Causality and functional relevance of BRCA1 and BRCA2 pathogenic variants in non-high-grade serous ovarian carcinomas.

The identification of causal BRCA1/2 pathogenic variants (PVs) in epithelial ovarian carcinoma (EOC) aids the selection of patients for genetic counselling and treatment decision-making. Current recommendations therefore stress sequencing of all EOCs, regardless of histotype. Although it is recognised that BRCA1/2 PVs cluster in high-grade serous ovarian carcinomas (HGSOC), this view is largely unsubstantiated by detailed analysis. Here, we aimed to analyse the results of BRCA1/2 tumour sequencing in a centrally revised, consecutive, prospective series including all EOC histotypes. Sequencing of n = 946 EOCs revealed BRCA1/2 PVs in 125 samples (13%), only eight of which were found in non-HGSOC histotypes. Specifically, BRCA1/2 PVs were identified in high-grade endometrioid (3/20; 15%), low-grade endometrioid (1/40; 2.5%), low-grade serous (3/67; 4.5%), and clear cell (1/64; 1.6%) EOCs. No PVs were identified in any mucinous ovarian carcinomas tested. By re-evaluation and using loss of heterozygosity and homologous recombination deficiency analyses, we then assessed: (1) whether the eight 'anomalous' cases were potentially histologically misclassified and (2) whether the identified variants were likely causal in carcinogenesis. The first 'anomalous' non-HGSOC with a BRCA1/2 PV proved to be a misdiagnosed HGSOC. Next, germline BRCA2 variants, found in two p53-abnormal high-grade endometrioid tumours, showed substantial evidence supporting causality. One additional, likely causal variant, found in a p53-wildtype low-grade serous ovarian carcinoma, was of somatic origin. The remaining cases showed retention of the BRCA1/2 wildtype allele, suggestive of non-causal secondary passenger variants. We conclude that likely causal BRCA1/2 variants are present in high-grade endometrioid tumours but are absent from the other EOC histotypes tested. Although the findings require validation, these results seem to justify a transition from universal to histotype-directed sequencing. Furthermore, in-depth functional analysis of tumours harbouring BRCA1/2 variants combined with detailed revision of cancer histotypes can serve as a model in other BRCA1/2-related cancers. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Long-term satisfaction of patients after laparoscopic and robotic-assisted hysterectomy.

INTRODUCTION: Da-Vinci-Xi is the most recent device used in gynecologic robotic surgery. The aim of the present study was to compare the long-term satisfaction of patients who had undergone conventional laparoscopic hysterectomy or robotic assisted laparoscopic hysterectomy using the Da-Vinci-Xi surgical system. METHODS: All hysterectomies performed at the University Hospital of Luebeck from 2018 to 2019 were reviewed. Postoperative outcomes were compared between women who had undergone total hysterectomy with da Vinci Xi (n = 42) or conventional laparoscopy (n = 97). Postoperative outcomes included pain, elimination of complaints after surgery, bladder function, sexual function, satisfaction with the cosmetic outcome, positive experiences after robotic surgery, and satisfaction with the surgeon's preoperative explanation. Obese patients were evaluated separately in a subgroup analysis. RESULTS: Both groups had similar baseline characteristics and complication rates. Preoperative complaints subsided after surgery in a little more than 90% of patients. No significant differences were noted between groups in this regard (p = 0.262), or with reference to postoperative pain after one week (p = 0.866) and one month (p = 0.580), stress incontinence (p = 0.343), sexual function (p = 0.766) and the cosmetic outcome of the abdominal incisions (p = 0.273). The majority of patients who had undergone robotic surgery (96.8%) would be willing to undergo the procedure again if necessary. The subgroup analysis of obese patients revealed no significant differences. CONCLUSION: The Da-Vinci-Xi device did not improve the long-term surgical satisfaction of normal-weight or obese patients who underwent hysterectomy compared with patients who underwent conventional laparoscopy performed by experienced laparoscopic surgeons.

Prognostic image-based quantification of CD8CD103 T cell subsets in high-grade serous ovarian cancer patients.

