.127). Independent factors for positive margins were histological tumour size more than 30 mm (adjusted OR (aOR) 10.73; 95 per cent c.i. 3.14 to 36.75; P < 0.001) and specimen size more than 50 mm (aOR 6.65; 95 per cent c.i. 2.00 to 22.08; P = 0.002). Immediate re-excision due to positive SR led to an absolute risk reduction in positive margins of 13.6 per cent (from 42.7 to 29.1 per cent). Conclusion: Specimen orientation with a radiopaque tissue transfer and X-ray system did not decrease the PMR in patients with microcalcification-associated breast cancer; however, SR and immediate re-excision proved to be helpful in the reduction of PMR. [ABSTRACT FROM AUTHOR]

Simple Summary: Negative margins are the most important prognostic factor in breast-conserving therapy (BCT) of ductal carcinoma in situ (DCIS). The impact of radiological underestimation ≥10 mm (defined as mammographic minus histological tumor size in millimeters) has not been further examined. The purpose was to verify the radiological underestimation of DCIS size as a risk factor for positive margins. A pooled analysis of two trials was performed. Inclusion criteria were patients receiving BCT in DCIS. The results show a clinically relevant radiological underestimation in 37% of patients. Radiological underestimation is an independent risk factor for positive margins in BCT of DCIS with microcalcifications. Furthermore, the influencing factors of radiological underestimation were analysed. In multivariate logistic regression, only a mammographic tumor size ≤20 mm was an independent risk factor associated with radiological underestimation. When planning and executing BCT, it has to be considered that a relevant radiological underestimation is significantly higher in mammographic DCIS sizes ≤20 mm. Background: Radiological underestimation of the actual tumor size is a relevant problem in reaching negative margins in ductal carcinoma in situ (DCIS) associated with microcalcifications in breast-conserving therapy (BCT). The aim of this study is to evaluate whether the radiological underestimation of tumor size has an influence on the histopathological margin status. Methods: Patients who underwent BCT with preoperatively diagnosed pure DCIS were included (pooled analysis of two trials). Multiple factors were analysed regarding radiological underestimation ≥10 mm. Radiological underestimation was defined as mammographic minus histological tumor size in mm. Results: Positive margins occurred in 75 of 189 patients. Radiological underestimation ≥10 mm was an independent influencing factor (OR 5.80; 95%CI 2.55–13.17; p < 0.001). A radiological underestimation was seen in 70 patients. The following parameters were statistically significant associated with underestimation: pleomorphic microcalcifications (OR 3.77; 95%CI 1.27–11.18), clustered distribution patterns (OR 4.26; 95%CI 2.25–8.07), and mammographic tumor sizes ≤20 mm (OR 7.47; 95%CI 3.49–15.99). Only a mammographic tumor size ≤20 mm was an independent risk factor (OR 6.49; 95%CI 2.30–18.26; p < 0.001). Grading, estrogen receptor status, and comedo necrosis did not influence the size estimation. Conclusion: Radiological underestimation is an independent risk factor for positive margins in BCT of DCIS associated with microcalcifications predominantly occurring in mammographic small tumors. [ABSTRACT FROM AUTHOR]

Paclitaxel and trastuzumab have been associated with adverse effects including chemotherapy-induced peripheral neuropathy (CIPN) or ocular complications. In vivo confocal laser scanning microscopy (CLSM) of the cornea could be suitable for assessing side effects since the cornea is susceptible to, i.e., neurotoxic stimuli. The study represents a one-year follow-up of a breast cancer patient including large-area in vivo CLSM of the subbasal nerve plexus (SNP), nerve function testing, and questionnaires during paclitaxel and trastuzumab therapy. Six monitoring sessions (one baseline, four during, and one after therapy) over 58 weeks were carried out. Large-area mosaics of the SNP were generated, and identical regions within all sessions were assigned. While corneal nerve morphology did not cause alterations, the number of dendritic cells (DCs) showed dynamic changes with a local burst at 11 weeks after baseline. Simultaneously, paclitaxel treatment was terminated due to side effects, which, together with DCs, returned to normal levels as the therapy progressed. Longitudinal in vivo CLSM of the SNP could complement routine examinations and be helpful to generate a comprehensive clinical picture. The applied techniques, with corneal structures acting as biomarkers could represent a diagnostic tool for the objective assessment of the severity of adverse events and the outcome. [ABSTRACT FROM AUTHOR]

