Nonspherical ultrasound microbubbles.

Surface tension provides microbubbles (MB) with a perfect spherical shape. Here, we demonstrate that MB can be engineered to be nonspherical, endowing them with unique features for biomedical applications. Anisotropic MB were generated via one-dimensionally stretching spherical poly(butyl cyanoacrylate) MB above their glass transition temperature. Compared to their spherical counterparts, nonspherical polymeric MB displayed superior performance in multiple ways, including i) increased margination behavior in blood vessel-like flow chambers, ii) reduced macrophage uptake in vitro, iii) prolonged circulation time in vivo, and iv) enhanced blood-brain barrier (BBB) permeation in vivo upon combination with transcranial focused ultrasound (FUS). Our studies identify shape as a design parameter in the MB landscape, and they provide a rational and robust framework for further exploring the application of anisotropic MB for ultrasound-enhanced drug delivery and imaging applications.

The prostate-specific membrane antigen holds potential as a vascular target for endogenous radiotherapy with [177Lu]Lu-PSMA-I&T for triple-negative breast cancer.

INTRODUCTION: Overexpression of prostate-specific membrane antigen (PSMA) on the vasculature of triple-negative breast cancer (TNBC) presents a promising avenue for targeted endogenous radiotherapy with [177Lu]Lu-PSMA-I&T. This study aimed to assess and compare the therapeutic efficacy of a single dose with a fractionated dose of [177Lu]Lu-PSMA-I&T in an orthotopic model of TNBC. METHODS: Rj:NMRI-Foxn1nu/nu mice were used as recipients of MDA-MB-231 xenografts. The single dose group was treated with 1 × 60 ± 5 MBq dose of [177Lu]Lu-PSMA-I&T, while the fractionated dose group received 4 × a 15 ± 2 MBq dose of [177Lu]Lu-PSMA-I&T at 7 day intervals. The control group received 0.9% NaCl. Tumor progression was monitored using [18F]FDG-PET/CT. Ex vivo analysis encompassed immunostaining, TUNEL staining, H&E staining, microautoradiography, and autoradiography. RESULTS: Tumor volumes were significantly smaller in the single dose (p < 0.001) and fractionated dose (p < 0.001) groups. Tumor growth inhibition rates were 38% (single dose) and 30% (fractionated dose). Median survival was notably prolonged in the treated groups compared to the control groups (31d, 28d and 19d for single dose, fractionated dose and control, respectively). [177Lu]Lu-PSMA-I&T decreased the size of viable tumor areas. We further demonstrated, that [177Lu]Lu-PSMA-I&T binds specifically to the tumor-associated vasculature. CONCLUSION: This study highlights the potential of [177Lu]Lu-PSMA-I&T for endogenous radiotherapy of TNBC.

On-treatment biopsies to predict response to neoadjuvant chemotherapy for breast cancer.

BACKGROUND: Patients with pathologic complete response (pCR) to neoadjuvant chemotherapy for invasive breast cancer (BC) have better outcomes, potentially warranting less extensive surgical and systemic treatments. Early prediction of treatment response could aid in adapting therapies. METHODS: On-treatment biopsies from 297 patients with invasive BC in three randomized, prospective neoadjuvant trials were assessed (GeparQuattro, GeparQuinto, GeparSixto). BC quantity, tumor-infiltrating lymphocytes (TILs), and the proliferation marker Ki-67 were compared to pre-treatment samples. The study investigated the correlation between residual cancer, changes in Ki-67 and TILs, and their impact on pathologic complete response (pCR) and disease-free survival (DFS). RESULTS: Among the 297 samples, 138 (46%) were hormone receptor-positive (HR+)/human epidermal growth factor 2-negative (HER2-), 87 (29%) were triple-negative (TNBC), and 72 (24%) were HER2+. Invasive tumor cells were found in 70% of on-treatment biopsies, with varying rates across subtypes (HR+/HER2-: 84%, TNBC: 62%, HER2+: 51%; p < 0.001). Patients with residual tumor on-treatment had an 8% pCR rate post-treatment (HR+/HER2-: 3%, TNBC: 19%, HER2+: 11%), while those without any invasive tumor had a 50% pCR rate (HR+/HER2-: 27%; TNBC: 48%, HER2+: 66%). Sensitivity for predicting residual disease was 0.81, with positive and negative predictive values of 0.92 and 0.50, respectively. Increasing TILs from baseline to on-treatment biopsy (if residual tumor was present) were linked to higher pCR likelihood in the overall cohort (OR 1.034, 95% CI 1.013-1.056 per % increase; p = 0.001) and with a longer DFS in TNBC (HR 0.980, 95% CI 0.963-0.997 per % increase; p = 0.026). Persisting or increased Ki-67 was associated with with lower pCR probability in the overall cohort (OR 0.957, 95% CI 0.928-0.986; p = 0.004) and shorter DFS in TNBC (HR 1.023, 95% CI 1.001-1.047; p = 0.04). CONCLUSION: On-treatment biopsies can predict patients unlikely to achieve pCR post-therapy. This could facilitate therapy adjustments for TNBC or HER2 + BC. They also might offer insights into therapy resistance mechanisms. Future research should explore whether standardized or expanded sampling enhances the accuracy of on-treatment biopsy procedures. Trial registration GeparQuattro (EudraCT 2005-001546-17), GeparQuinto (EudraCT 2006-005834-19) and GeparSixto (EudraCT 2011-000553-23).

