BackgroundImmune infiltration is implicated in the development of acquired resistance to anti-angiogenic cancer therapy. We therefore investigated the correlation between neutrophil infiltration in metastasis of colorectal cancer (CRC) patients and survival after treatment with bevacizumab. Our study identifies CD177+ tumour neutrophil infiltration as an adverse prognostic factor for bevacizumab treatment. We further demonstrate that a novel anti-VEGF/anti-Ang2 compound (BI-880) can overcome resistance to VEGF inhibition in experimental tumour models.MethodsA total of 85 metastatic CRC patients were stratified into cohorts that had either received chemotherapy alone (n = 39) or combined with bevacizumab (n = 46). Tumour CD177+ neutrophil infiltration was correlated to clinical outcome. The impact of neutrophil infiltration on anti-VEGF or anti-VEGF/anti-Ang2 therapy was studied in both xenograft and syngeneic tumour models by immunohistochemistry.ResultsThe survival of bevacizumab-treated CRC patients in the presence of CD177+ infiltrates was significantly reduced compared to patients harbouring CD177− metastases. BI-880 treatment reduced the development of hypoxia associated with bevacizumab treatment and improved vascular normalisation in xenografts. Furthermore, neutrophil depletion or BI-880 treatment restored treatment sensitivity in a syngeneic tumour model of anti-VEGF resistance.ConclusionsOur findings implicate CD177 as a biomarker for bevacizumab and suggest VEGF/Ang2 inhibition as a strategy to overcome neutrophil associated resistance to anti-angiogenic treatment.

Introduction: Implant-based immediate breast reconstruction (IBR) is a common surgical procedure in breast cancer patients. Comparative analysis concerning the placement of implants is still lacking. Hence, we aimed to analyze pre- versus subpectoral IBR in breast cancer patients. Patients: A single-center experience with implant-based IBR following skin/nipple-sparing mastectomy was evaluated. Patient demographics, incidence of major complications, and quality of life assessed with BREAST-Q were compared between the pre- and subpectoral cohort. Results: A total of 63 patients were included in this analysis of whom 29 underwent subpectoral and 34 underwent prepectoral IBR. Median duration of surgery was prolonged in the subpectoral versus the prepectoral group (104 ± 28 vs. 80 ± 91 min; p < 0.05). The mean number of major complications was significantly increased in the subpectoral group (1.41 ± 1.76 vs. 0.47 ± 0.75 per patient; p < 0.05). Detailed analysis showed a significantly increased incidence of implant dislocation (p < 0.05) and a trend concerning capsular contracture (p = 0.086, not significant) and necrosis (p = 0.092, not significant) in the subpectoral group. Quality of life was equal in both groups. Conclusion: The mean number of major complications in the subpectoral group should be considered when IBR is indicated. Prepectoral IBR seems to be a feasible alternative surgical treatment option with less major complications in selected patients.

Purpose: BRCA1-deficient breast cancers carry a specific DNA copy-number signature ("BRCA1-like") and are hypersensitive to DNA double-strand break (DSB) inducing compounds. Here, we explored whether (i) EZH2 is overexpressed in human BRCA1-deficient breast tumors and might predict sensitivity to DSB-inducing drugs; (ii) EZH2 inhibition potentiates cisplatin efficacy in Brca1-deficient murine mammary tumors. Experimental Design: EZH2 expression was analyzed in 497 breast cancers using IHC or RNA sequencing. We classified 370 tumors by copy-number profiles as BRCA1-like or non-BRCA1-like and examined its association with EZH2 expression. Additionally, we assessed BRCA1 loss through mutation or promoter methylation status and investigated the predictive value of EZH2 expression in a study population of breast cancer patients treated with adjuvant high-dose platinumbased chemotherapy compared with standard anthracyclinebased chemotherapy. To explore whether EZH2 inhibition by GSK126 enhances sensitivity to platinum drugs in EZH2-overexpressing breast cancers we used a Brca1-deficient mouse model. Results: The highest EZH2 expression was found in BRCA1associated tumors harboring a BRCA1 mutation, BRCA1-promoter methylation or were classified as BRCA1 like. We observed a greater benefit from high-dose platinum-based chemotherapy in BRCA1-like and non-BRCA1-like patients with high EZH2 expression. Combined treatment with the EZH2 inhibitor GSK126 and cisplatin decreased cell proliferation and improved survival in Brca1-deficient mice in comparison with single agents. Conclusions: Our findings demonstrate that EZH2 is expressed at significantly higher levels in BRCA1-deficient breast cancers. EZH2 overexpression can identify patients with breast cancer who benefit significantly from intensified DSB-inducing platinum-based chemotherapy independent of BRCA1-like status. EZH2 inhibition improves the antitumor effect of platinum drugs in Brca1-deficient breast tumors in vivo.