Introduction: The aim of this study was to gather information on the prevalence and risk factors for scar pain and sensibility disorders after breast cancer surgery, as only limited information of these complaints are available. Material and Methods: A clinical cohort study using a non-validated questionnaire was conducted among women who presented to routine follow-up at the Breast Cancer Center Rostock, Germany. The subjects were informed that the subjective perception and sensation were in the foreground and that the questionnaire had to be filled out independently according to the current feeling. Results: Overall 175 patients could be evaluated. The prevalence of scar pain was 30.8% after breast conserving therapy (BCT) and 34.5% after mastectomy. Following BCT 87.5%, respectively 81.8% of women after mastectomy were very satisfied or satisfied with the scarring. Sensory disorders were increased in the mastectomy group (p = 0.001). Scar pain after previous surgery was a risk factor to develop sensory disorders after BCT (p = 0.008) and mastectomy (p = 0.029). For patients receiving mastectomy, sensory disorders after previous breast surgeries increased the risk for sensory disorders (p = 0.029). Smoking was a risk factor for sensory disorders after mastectomy (p = 0.048). Multivariate analysis could not confirm any of the risk factors. Conclusion: This study demonstrated a high satisfaction with scarring after breast surgery and a low level of scar pain. A lack of postoperative information, as well as a low level of actually performed scar care after surgery were observed. Increased focus should be on improved information on postoperative scare care. [ABSTRACT FROM AUTHOR]

Clipping and selective removal of axillary lymph nodes in breast cancer patients presenting with initially node-positive disease and achieving a nodal downstaging after primary systemic therapy is a less invasive method for axillary staging. An imaging guided localization and successful extirpation of these clipped lymph nodes is not possible in all patients. To date no follow-up data regarding patients with lost clips are available. The oncological outcome of all participants of the CLIP-study and the results of postoperative axillary imaging in those patients with unproven clip resection are presented. A total of thirty patients were included into the pilot study. In ten of these patients (33%) the removal of the clipped axillary lymph node could not be verified by intraoperative radiograph. Postoperative imaging did not find lost clips in eight of these ten patients (80%). The lost clip was detected in two patients after surgery (20%), by mammography in one patient during routine follow-up and by computed tomography scan in one patient before radiotherapy. After a median follow-up of 40 months, 26 (87%) patients were still alive. Seven patients (23%) developed distant recurrent disease. No local or axillary recurrences were observed. Lost clips were detected by postoperative imaging only in a minority of patients. The impact of lost clips on axillary recurrences in breast cancer patients is still unclear and should be further clarified in larger, multicentric trials. [ABSTRACT FROM AUTHOR]

Purpose: After publication of the radiation field design in the American College of Surgeons Oncology Group Z0011 trial, a radiation therapy quality assurance review was integrated into the Intergroup-Sentinel-Mamma (INSEMA) trial. We aimed to investigate the role of patient characteristics, extent of axillary surgery, and radiation techniques for dose distribution in ipsilateral axillary levels.Methods and Materials: INSEMA (NCT02466737) has randomized 5542 patients who underwent breast-conserving surgery. Of these, 276 patients from 108 radiation therapy facilities were included in the central review, using the planning records of the first 3 patients treated at each site.Results: Of the 276 patients, 41 had major deviations (ie, no axillary contouring or submission of insufficient records) leading to exclusion. A total of 235 (85.1%) radiation therapy planning records were delineated according to the INSEMA protocol, including 9 (3.8%) cases with minor deviations. At least 25% of INSEMA patients were unintentionally treated with ≥95% of the prescribed breast radiation dose in axillary level I. Approximately 50% of patients were irradiated with a median radiation dose of more than 85% of prescription dose in level I. Irradiated volumes and applied doses were significantly lower in levels II and III compared with level I. However, 25% of patients still received a median radiation dose of ≥75% of prescription dose to level II. Subgroup analysis revealed a significant association between incidental radiation dose in the axilla and obesity. Younger age, boost application, and fractionation schedule showed no impact on axillary dose distribution.Conclusions: Assuming ≥80% of prescribed breast dose as the optimal dose for curative radiation of low-volume disease in axillary lymph nodes, at least 50% of reviewed INSEMA patients received an adequate dose in level I, even with contemporary 3-dimensional techniques. Dose coverage was much less in axillary levels II and III, and far below therapeutically relevant doses. [ABSTRACT FROM AUTHOR]