Combining Radiomics and Autoencoders to Distinguish Benign and Malignant Breast Tumors on US Images.

Background US is clinically established for breast imaging, but its diagnostic performance depends on operator experience. Computer-assisted (real-time) image analysis may help in overcoming this limitation. Purpose To develop precise real-time-capable US-based breast tumor categorization by combining classic radiomics and autoencoder-based features from automatically localized lesions. Materials and Methods A total of 1619 B-mode US images of breast tumors were retrospectively analyzed between April 2018 and January 2024. nnU-Net was trained for lesion segmentation. Features were extracted from tumor segments, bounding boxes, and whole images using either classic radiomics, autoencoder, or both. Feature selection was performed to generate radiomics signatures, which were used to train machine learning algorithms for tumor categorization. Models were evaluated using the area under the receiver operating characteristic curve (AUC), sensitivity, and specificity and were statistically compared with histopathologically or follow-up-confirmed diagnosis. Results The model was developed on 1191 (mean age, 61 years ± 14 [SD]) female patients and externally validated on 50 (mean age, 55 years ± 15]). The development data set was divided into two parts: testing and training lesion segmentation (419 and 179 examinations) and lesion categorization (503 and 90 examinations). nnU-Net demonstrated precision and reproducibility in lesion segmentation in test set of data set 1 (median Dice score [DS]: 0.90 [IQR, 0.84-0.93]; P = .01) and data set 2 (median DS: 0.89 [IQR, 0.80-0.92]; P = .001). The best model, trained with 23 mixed features from tumor bounding boxes, achieved an AUC of 0.90 (95% CI: 0.83, 0.97), sensitivity of 81% (46 of 57; 95% CI: 70, 91), and specificity of 87% (39 of 45; 95% CI: 77, 87). No evidence of difference was found between model and human readers (AUC = 0.90 [95% CI: 0.83, 0.97] vs 0.83 [95% CI: 0.76, 0.90]; P = .55 and 0.90 vs 0.82 [95% CI: 0.75, 0.90]; P = .45) in tumor classification or between model and histopathologically or follow-up-confirmed diagnosis (AUC = 0.90 [95% CI: 0.83, 0.97] vs 1.00 [95% CI: 1.00,1.00]; P = .10). Conclusion Precise real-time US-based breast tumor categorization was developed by mixing classic radiomics and autoencoder-based features from tumor bounding boxes. ClinicalTrials.gov identifier: NCT04976257 Published under a CC BY 4.0 license. Supplemental material is available for this article. See also the editorial by Bahl in this issue.

Predictors of significant distress in cervical cancer patients: a cross sectional study.

