The role of mesothelial cells in the host defence against bacteria : in vitro studies of peritonitis

The peritoneum is a serous membrane that lines both the intra-abdominal wall and the viscera contained wilhin the peritoneal cavity. Etymologically, 'peritoneum' means 'wrapped tightly around." The first description of the structure and function of the human peritoneum was given by James Doughlas in 1730. He observed that it was everywhere smooth and even and lubricated by a fiuid in order to preserve it from those inconveniences which otherwise would have followed from its continual attrilion wilh olher viscera. Human periloneum covers roughly the same surface area as the skin, approximately 2 m' in the adult. The parietal peritoneum covering the abdominal wall conslitutes about 10%, while the peritoneum covering the visceral organs, constitutes about 90% of this surface area. In males the peritoneum is completely closed, but in females it is open at the site of the uterine tubes, where the tubal peritoneum meets the non-peritonized fimbriated mucosa of the Fallopian tube. The peritoneum is a derivative of the embryological mesoderm and belongs to a distinct family of body tissues that share the same cellular composition and exhibit an identical histological architecture known as the serosa. The basic structure of the peritoneum appears to be rather simple; it is composed of a monolayer of mesothelial cells separated from the capillaries by a thin layer of loose conneclive interstilial tissue

Health care professionals overestimate the risk for locoregional recurrences after breast cancer treatment depending on their specialty

Purpose: For the implementation of personalised surveillance, it is important to create more awareness among HCPs with regard to the risk for locoregional recurrences (LRRs). The aim of this study is to evaluate the current awareness and estimations of individual risks for LRRs after completion of primary treatment for breast cancer among health care professionals (HCPs) in the Netherlands, without using any prediction tools.Methods: A cross-sectional survey was performed among 60 HCPs working in breast cancer care in seven Dutch hospitals and 25 general practitioners (GPs). The survey consisted of eleven realistic surgically treated breast cancer cases. HCPs were asked to estimate the 5-year risk for LRRs for each case, which was compared to the estimations by the INFLUENCE-nomogram using one-sample Wilcoxon tests. Differences in estimations between HCPs with different specialities were determined using Kruskal–Wallis tests and Dunn tests.Results: HCPs tended to structurally overestimate the 5-year risk for LRR on each case. Average overestimations ranged from 4.8 to 26.1%. Groups of HCPs with varying specialities differed significantly in risk estimations. GPs tended to overestimate the risk for LRRs on average the most (15.0%) and medical oncologists had the lowest average overestimation (2.7%).Conclusions: It is important to create more awareness of the risk for LRRs, which is a pre-requisite for the implementation of personalised surveillance after breast cancer. Besides education for HCPs, the use of prediction models such as the INFLUENCE-nomogram can support in estimating an objective estimate of each individual patient’s risk.</p

Clinical impact of molecular breast imaging as adjunct diagnostic modality in evaluation of indeterminate breast abnormalities and unresolved diagnostic concerns

Purpose Improvements in molecular breast imaging (MBI) have increased the use of MBI as adjunct diagnostic modality and alternative to MRI. We aimed to assess the value of MBI in patients with equivocal breast lesions on conventional imaging, especially in terms of its ability to rule out malignancy. Methods We selected patients who underwent MBI in addition to conventional diagnostics due to equivocal breast lesions between 2012 and 2015. All patients underwent digital mammography, target ultrasound and MBI. MBI was performed using a single-head Dilon 6800 gamma camera after administration of 600 MBq 99mTc-sestamibi. Imaging was reported according to BI-RADS classification and compared with pathology or follow-up of ≥6 months. Results Of 226 women included, pathology was obtained in 106 (47%) and (pre)malignant lesions were found in 25 (11%). Median follow-up was 5.4 years (IQR 3.9-7.1). Sensitivity was higher for MBI compared to conventional diagnostics (84% vs. 32%; P = 0.002), identifying malignancy in 21 and 6 patients, respectively, but specificity did not differ (86% vs. 81%; P = 0.161). Positive and negative predictive value were 43% and 98% for MBI and 17% and 91% for conventional diagnostics. MBI was discordant with conventional diagnostics in 68 (30%) patients and correctly changed diagnosis in 46 (20%) patients, identifying 15 malignant lesions. In subgroups with nipple discharge (N = 42) and BI-RADS 3 lesions (N = 113) MBI detected 7 of 8 occult malignancies. Conclusion MBI correctly adjusted treatment in 20% of patients with diagnostic concerns after conventional work-up, and could rule out malignancy with a high negative predictive value of 98%.</p