Background: Patients with endometrial carcinoma (EC) frequently are obese and have various secondary diseases. We investigated the oncologic safety and complication rates of early-stage EC treated with laparotomy (LAP) versus minimally invasive hysterectomy (MIH). A secondary study aim was the evaluation of risk factors for relapse and complications. Methods: Data from the Cancer Registry Rostock, Germany, and the medical records of women diagnosed with type 1 EC between January 2005 and December 2014 were retrospectively evaluated. The baseline characteristics were analyzed with the χ2 test and Fisher's exact test. Multivariate analysis with the Cox proportional-hazards model and logistic regression were performed to identify prognostic factors for time to event and risk factors for complications. Kaplan-Meier analysis was performed for disease-free and overall survival. Results: Of 350 evaluated patients, 242 underwent traditional LAP; on 108 patients, MIH was performed. The median follow-up period in the LAP group and the MIH group was 82 ± 31.1 and 71.1 ± 33.6 months, respectively (p = 0.10). The median time to event was 40.3 ± 28.1 months in the LAP group and 38.0 ± 27.5 months in the MIH group (p = 0.476). Significantly longer surgery times (p < 0.001) and more complications (p < 0.001) were observed in the LAP group. Disease-free survival after MIH was not significantly different from that after LAP (log-rank p = 0.052). Multimorbidity remained as the single risk factor for event/recurrence (p = 0.019) in multivariate analysis. Conclusions: MIH for early-stage EC may be an oncologically safe approach when compared to LAP, and its complication rates are lower; therefore, MIH represents the preferred approach for this patient cohort. [ABSTRACT FROM AUTHOR]

Background: Most clinical breast changes in women are benign; in only 3% to 6% of cases are they due to breast cancer. However, there is a lack of up-to-date, evidence-based treatment recommendations for the various benign differential diagnoses. Methods: Selective literature search of PubMed from 1985 to May 2019, including current national (AWMF, Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften [Association of Scientific Medical Societies in Germany]) and international guidelines. Results: Mastalgia and fibrocystic changes are common (around 50% of all women over the age of 30). Fibroadenomas occur in 25% of women; they are the most common benign tumors of the breast and do not require treatment. With most benign breast changes the risk of dedifferentiation is very low. However, it is important in the differential diagnosis to distinguish between such benign changes and breast cancer or changes that carry a risk of malignancy. Complex cysts, for example, carry a risk of malignancy of 23% to 31%, papillary lesions 16%, and radial scars 7%. Where there is doubt, histological confirmation should be sought by means of percutaneous biopsy. Conclusion: Benign breast changes can be definitively distinguished from malignant lesions through the selective use of available diagnostic investigations and interdisciplinary collaboration. When lesions of uncertain malignant potential are found (B3 in the biopsy classification), complete excision is indicated. Prospective studies on the early diagnosis of breast cancer in lesions carrying a risk of malignancy are desirable. [ABSTRACT FROM AUTHOR]