PURPOSE: This cross-sectional study aims to investigate parameters that predict relevant levels of distress in women in a perioperative setting undergoing treatment for cervical cancer. MATERIALS AND METHODS: Data from 495 patients with cervical cancer that were treated at the university hospital Aachen between 2010 and 2022 were analysed based on their respective National Comprehensive Cancer Network (NCCN) Distress Thermometer score (DT) and Problem List (PL) and their clinical history. 105 patients were enrolled in the study. 18 medical and demographic variables were analysed using multivariate logistic regression. RESULTS: Three variables contributed significantly to the prediction of a DT score ≥ 5. Significant distress was defined as a DT score of ≥ 5, which was observed in 70.5% of the participants (mean: 5.58 ± 2.892). Women who chose to receive psycho-oncological counselling were more likely to have a DT score ≥ 5 (Odds Ratio(OR) = 3.323; Confidence Interval (CI95%): 1.241-8.900; p-value: 0.017). In addition, women who did not receive chemoradiation had significantly higher DT scores (OR = 3.807; CI 95%:1.185-12.236; p-value: 0.025), as did women whose Distress Thermometer was assessed in the first month after their initial diagnosis (OR = 3.967; CI 95%:1.167-13.486; p-value: 0.027). CONCLUSION: Increased distress in women with cervical cancer is common especially in the first month after diagnosis, in patients who do not receive chemoradiation and in patients who seek psycho-oncological counselling. Surgical factors do not play a major role in patient distress.

Patient satisfaction and sexual issues in vulvar lichen sclerosus treatment: a monocentric certified dysplasia unit survey analysis.

OBJECTIVE: Vulvar lichen sclerosus (VLS) is an underestimated chronic disease. It can cause significant symptom burden and sexual dysfunction. This study aimed to evaluate patient satisfaction and current challenges in the management of VLS in a certified dysplasia unit, particularly during the COVID-19 pandemic. METHODS: This survey analyzed patients who had been diagnosed with VLS and treated at our DKG-certified dysplasia unit. The study was conducted during the COVID-19 pandemic in the Department of Gynecology and Obstetrics at the University of Aachen. The questionnaire contained 43 questions on general treatment, diagnostic delays, disease education, psychologic and sexual issues, and specific questions regarding the COVID-19 pandemic. The questionnaires were distributed between January 2021 and September 2023. RESULTS: This study included 103 patients diagnosed with VLS, who were treated at our certified dysplasia unit. Overall, 48% of the patients were satisfied with the success of the therapy. Most participants reported psychologic problems (36.8%), fear of cancer (53.3%), or sexual restrictions (53.3%). Among the patients, 38% were bothered by the regular application of topical cortisone. However, 72% were willing to undergo treatment for more than 24 months. The COVID-19 outbreak in March 2020 had a significant negative impact on general VLS care from the patient's perspective (3.83/5 before vs. 3.67/5 after; p = 0.046). There was a general request for booklets to inform and educate the patients about their disease. Furthermore, the respondents demanded a telephone hotline to answer the questions and wished for follow-up visits via e-mail to cope better with their current situation. CONCLUSION: This study highlights the need for more effective treatments for VLS and an increased awareness of psychologic and sexual distress. To ensure patient well-being and satisfaction, it is imperative to offer individualized care with adequate disease education in a team of specialists from various disciplines.

[Prediction and timely identification of postpartum depression: results of the longitudinal RiPoD study in the context of the literature]. / Vorhersage und frühzeitige Identifikation einer postpartalen Depression: Ergebnisse der longitudinalen RiPoD-Studie im Kontext der Literatur.

The first 4-6 weeks after childbirth are defined as the onset time for postpartum depression (PPD). Despite this known time frame there are significant gaps in the identification and treatment of PPD. The risk for postpartum depression (RiPoD) study investigated specific risk factors and predictors of postpartum psychological adjustment processes and the results are presented within the framework of a state of the art review of research. The dynamic neuroplastic changes in the maternal brain during pregnancy and the postpartum period appear to be closely linked to peripartum hormone fluctuations, which jointly influence the development of postpartum mood disorders. Hormonal risk factors such as baby blues and premenstrual syndrome have been found to have a bearing on PPD. The combination of these two factors predicts the risk of PPD with 83% sensitivity within the first week postpartum. Follow-up digital monitoring of symptom development in the first 6 weeks postpartum has enabled an accurate identification of women with PPD. Understanding the interaction between hormone fluctuations, neuroplasticity and psychiatric disorders should be an important target for future research. Early identification and diagnosis of PPD can be easily integrated into the clinical routine and everyday life.