Excision of both pretreatment marked positive nodes and sentinel nodes improves axillary staging after neoadjuvant systemic therapy in breast cancer

Background: Marking the axilla with radioactive iodine seed and sentinel lymph node (SLN) biopsy have been proposed for axillary staging after neoadjuvant systemic therapy in clinically node-positive breast cancer. This study evaluated the identification rate and detection of residual disease with combined excision of pretreatment-positive marked lymph nodes (MLNs) together with SLNs. Methods: This was a multicentre retrospective analysis of patients with clinically node-positive breast cancer undergoing neoadjuvant systemic therapy and the combination procedure (with or without axillary lymph node dissection). The identification rate and detection of axillary residual disease were calculated for the combination procedure, and for MLNs and SLNs separately. Results: At least one MLN and/or SLN(s) were identified by the combination procedure in 138 of 139 patients (identification rate 99·3 per cent). The identification rate was 92·8 per cent for MLNs alone and 87·8 per cent for SLNs alone. In 88 of 139 patients (63·3 per cent) residual axillary disease was detected by the combination procedure. Residual disease was shown only in the MLN in 20 of 88 patients (23 per cent) and only in the SLN in ten of 88 (11 per cent), whereas both the MLN and SLN contained residual disease in the remainder (58 of 88, 66 per cent). Conclusion: Excision of the pretreatment-positive MLN together with SLNs after neoadjuvant systemic therapy in patients with clinically node-positive disease resulted in a higher identification rate and improved detection of residual axillary disease

Tamoxifen Pharmacogenetics and Metabolism: Results From the Prospective CYPTAM Study

PURPOSE: Tamoxifen is widely prescribed as adjuvant therapy in patients with early-stage breast cancer. It has been postulated that concentrations of endoxifen, the active metabolite of tamoxifen, are a better predictor of tamoxifen efficacy than CYP2D6 genotypes. Although in a retrospective study, an endoxifen threshold of 5.9 ng/mL for efficacy was described, confirmation based on prospective studies is lacking. The objective of the prospective CYPTAM (The Netherlands National Trial Register: NTR1509) study was to associate endoxifen concentrations and CYP2D6 genotypes with clinical outcome in patients with early-stage breast cancer receiving tamoxifen. PATIENTS AND METHODS: From February 2008 to December 2010, patients with breast cancer treated with adjuvant tamoxifen were included. Patients could be enrolled up to a maximum of 12 months after tamoxifen initiation. Blood samples were retrieved for CYP2D6 genotyping and endoxifen measurements by Amplichip (Roche Diagnostics, Indianapolis, IN) and high-performance liquid chromatography-tandem mass spectrometry, respectively. Endoxifen concentrations were analyzed as a continuous variable, classifying patients into quartiles and using an endoxifen threshold of 5.9 ng/mL. Endoxifen concentrations and CYP2D6 genotypes were associated with relapse-free survival (censored at the time of tamoxifen discontinuation; RFSt) by Cox regression analysis. RESULTS: A total of 667 pre- and postmenopausal patients were enrolled and had received tamoxifen for a median time of 0.37 years (range, 0.23 to 0.6 years) before study entry. No association was found between endoxifen concentrations and RFSt (adjusted hazard ratio, 0.991; 95% CI, 0.946 to 1.038; P = .691). Also, neither categorizing endoxifen concentrations into quartiles nor using 5.9 ng/mL as threshold altered these results. In addition, no association was found between CYP2D6 genotype and RFSt (adjusted hazard ratio, 0.929; 95% CI, 0.525 to 1.642; P = .799). CONCLUSION: This prospective clinical study shows no association between endoxifen concentrations or CYP2D6 genotypes and clinical outcome in patients with early-stage breast cancer receiving adjuvant tamoxifen.status: publishe