CD103-positive tissue resident memory-like CD8+ T cells (CD8CD103 TRM) are associated with improved prognosis across malignancies, including high-grade serous ovarian cancer (HGSOC). However, whether quantification of CD8, CD103 or both is required to improve existing survival prediction and whether all HGSOC patients or only specific subgroups of patients benefit from infiltration, remains unclear. To address this question, we applied image-based quantification of CD8 and CD103 multiplex immunohistochemistry in the intratumoral and stromal compartments of 268 advanced-stage HGSOC patients from two independent clinical institutions. Infiltration of CD8CD103 immune cell subsets was independent of clinicopathological factors. Our results suggest CD8CD103 TRM quantification as a superior method for prognostication compared to single CD8 or CD103 quantification. A survival benefit of CD8CD103 TRM was observed only in patients treated with primary cytoreductive surgery. Moreover, survival benefit in this group was limited to patients with no macroscopic tumor lesions after surgery. This approach provides novel insights into prognostic stratification of HGSOC patients and may contribute to personalized treatment strategies in the future.

Use of Pre- and Intensified Postprocedural Physiotherapy in Patients with Symptomatic Aortic Stenosis Undergoing Transcatheter Aortic Valve Replacement Study (the 4P-TAVR Study).

BACKGROUND: Physiotherapy prior to open-heart surgery lowers the rate of pneumonia and length of the hospital stay. Pneumonia is a major contributor to short-term mortality following transcatheter aortic valve replacement (TAVR). Hence, we hypothesized that pre- and intensified postprocedural physiotherapy in patients undergoing TAVR might impact the net functional and clinical outcome. METHODS AND RESULTS: The 4P-TAVR study was a prospective, monocentric, randomized trial. The study was designed to compare the efficacy and safety of intensified periprocedural physiotherapy including inspiratory muscle training versus standard postprocedural physiotherapy. Patients were randomized in a 1 : 1 fashion. 108 patients were included and followed up for 90 days after TAVR. While patients in group A (control group: 50 patients, age: 81.7 ± 5.0 years, 52% male) did not receive physiotherapy prior to TAVR, group B (intervention group: 58 patients, age: 82.2 ± 5.82 years, 47% male) participated in intensive physiotherapy. Compared to the control group, patients in the interventional group showed a lower incidence of postinterventional pneumonia (10 [20.0%] vs. 3 [5.1%], p=0.016) and had a 3-day shorter mean hospital stay (13.5 ± 6.1 days vs. 10.1 ± 4.7 days, p=0.02). The primary composite endpoint of mortality and rehospitalization was not different between the groups. CONCLUSION: Intensified physiotherapy is safe and has positive effects on clinical outcomes up to 90 days after TAVR but has no impact on the primary combined endpoint of mortality and rehospitalization. Longer follow-up, a multicenter design, and a higher number of subjects are needed to confirm these preliminary results. This trial is registered with DRKS00017239.

The Ocean 100: Transnational corporations in the ocean economy.

The ocean economy is growing as commercial use of the ocean accelerates, while progress toward achieving international goals for ocean conservation and sustainability is lagging. In this context, the private sector is increasingly recognized as having the capacity to hamper efforts to achieve aspirations of sustainable ocean-based development or alternatively to bend current trajectories of ocean use by taking on the mantle of corporate biosphere stewardship. Here, we identify levels of industry concentration to assess where this capacity rests. We show that the 10 largest companies in eight core ocean economy industries generate, on average, 45% of each industry's total revenues. Aggregating across all eight industries, the 100 largest corporations (the "Ocean 100") account for 60% of total revenues. This level of concentration in the ocean economy presents both risks and opportunities for ensuring sustainability and equity of global ocean use.

Optical communications downlink from a low-earth orbiting 1.5U CubeSat.

In this article, we present the first demonstration of an optical communications downlink from a low-earth orbiting free-flying CubeSat. Two 1.5U vehicles, AC7-B&C, built under NASA's Optical Communications and Sensors Demonstration (OCSD) program were launched in November 2017 and subsequently placed into a 450-km, 51.6° inc. circular orbit. Pseudorandom data streams using on-off key (OOK) modulation were transmitted from AC-7B to a 40 cm aperture telescope located at sea level in El Segundo, CA. At 200 Mbps, without forward error correction (FEC), we achieved a 115-second link that was ~78% error free, with the remaining portion exhibiting an error rate below 1E-5. At the time of the engagement, the 1064-nm laser transmitter was operating at 2 W (half capacity) with a full width half maximum (FWHM) beam divergence of ~1 mrad, which was approximately double the anticipated pointing accuracy of the vehicle.

Prediabetes is associated with lower brain gray matter volume in the general population. The Study of Health in Pomerania (SHIP).