Spontaneous Heterotopic Pregnancy with Ovarian Localization: Case Report.

Heterotopic pregnancies are a rare phenomenon defined by the simultaneous occurrence of intrauterine and extrauterine pregnancy. The incidence of heterotopic pregnancy occurring through natural fertilization is low but is increased by risk factors such as assisted reproductive techniques or pelvic inflammatory disease increase. We report the case of a 36-year-old female patient in the 6th week of pregnancy who presented to the emergency unit with severe acute lower abdominal pain. Laboratory chemistry and sonography revealed a suspected heterotopic pregnancy. The patient was admitted for observation. The sonographic reevaluation on the next day confirmed the suspicion of extrauterine gravidity with intact intrauterine gravidity with additional decreasing hemoglobin and hematoperitoneum, so that laparoscopy was indicated. Intraoperatively, the mass on the left ovary was removed without complications. The patient could be discharged quickly postoperatively after a complication-free course and gave birth to a healthy child by spontaneous partus in the 38th week of gestation. Due to their rarity, there is limited research related to heterotopic pregnancies, and most scientific articles are case studies. Diagnostically, the most important thing in clinical practice is to think about the possibility of EUG even if there is evidence of an intact IUG. Transvaginal sonography is of particular importance in diagnostics. The performance of prospective cohort studies is desirable for the evidence-based diagnosis and therapy of affected patients in the future.

Fluorescence in situ hybridization test for detection of endometrial carcinoma cells by non-invasive vaginal swab.

Endometrial cancer (EC) is the most common gynaecological malignancy with increasing incidence in developed countries. As gold standard, hysteroscopy confirms only 30% of suspected ECs. The detection of EC cells in the vagina by fluorescence in situ hybridization (FISH) after a smear test could reduce invasive procedures in the future. Using array-based comparative genome hybridization (aCGH) on 65 endometrial carcinomas, most frequently imbalanced regions of the tumour genome were identified. Bacterial artificial chromosomes were used to generate FISH-probes homologue to these human regions. The FISH test was hybridized on swabs specimens collected from the vaginal cavity. Samples from six patients without EC were selected as a negative control and on 13 patients with known EC as a positive control. To distinguish between benign and EC cases, the cut-off value has been defined. A first validation of this EC-FISH Test was performed with swabs from 41 patients with suspected EC. The most common genomic imbalances in EC are around the CTNNB1, FBXW7 and APC genes. The cut-off is defined at 32% of analysed cells without diploid signal pattern. This differs significantly between the positive and negative controls (p < 0.001). In a first validation cohort of 41 patients with suspected EC, the EC-FISH Test distinguishes patients with and without EC with a sensitivity of 91% and a specificity of 83%. The negative predictive value is 96%. This is the first report of a non-invasive EC-FISH Test to predict EC in women with suspected EC.

Applicability of magnetic seeds for target lymph node biopsy after neoadjuvant chemotherapy in initially node-positive breast cancer patients: data from the AXSANA study.

PURPOSE: Currently, various techniques are available to mark and selectively remove initially suspicious axillary lymph nodes (target lymph nodes, TLNs) in breast cancer patients receiving neoadjuvant chemotherapy (NACT). To date, limited data are available on whether the use of magnetic seeds (MS) is suitable for localizing TLNs. This study aimed to investigate the feasibility of MS in patients undergoing target lymph node biopsy (TLNB) or targeted axillary dissection (TAD) after NACT. METHODS: Prospective data from the ongoing multicentric AXSANA study were extracted from selected patients in whom the TLN had been marked with an MS before NACT and who were enrolled from June 2020 to June 2023. The endpoints of the analysis were the detection rate, the rate of lost markers, and the potential impairment on magnetic resonance imaging (MRI) assessment. RESULTS: In 187 patients from 27 study sites in seven countries, MS were placed into the TLN before NACT. In 151 of these, post-NACT surgery had been completed at the time of analysis. In 146 patients (96.0%), a TLN could successfully be detected. In three patients, the seed was removed but no lymphoid tissue was detected on histopathology. The rate of lost markers was 1.2% (2 out of 164 MS). In 15 out of 151 patients (9.9%), MRI assessment was reported to be compromised by MS placement. CONCLUSION: MS show excellent applicability for TLNB/TAD when inserted before NACT with a high DR and a low rate of lost markers. Axillary MS can impair MRI assessment of the breast. TRIAL REGISTRATION NUMBER: NCT04373655 (date of registration May 4, 2020).