Ten-year follow-up of the observational RASTER study, prospective evaluation of the 70-gene signature in ER-positive, HER2-negative, node-negative, early breast cancer

Introduction: Prognostic gene expression signatures can be used in combination with classical clinicopathological factors to guide adjuvant chemotherapy decisions in ER-positive, HER2-negative breast cancer. However, long-term outcome data after introduction of genomic testing in the treatment decision-making process are limited. Methods: In the prospective RASTER study, the tumours of 427 patients with cTanyN0M0 breast cancer were tested to assess the 70-gene signature (MammaPrint). The results were provided to their treating physician to be incorporated in the decision-making on adjuvant systemic therapy. Here, we report the long-term outcome of the 310 patients with ER-positive, HER2-negative tumours by clinical and genomic risk categories at a median follow-up of 10.3 years. Results: Among the clinically high-risk patients, 45 (49%) were classified as genomically low risk. In this subgroup, at 10 years, distant recurrence free interval (DRFI) was similar between patients treated with (95.7% [95% CI 87.7–100]) and without (95.5% [95% CI 87.1–100]) chemotherapy. Within the group of clinically low-risk patients, 56 (26%) were classified as genomically high risk. Within the clinically low-risk group, beyond 5 years, a difference emerged between the genomically high- and low-risk subgroup resulting in a 10-year DRFI of 84.3% (95% CI 74.8–95.0) and 93.4% (95% CI 89.5–97.5), respectively. Interestingly, genomic ultralow-risk patients have a 10-year DRFI of 96.7% (95% CI 90.5–100), largely (79%) without systemic therapy. Conclusions: These data confirm that clinically high-risk, genomically low-risk tumours have an excellent outcome in the real-world setting of shared decision-making. Together with the updated results of the MINDACT trial, these data support the use of the MammaPrint, in ER-positive, HER2-negative, node-negative, clinically high-risk breast cancer patients

Ten-year follow-up of the observational RASTER study, prospective evaluation of the 70-gene signature in ER-positive, HER2-negative, node-negative, early breast cancer

Introduction: Prognostic gene expression signatures can be used in combination with classical clinicopathological factors to guide adjuvant chemotherapy decisions in ER-positive, HER2-negative breast cancer. However, long-term outcome data after introduction of genomic testing in the treatment decision-making process are limited. Methods: In the prospective RASTER study, the tumours of 427 patients with cTanyN0M0 breast cancer were tested to assess the 70-gene signature (MammaPrint). The results were provided to their treating physician to be incorporated in the decision-making on adjuvant systemic therapy. Here, we report the long-term outcome of the 310 patients with ER-positive, HER2-negative tumours by clinical and genomic risk categories at a median follow-up of 10.3 years. Results: Among the clinically high-risk patients, 45 (49%) were classified as genomically low risk. In this subgroup, at 10 years, distant recurrence free interval (DRFI) was similar between patients treated with (95.7% [95% CI 87.7–100]) and without (95.5% [95% CI 87.1–100]) chemotherapy. Within the group of clinically low-risk patients, 56 (26%) were classified as genomically high risk. Within the clinically low-risk group, beyond 5 years, a difference emerged between the genomically high- and low-risk subgroup resulting in a 10-year DRFI of 84.3% (95% CI 74.8–95.0) and 93.4% (95% CI 89.5–97.5), respectively. Interestingly, genomic ultralow-risk patients have a 10-year DRFI of 96.7% (95% CI 90.5–100), largely (79%) without systemic therapy. Conclusions: These data confirm that clinically high-risk, genomically low-risk tumours have an excellent outcome in the real-world setting of shared decision-making. Together with the updated results of the MINDACT trial, these data support the use of the MammaPrint, in ER-positive, HER2-negative, node-negative, clinically high-risk breast cancer patients. Registry: ISRCTN7191791