Introduction Clipping and selective removal of initially suspicious axillary lymph nodes in breast cancer patients who have been sonographically down-staged by primary systemic therapy improves the accuracy of surgical staging and provides the opportunity for more conservative axillary surgery. This study evaluated whether preoperative ultrasound-guided wire localization of the clipped node is useful for routine clinical practice. Material and methods This prospective, single-center feasibility trial included patients with invasive breast cancer (cT1-3N1-3M0) treated by primary systemic therapy. They underwent ultrasound-guided core needle biopsy and clip placement into the most suspicious axillary lymph node prior to chemotherapy. After primary systemic therapy the clipped lymph node was localized by a wire. All patients underwent target lymph node biopsy, completion axillary lymph node dissection and, if yiN0, axillary sentinel lymph node biopsy. The primary study endpoint was the identification rate of the target lymph node. Results All patients (n = 30) underwent successful clip insertion into the lymph node. After chemotherapy, the clipped target lymph node was visible by ultrasound in 83.3% (25/30). Wire localization was possible in 24 cases (80%), and the clipped node identification rate was 70.8% (17/24 cases). In 9/30 patients (30%) clipped node removal was not confirmed by intraoperative radiography. Conclusion Ultrasound-guided wire localization of the target lymph node is not suitable for clinical practice because of limitations regarding clip visibility and selective surgical preparation of the target lymph node. Further prospective evaluation of alternative techniques is needed. [ABSTRACT FROM AUTHOR]

Breast reconstruction after breast cancer is an emotional subject for women. Consequently, the correct timing and surgical procedure for each individual woman are important. In general, heterologous or autologous reconstructive procedures are available, both having advantages and disadvantages. Breast size, patient habitus, and previous surgeries or radiation therapy need to be considered, independent of the chosen procedure. New surgical techniques, refinement of surgical procedures, and the development of supportive materials have increased the general patient collective eligible for breast reconstruction. This review highlights the different approaches to immediate breast reconstruction using autologous or heterologous techniques. [ABSTRACT FROM AUTHOR]

Background: Implant rupture as a late complication of breast implant surgery is often a silent phenomenon that is difficult to diagnose. Sonoelastography is a new ultrasound-based technique that allows assessment of tissue elasticity. Objectives: This study was undertaken to evaluate elastographic findings in normal and ruptured breast implants. Methods: This prospective study included 28 implants in 16 patients, all of whom underwent high-resolution ultrasound and real-time elastography. The diagnosis of implant rupture was confirmed by surgery. Results: Implant rupture was diagnosed in 5 out of 28 implants (17.9%). In those patients with ruptured implants, 3 had no symptoms, 1 presented with pain, and 1 complained of ipsilateral axillary lymph node swelling. Implants with a homogenous anechoic interior were considered to be intact. Ultrasound findings indicating implant rupture included multiple parallel echogenic lines in the implant interior in 2 cases and a mix of hyperechoic and hypoechoic masses in 3 cases. The feasibility of real-time elastography of implants was demonstrated in all cases. Elastograms of intact implants revealed a typical blue-green-red pattern familiar from cystic lesions. In all 5 ruptured implants, elastography revealed yellow-green figures without typical layering. Conclusions: To the authors' knowledge this is the first series to combine high-resolution ultrasound with real-time elastography for the diagnosis of implant rupture. Since there are distinct differences between elastograms of intact and ruptured implants, addition of real-time elastography to conventional ultrasound may improve implant surveillance and obviate the need for magnetic resonance imaging. [ABSTRACT FROM AUTHOR]

The impact of treatment for the primary tumor on distant metastases and survival in primary metastatic breast cancer patients is controversial. Previous retrospective studies and meta-analyses suggested a survival benefit for the removal of the primary tumor. Early follow-up data from 2 prospectively randomized trials presented at San Antonio Breast Cancer Symposium 2013 could not confirm this. Only a very small subgroup of patients with solitary bone metastases seemed to profit from surgery, while patients with multiple visceral metastases showed a worse prognosis with initial surgery. There are no studies available with the primary aim to investigate the impact of axillary lymph node surgery or locoregional radiotherapy on the survival of stage IV breast cancer patients. Based on current data, locoregional treatment in primary metastatic breast cancer should not be recommended in patients with asymptomatic primary tumor as a matter of routine. More solid conclusion of the impact of primary tumor treatment in stage IV breast cancer patients on their prognosis will be reached with the completion of the ongoing prospectively randomized trials. Until these studies are completed, locoregional therapy, which can provoke additional morbidity in a metastatic setting with limited live expectancy, is exclusively indicated for palliative reasons. © 2014 S. Karger GmbH, Freiburg [ABSTRACT FROM AUTHOR]