99mTc­labeled single-domain antibody for SPECT/CT assessment of HER2 expression in diverse cancer types.

The expression status of human epidermal growth factor receptor 2 (HER2) in cancer predicts response to HER2-targeted therapy. Therefore, its accurate determination is of utmost importance. In recent years, there has been an increase in research on noninvasive techniques for molecular imaging, as this method offers the advantages of a more accurate determination of HER2 status without the need for multiple biopsies. The technetium-labeled single-domain antibody RAD201, previously known as 99mTc-NM-02, has been shown to be safe for use in breast cancer imaging with reasonable radiation doses, favorable biodistribution, and imaging characteristics. METHODS: A total of six HER2-positive, heavily pretreated patients with different cancer types aged between 42 and 69 years (5 women and 1 man; the median age of 55.5) have been examined. In six of seven scans, the patients were administered 500 ml of Gelofusine® solution (40 mg/ml) for radiation protection before the tracer injection (434 ± 42 MBq). Planar scans were acquired with the patient supine at 10 min, 60 min, 160 min, 20 h, and 24 h after injection. A CT scan was acquired at 95 min, followed by local tomographic SPECT imaging. RESULTS: One patient was scanned twice with RAD201, 3 months apart, resulting in a total of seven scans for six patients. Here, we show that the use of RAD201 in our patient group shows the same favorable biodistribution as in a previous study with RAD201 (NCT04040686) and that the radiation dose to the critical organ kidney can be reduced by the application of the plasma expander Gelofusine® by almost 50%. CONCLUSION: RAD201 appears safe for use in humans and is a promising noninvasive tool for discriminating HER2 status in metastatic (breast) cancer, regardless of ongoing HER2-targeted antibody treatment.

New treatment strategies for human epidermal growth factor receptor 2-positive breast cancer in 2023.

PURPOSE OF REVIEW: Taxanes in combination with trastuzumab and pertuzumab are the established first-line standard in the treatment of human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer. In the last years, several new HER2-targeted therapies, including antibody-drug conjugates (ADCs) and tyrosine kinase inhibitors, have been approved for therapy after trastuzumab or dual blockade. In this review, the current treatment algorithms are discussed, including these new treatment options. RECENT FINDINGS: The ADC T-DM1 was the established second-line standard based on the results of the EMILIA trial. Recently, the DESTINY-Breast03 trial compared T-DM1 with the new ADC trastuzumab deruxtecan (T-DXd) in patients with disease progression after treatment with taxanes and trastuzumab. T-DXd was associated with an improved progression-free survival and a trend toward improved overall survival, establishing T-DXd as a new second-line standard. The HER2CLIMB trial demonstrated a significant progression-free survival and overall survival benefit for the tyrosine kinase inhibitor tucatinib in combination with trastuzumab and capecitabine after T-DM1 and trastuzumab/pertuzumab. This benefit was also observed in patients with active brain metastases defining this combination as the preferred second or third-line option in these patients. SUMMARY: New treatment strategies in HER2-positive metastatic breast cancer have substantially improved the clinical outcome of these patients, including those with active brain metastases.

CIN2 + detection in high-risk HPV patients with no or minor cervical cytologic abnormalities: a clinical approach validated by machine learning.