Background/Aim: Clinical data concerning synthetic meshes in comparison to acellular dermal matrices (ADMs) in breast reconstruction are limited. Also, direct comparisons between titanium-coated polypropylene mesh and partially absorbable polypropylene mesh have not yet been reported. Materials and Methods: This analysis represents a retrospective, single-surgeon, multi-center study of 320 cases using either TiLoop Bra/TiMesh ® (n=192) or Seragyn ® (n=128) in breast reconstruction. Results were compared with ADM-based reconstructions (Epiflex ® and SurgiMend ® ). Results: Major complication rates (i.e. revision surgery) occurred in 3.9% (Seragyn ® ) and 8.3% (TiLoop Bra/TiMesh ® ) of all cases. Minor complications occurred in 18% (Seragyn ® ) and 8.9% (TiLoop Bra/TiMesh ® ). Subgroup analysis showed red breast syndrome to occur more often in the Seragyn group (3.9% Seragyn ® vs. 0.5% TiLoop Bra/TiMesh ® , p<0.05). Conclusion: TiLoop Bra/TiMesh ® and Seragyn ® do not differ significantly in complication rates. There was no difference in performance when compared to ADMs. Materials and MethodsThis work evaluated a multicenter, single surgeon experience over the course of 14 years with a total of 320 cases (Seragyn ® , n=128; TiLoop Bra/TiMesh ® , n=192) (Figure 1

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The role of B cells in antitumor immunity and their impact on emerging immunotherapies is increasingly gaining attention. B-cell effector functions include not only secretion of antibodies, but also presentation of antigens to T cells. A physiologic B-cell subset with immunostimulatory properties was described in humans, defined by a high expression of CD86 and downregulation of CD21. We used multicolor flow cytometry and IHC to elucidate abundance and spatial distribution of these antigen-presenting B cells (BAPC) in blood (peripheral blood mononuclear cells, PBMC) and tumor samples of 237 patients with cancer. Antigen-specific T-cell responses to cancer testis antigens were determined using tetramer staining and sorted BAPCs in FluoroSpot assays for selected patients. We found that BAPCs were increased in the tumor microenvironment of 9 of 10 analyzed cancer types with site-specific variation. BAPCs were not increased in renal cell carcinoma, whereas we found a systemic increase with elevated fractions in tumor-infiltrating lymphocytes (TIL) and PBMCs of patients with colorectal cancer and gastroesophageal adenocarcinoma. BAPCs were localized in lymphoid follicles of tertiary lymphoid structures (TLS) and were enriched in tumors with increased numbers of TLSs. BAPCs isolated from tumor-draining lymph nodes of patients with cancer showed increased percentages of tumor antigen–specific B cells and induced responses of autologous T cells in vitro. Our results highlight the relevance of BAPCs as professional antigen-presenting cells in tumor immunity and provide a mechanistic rationale for the observed correlation of B-cell abundance and response to immune checkpoint inhibition.

Background/Aim: The problem of adequately marking any given lesion within a breast surgical site is commonly solved by introducing a titanium clip. However, clip dislocation and/or stereotactic hook-wire dislocation are common problems. An ideal solution would be a clip that can be easily found without the use of stereotactic intervention. This work reviews the available data on radiofrequency identification devices (RFID) in breast surgery, reports initial experience data in Europe and discusses surgical pitfalls, advantages and disadvantages. Patients and Methods: This study represents a single center, consecutively recruited, initiation trial with subsequent surgeon questionnaire for the first institution in Europe to report Faxitron LOCalizer™ chip data. Four patients with non-palpable tumors were marked with the system and were correlated via mammography, pre-and intra-operative ultrasound and pathology. Data were then compared to available literature and a literature review was added. Results: The four patients marked with this RFID system, displayed a 100% success location rate at a 0%

Background/Aim: The aim of this study was to determine the value of Doppler indices and notching assessment of uterine artery between the 19th and 22nd week of gestation in the prediction of pregnancy outcome such as delivery mode, birth weight, Apgar score, afterbirth pH, fetal presentation, preeclampsia and fetal growth restriction in singleton pregnancy. Patients and Methods: This is a retrospective cohort study of Doppler ultrasound of the uterine arteries at 19-22 week of gestation in 1,472 women with singleton pregnancies. Results: Patients with bilateral high resistance-index (RI) and pulsatility-index (RI) or with the presence of a notch showed a significantly higher prevalence of small for gestational age (SGA) fetuses and intrauterine growth restriction (IUGR), low Apgar Scores at the 1st and the 5th min, high c-section rate, preterm birth, breech birth, placental insufficiency and placental abruption. The presence of a notch significantly increased the prevalence of severe preeclampsia, HELLP-syndrome and oligohydramnios. Also, patients with a bilateral uterine notching had a higher c-section rate along with higher prevalence of SGA and IUGR at screening time. Conclusion: Uterine artery Doppler waveform analysis as well as the assessment of the presence of a notch in the second trimester can be used as a screening method to identify women who will thereafter develop a severe adverse outcome.