Simple Summary: Currently, the optimal axillary surgical approach for breast cancer patients with initial node-positive disease and conversion to clinically node-negative status after primary systemic therapy is unclear. The aim of our study was to evaluate the clinical impact of removing the initially most suspicious, labeled axillary lymph node in addition to the sentinel lymph node. Metastatic target lymph nodes were found in five out of 63 patients (7.9%), while the sentinel lymph node was either tumor-free or not detected. The removal of the target lymph node influenced the adjuvant systemic therapy in only one case (1.6%). However, complete axillary dissection was indicated in all five cases. Furthermore, with fewer than three sentinel lymph nodes removed, the target lymph node reduced the false-negative rate to less than 10%. We therefore conclude that although the target lymph node has a minor impact on adjuvant systemic therapy, it is relevant for surgical axillary management. Purpose: To assess the impact of the removal of the target lymph node (TLN) on therapy after the completion of primary systemic therapy (PST) in initially node-positive breast cancer patients. Methods: Pooled data analysis of participants of the prospective CLIP- and TATTOO-study at the University of Rostock was performed. Results: A total of 75 patients were included; 63 of them (84.0%) converted to clinically node-negative after PST. Both TLN and sentinel lymph node (SLN) were identified in 41 patients (51.2%). In five out of 63 patients (7.9%), the TLN was metastatic after PST and the SLN was either tumor-free or not detected. Axillary lymph node dissection (ALND) was conducted in all five patients. In one patient, systemic therapy recommendation was influenced by the TLN; adjuvant radiotherapy was influenced by the TLN in zero patients. For patients with fewer than three removed SLNs, the FNR was 28.6% for the SLN biopsy alone and 7.1% for targeted axillary dissection (TAD). Conclusions: Removal of the TLN in addition to the SLN after PST has only minimal impact on the type of adjuvant systemic therapy and radiotherapy. However, the extent of axillary surgery was relevantly affected and FNR was improved by TAD. [ABSTRACT FROM AUTHOR]

During breast cancer therapy, paclitaxel and trastuzumab are both associated with adverse effects such as chemotherapy-induced peripheral neuropathy and other systemic side effects including ocular complications. Corneal nerves are considered part of the peripheral nervous system and can be imaged non-invasively by confocal laser scanning microscopy (CLSM) on the cellular level. Thus, in vivo CLSM imaging of structures of the corneal subbasal nerve plexus (SNP) such as sensory nerves or dendritic cells (DCs) can be a powerful tool for the assessment of corneal complications during cancer treatment. During the present study, the SNP of a breast cancer patient was analyzed over time by using large-scale in vivo CLSM in the course of paclitaxel and trastuzumab therapy. The same corneal regions could be re-identified over time. While the subbasal nerve morphology did not alter significantly, a change in dendritic cell density and an additional local burst within the first 11 weeks of therapy was detected, indicating treatment-mediated corneal inflammatory processes. Ocular structures such as nerves and dendritic cells could represent useful biomarkers for the assessment of ocular adverse effects during cancer therapy and their management, leading to a better visual prognosis. [ABSTRACT FROM AUTHOR]

We describe a 34-year-old woman who, at the age of 11 years, had had Hodgkin disease treated by irradiation of the axillary nodes. Twenty-two years later she developed a secondary breast carcinoma which was managed by skin-sparing mastectomy and immediate reconstruction with a pedicled latissimus dorsi flap. [ABSTRACT FROM AUTHOR]