PURPOSE: To evaluate the feasibility and diagnostic value of the combination of colposcopy, cytology and hrHPV (high-risk human papilloma virus) PCR (polymerase chain reaction) testing in patients with no or minor cytologic abnormalities and HPV high risk infection and to find the best predictors for the presence of CIN2 + in this patient collective. METHODS: Three hundred and thirty-four hrHPV patients with normal cytology or minor cytologic abnormalities who had a colposcopic examination at the center of colposcopy at the university hospital Aachen in 2021 were enrolled in this retrospective cohort analysis. Multivariate logistic regression and a machine-learning technique (random forests, leave-one-out analysis) were used. RESULTS: The overall risk for CIN2 + in hrHPV-positive patients with normal cytology was 7.7% (N = 18) (5% for CIN3 +), 18% (N = 16) (10.1% for CIN3 +) in patients with PAP IIp (ASC-US) and 62.5% (N = 5) (25% for CIN3 +) in patients with PAP IIg (AGC). Variables that show a statistically significant influence for the CIN-status are 'major change' as the result of colposcopy, transformation zone type T1, PAP IIg upon referral (AGC) and hrHPV category 1a (HPV 16/18) detection. Using machine learning (random forests) techniques, the main influencing variables were confirmed. A monotonously decreasing risk for CIN2 + from hrHPV category 1a to 3 (in accordance to the IACR guidelines) was found. CONCLUSION: In the collective of hrHPV patients with no or minor cytologic abnormalities, the result of colposcopy and HPV PCR status are key predictors for the detection of CIN2 + with a monotonously decreasing risk for CIN2 + from hrHPV category 1a to 3.

Current trends in diagnostic and therapeutic management of the axilla in breast cancer patients receiving neoadjuvant therapy: results of the German-wide NOGGO MONITOR 24 survey.

PURPOSE: In the last 2 decades, the optimal management of the axilla in breast cancer patients receiving neoadjuvant chemotherapy (NACT) has been one of the most frequently discussed topics. Little is known about the attitudes of surgeons/radiologists towards new developments such as targeted axillary dissection. Therefore, the NOGGO conducted a survey to evaluate the current approach to axillary management. METHODS: A standardized digital questionnaire was sent out to > 200 departments in Germany between 7/2021 and 5/2022. The survey was supported by EUBREAST. RESULTS: In total, 116 physicians completed the survey. In cN0 patients scheduled to receive NACT, 89% of respondents recommended sentinel lymph node biopsy (SLNB) after NACT. In case of ypN1mi(sn), 44% advised no further therapy, while 31% proposed ALND and 25% axillary irradiation. 64% of respondents recommended a minimally invasive axillary biopsy to cN + patients. TAD was used at the departments of 82% of respondents and was offered to all cN + patients converting to ycN0 by 57% and only to selected patients, usually based on the number of suspicious nodes at time of presentation, by 43%. The most common marking technique was a clip/coil. 67% estimated that the detection rate of their marker was very good or good. CONCLUSION: This survey shows a heterogenous approach towards axillary management in the neoadjuvant setting in Germany. Most respondents follow current guidelines. Since only two-thirds of respondents experienced the detection rate of the marker used at their department as (very) good, future studies should focus on the comparative evaluation of different marking techniques.

Reliability and Reproducibility of Analyzing 3D Transperineal Ultrasound Volumes Obtained in the First Phase of Labor - A Pilot Study.

PURPOSE: The aim of this study was to investigate the reliability and reproducibility of transperineal ultrasound (TPUS) in the initial phase of labor. As TPUS is a common method, it could supplement vaginal palpation and even replace it in certain situations. In addition, we used a 4-dimensional method for the assessment of cervical effacement. MATERIALS AND METHODS: 54 women in labor were included and underwent TPUS. The resulting images from the acquired 4D volumes were evaluated after the examination for the first time and a second time after 21 days. The measured values were cervical length, dilatation and effacement, the angle of progression (AoP), and head-perineum distance. RESULTS: 54 patients were examined. TPUS images were unable to be evaluated in 12 patients because of cervical dilatation of more than 5 cm or poor image quality. Thus, 42 measurements were included. The concordance correlation coefficients according to Lin are satisfactory overall, with one exception for cervical effacement. The accuracy component of cervical length (CCCLin: 0.93; accuracy: 1.00), dilatation (CCCLin: 0.93; accuracy: 1.00), and AoP (CCCLin: 0.87; accuracy: 1.00) is excellent and still high for the head-perineum distance (CCCLin: 0.89; accuracy: 0.96) and cervical effacement (CCCLin: 0.77; accuracy: 0.97). CONCLUSION: TPUS is a valuable noninvasive tool with good diagnostic accuracy for the AoP, cervical length, and dilatation. Our study provides support for the use of TPUS to complement a vaginal examination. It should not replace a digital examination but should serve as a suitable alternative method for monitoring labor progression in the future.