BACKGROUND AND AIMS: We investigated the associations of fasting (FG) and 2-h postload (2HG) plasma glucose from oral glucose tolerance test (OGTT) with gray (GMV) and white (WMV) matter volume. METHODS AND RESULTS: We analyzed data from 1330 subjects without known diabetes mellitus, aged 21 to 81, from the second cohort (SHIP-Trend-0) of the population-based Study of Health in Pomerania (SHIP). Following the OGTT, individuals were classified in five groups (according to the American Diabetes Association criteria): normal glucose tolerance (NGT), isolated impaired fasting glucose (i-IFG), isolated impaired glucose tolerance (i-IGT), combined IFG and IGT (IFG + IGT) and unknown type 2 diabetes mellitus (UDM). GMV and WMV were determined by magnetic resonance imaging. FG, 2HG and OGTT groups were associated with GMV and WMV by linear regression models adjusted for confounders. FG and 2HG were inversely associated with GMV. The adjusted mean GMV, when compared with the NGT group (584 ml [95% CI: 581 to 587]), was significantly lower in the groups i-IFG (578 ml [95% CI: 573 to 582]; p = 0.035) and UDM (562 ml [95% CI: 551 to 573]; p < 0.001), but not different in the i-IGT (586 ml [95% CI: 576 to 596]; p = 0.688) and IFG + IGT (579 ml [95% CI: 571 to 586]; p = 0.209) groups. There were no associations of FG, 2HG and OGTT parameters with WMV. CONCLUSION: Our findings suggest that elevated FG levels, even within the prediabetic range, might already have some harmful effects on GMV.

Interventional treatment of the aortic valve : Current evidence.

Transcatheter aortic valve replacement (TAVR) has become a standard treatment for patients with severe, symptomatic aortic stenosis. Whereas its use was first limited to inoperable high-risk patients, recent studies demonstrated that TAVR was not inferior to standard surgical aortic valve replacement (SAVR) for intermediate-risk patients. Besides equivalent outcomes, the type and rates of complications differ between the two procedures. Here, we provide an overview of the latest randomized study results comparing TAVR with SAVR and describe possible future directions in transcatheter aortic valve treatment.

Dichotomous ALK-IHC Is a Better Predictor for ALK Inhibition Outcome than Traditional ALK-FISH in Advanced Non-Small Cell Lung Cancer.

Purpose: ALK rearrangement detection using FISH is the standard test to identify patients with non-small cell lung carcinoma (NSCLC) eligible for treatment with ALK inhibitors. Recently, ALK protein expression in resectable NSCLC showed predictive value. We evaluated tumor response rate and survival after crizotinib treatment of patients with advanced NSCLC with ALK activation using both dichotomous immunohistochemical (IHC) staining and FISH.Experimental Design: Patients with stage IV NSCLC treated with crizotinib were selected. Tumor response was assessed. ALK rearrangements were detected by FISH (Vysis ALK-break-apart FISH-Probe KIT) and IHC [Ventana ALK (D5F3) CDx assay]. Cohorts of patients with ALK-FISH-positive advanced NSCLC from four other hospitals were used for validation.Results: Twenty-nine consecutive patients with ALK-positive advanced NSCLC diagnosed by FISH and/or IHC on small biopsies or fine-needle aspirations (FNA) were treated with ALK inhibitors. All ALK-IHC-positive patients responded to crizotinib except three with primary resistance. No tumor response was observed in 13 ALK-FISH-positive but ALK-IHC-negative patients. This was confirmed in an external cohort of 16 patients. Receiver operator characteristic (ROC) curves for ALK-IHC and ALK-FISH compared with treatment outcome showed that dichotomous ALK-IHC outperforms ALK-FISH [tumor response area under the curve: (AUC), 0.86 vs. 0.64, P = 0.03; progression-free survival (PFS): AUC 0.86 vs. 0.36, P = 0.005; overall survival (OS): AUC, 0.78 vs. 0.41, P = 0.01, respectively].Conclusions: Dichotomous ALK-IHC is superior to ALK-FISH on small biopsies and FNA to predict tumor response and survival to crizotinib for patients with advanced NSCLC. Our data strongly suggest adapting the guidelines and using dichotomous ALK-IHC as standard companion diagnostic test to select patients with NSCLC who benefit from ALK-targeting therapy. Clin Cancer Res; 23(15); 4251-8. ©2017 AACR.

[Acute coronary syndrome in acute stroke]. / Akutes Koronarsyndrom bei akutem Schlaganfall.