IRAK2 Downregulation in Triple-Negative Breast Cancer Cells Decreases Cellular Growth In Vitro and Delays Tumour Progression in Murine Models.

Breast cancer stem cells (BCSCs) are responsible for tumour recurrence and therapy resistance. We have established primary BCSC cultures from human tumours of triple-negative breast cancer (TNBC), a subgroup of breast cancer likely driven by BCSCs. Primary BCSCs produce xenografts that phenocopy the tumours of origin, making them an ideal model for studying breast cancer treatment options. In the TNBC cell line MDA-MB-468, we previously screened kinases whose depletion elicited a differentiation response, among which IRAK2 was identified. Because primary BCSCs are enriched in IRAK2, we wondered whether IRAK2 downregulation might affect cellular growth. IRAK2 was downregulated in primary BCSCs and MDA-MB-468 by lentiviral delivery of shRNA, causing a decrease in cellular proliferation and sphere-forming capacity. When orthotopically transplanted into immunocompromised mice, IRAK2 knockdown cells produced smaller xenografts than control cells. At the molecular level, IRAK2 downregulation reduced NF-κB and ERK phosphorylation, IL-6 and cyclin D1 expression, ERN1 signalling and autophagy in a cell line-dependent way. Overall, IRAK2 downregulation decreased cellular aggressive growth and pathways often exploited by cancer cells to endure stress; therefore, IRAK2 may be considered an interesting target to compromise TNBC progression.

Characterization of Hormone Receptor and HER2 Status in Breast Cancer Using Mass Spectrometry Imaging.

Immunohistochemical evaluation of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor-2 status stratify the different subtypes of breast cancer and define the treatment course. Triple-negative breast cancer (TNBC), which does not register receptor overexpression, is often associated with worse patient prognosis. Mass spectrometry imaging transcribes the molecular content of tissue specimens without requiring additional tags or preliminary analysis of the samples, being therefore an excellent methodology for an unbiased determination of tissue constituents, in particular tumor markers. In this study, the proteomic content of 1191 human breast cancer samples was characterized by mass spectrometry imaging and the epithelial regions were employed to train and test machine-learning models to characterize the individual receptor status and to classify TNBC. The classification models presented yielded high accuracies for estrogen and progesterone receptors and over 95% accuracy for classification of TNBC. Analysis of the molecular features revealed that vimentin overexpression is associated with TNBC, supported by immunohistochemistry validation, revealing a new potential target for diagnosis and treatment.

EVI1 expression in early-stage breast cancer patients treated with neoadjuvant chemotherapy.

BACKGROUND: Overexpression of the EVI1 (ecotropic viral integration site 1) oncogene has recently been implicated as a prognostic factor in breast cancer (BC), particularly in triple-negative BC (TNBC). In this study we aimed to investigate frequency and clinical relevance of EVI1 expression in newly diagnosed BC treated with neoadjuvant chemotherapy. METHODS: EVI1 expression was determined by immunohistochemistry using H-score as a cumulative measurement of protein expression in pretherapeutic biopsies of BC patients treated with anthracycline/taxane based neoadjuvant chemotherapy within the GeparTrio trial. EVI1 was analyzed as a continuous variable and dichotomized into low or high based on median expression. Endpoints were pathological complete response (pCR), disease-free survival (DFS) and overall survival (OS). RESULTS: Of the 993 tumors analyzed, 882 had available subtype information: 50.8% were HR + /HER2-, 15% HR + /HER2 + , 9.8% HR-/HER2 + , and 24.5% TNBC. Median EVI1 H-score was 112.16 (range 0.5-291.4). High EVI1 expression was significantly associated with smaller tumor size (p = 0.002) but not with BC subtype. Elevated EVI1 levels were not significantly associated with therapy response and survival in the entire cohort or within BC subtypes. However, TNBC patients with high EVI1 showed a trend towards increased pCR rates compared to low group (37.7% vs 27.5%, p = 0.114; odds ratio 1.60 (95%CI 0.90-2.85, p = 0.110) and numerically better DFS (HR = 0.77 [95%CI 0.48-1.23], log-rank p = 0.271) and OS (HR = 0.76 [95% 0.44-1.31], log-rank p = 0.314) without reaching statistical significance. CONCLUSION: EVI1 was not associated with response to neoadjuvant therapy or patient survival in the overall cohort. Further analyses are needed to verify our findings especially in the pathological work-up of early-stage HER2-negative BC patients. TRIAL REGISTRATION: NCT00544765.

Warm and humidified insufflation gas during gynecologic laparoscopic surgery reduces postoperative pain in predisposed patients-a randomized, controlled multi-arm trial.

BACKGROUND: Postoperative pain remains a common problem in gynecologic laparoscopy, especially in head zone-related regions, triggered by intra-abdominal pressure during capnoperitoneum. Humidified and prewarmed insufflation gas may ameliorate pain and be beneficial. METHODS: This prospective randomized controlled parallel group multi-arm single-center study investigated the effects of temperature and humidity of insufflation gas on postoperative pain during gynecologic laparoscopy with a duration ≥ 60 min. Female participants (18-70 years) were blinded and randomly assigned-computer generated-to either insufflation with dry cold CO2 with forced air warming blanket ("AIR"), humidified warm gas without forced air warming blanket ("HUMI"), or humidified warm gas with forced air warming blanket ("HUMI +"). We hypothesized that using humidified warm gas resulted in lower pain scores and less analgesic consumption. The primary endpoint postoperative pain was assessed for different pain localizations every 12 h during 7 days after surgery. Secondary endpoints were demand for painkillers and epidural anesthetics, length of stay in recovery room, and hospital stay. (Registration: ClinicalTrials.gov NCT02781194-completed). RESULTS: 150 participants were randomized. Compared to group "AIR" (n = 48), there was significantly less pain in group "HUMI +" (n = 48) in the recovery room (- 1.068; 95% CI - 2.08 to - 0.061), as well as significantly less ibuprofen use at day two (- 0.5871 g ± 0.258; p-value = 0.0471). Other variables did not change significantly. Stratification for presence of endometriosis or non-previous abdominal surgery in patient history revealed significantly less pain in both groups "HUMI" (n = 50) and "HUMI +" versus group "AIR." Related side effects were not noted. CONCLUSION: In the overall population, the use of warm, humidified insufflation gas did not yield clinically relevant effects; however, in predisposed patients with endometriosis and who could otherwise expect high pain levels, warm and humidified gas may be beneficial.

Evaluation of urinary continence status and its influence on quality of life after gyneco-oncological treatment of female pelvic malignancies at an oncological center.

Urinary incontinence (UI) could negatively affect a person's quality of life (QoL). This study investigates the association among gynecological cancers, their treatments, UI, and its effect on the QoL of survivors of gynecological cancer. This cross-sectional questionnaire-based study included 121 cases from 405 patients who had undergone gyneco-oncological therapy. The participants were asked whether they experienced any form of UI and whether it impacted their QoL. The following therapies were used to treat the 12 gynecologic tumor types found in the participants: surgery (n = 116, 95.87%), chemotherapy (CTx) (n = 51, 42.2%), radiotherapy (RTx) (n = 31, 25.6%), and antibody therapy (ABT) (n = 11, 9.1%). No significant association was determined between tumor type and UI. However, body mass index (BMI), radical hysterectomy, vulvar or vaginal surgery, and presence of UI before treatment had significant impacts on the presence of UI. The surgical access routes, CTx, ABT, and hysterectomy had significant impacts on the severity of UI after treatment. Among all patients, 55.4% reported very good QoL. These reports of good QoL by patients could be due to their very good adjustment to the situation, with regard to being diagnosed with and receiving treatment for cancer, or due to the patients considering UI to not be much of an issue. Additionally, 34% of patients reported they had not been informed about the risk of UI before treatment. Informing patients about UI as one of the risks of therapy before initiating the treatment is crucial as patients who had been informed beforehand coped with UI far better than those who were not informed. Hence, the treatment of UI is often successful, so patients should be encouraged to receive urogynecological consultation.