BACKGROUND: Elevated troponin levels are commonly found in patients with acute stroke and approximately 60 % of stroke patients suffer from an accompanying coronary artery disease. Troponin release can be caused either by an acute thrombotic myocardial infarction or by insufficient coronary perfusion due to neurocardiogenic causes like blood pressure or heart rate variability without thrombotic coronary occlusion. Due to the often unclear pathological cause of troponin release and the risk of secondary hemorrhage during dual antiplatelet therapy, the determination of the best time point for coronary diagnostics and therapy in stroke patients is a common challenge in clinical daily routine. MATERIALS AND METHODS: Based on the current literature, we describe a potential diagnostic and therapeutic approach in stroke patients with increased troponin levels. RESULTS: First, the probability of an acute thrombotic myocardial infarction should be evaluated based on clinical, laboratory, and electrocardiographic parameters. In case of suspected myocardial infarction, a diagnostic coronary angiography/CT angiography should be performed and dual antiplatelet therapy should be given depending on the intracranial bleeding risk. In patients with high risk of intracranial bleeding, thrombus aspiration and balloon dilatation should be considered. CONCLUSION: In patients with acute stroke and elevated troponin levels, a thorough diagnostic workup is necessary to estimate the probability for a thrombotic myocardial infarction and to prevent cardiac and neurologic complications.

[Diagnostic and Therapeutic Implications of Elevated Plasma Troponin in Acute Exacerbated Chronic Obstructive Pulmonary Disease]. / Diagnostische und therapeutische Implikationen der Troponinerhöhung bei akut exazerbierter chronisch obstruktiver Lungenerkrankung.

AIMS: Cardiovascular comorbid conditions are frequent in chronic obstructive pulmonary disease (COPD) and substantially influence morbidity and mortality. Elevated plasma levels of cardiac troponin have been detected in up to 74 % of patients with acute exacerbated COPD (AECOPD), pointing at concomitant myocardial damage that can primarily be ascribed to systemic inflammatory processes. The mechanisms promoting troponin release in AECOPD are manifold and comprise: type 1 myocardial infarction as a consequence of intraluminal thrombus formation, type 2 myocardial infarction due to an imbalance between myocardial oxygen supply and demand, as well as right and left heart failure. Given its multifactorial aetiology, no standardized diagnostic and therapeutic approach are as yet available. MATERIAL AND METHODS: On the basis of current literature, we propose a potential diagnostics and therapeutics algorithm for AECOPD patients with elevated troponin levels. RESULTS: Clinical presentation, electro- and echocardiogram, as well as cardiac troponin levels and their dynamics represent sufficient risk stratifiers that permit evaluation and timing of invasive coronary strategy. CONCLUSION: The necessity for a standardized approach to elevated troponin during AECOPD arises from the frequent presence of concomitant coronary heart disease and the potential risk of oversight of type 1 myocardial infarction.

Prenatal and postnatal markers of severity in congenital diaphragmatic hernia have similar prognostic ability.

OBJECTIVES: The purpose of this study was to compare prenatal versus postnatal markers of congenital diaphragmatic hernia (CDH) severity at a single fetal-care center. METHODS: A retrospective study was performed of patients having a complete prenatal evaluation and surgical repair (n = 55). Observed-to-expected lung-to-head ratio (o/eLHR), observed-to-expected total lung volume (o/eTLV), liver position (LP), a predictive dependent variable from logistic regression of o/eLHR and liver position (o/eLHR + LP), and diaphragmatic defect size per the CDH Study Group A-D classification were plotted into receiver-operating characteristics (ROC) curves. Survival and need for extracorporeal membrane oxygenation (ECMO) were primary outcomes. RESULTS: Survival was 69%, and ECMO utilization was 56%. Distribution was 80% left-sided defects. In the survival ROC curve, the area under the curve (AUC) for o/eLHR was 0.73, o/eTLV 0.74, LP 0.73, o/eLHR + LP 0.78, and defect size 0.84 (p = 0.23). The ROC curve for ECMO support showed o/eLHR had an AUC of 0.82, o/eTLV 0.89, LP 0.79, o/eLHR + LP 0.87, and defect size 0.90 (p = 0.19). The AUCs were similar when only left-sided CDH was analyzed. CONCLUSIONS: These data suggest that prenatal evaluation was equivalent to the postnatal diaphragmatic defect classification for predicting survival and need for ECMO in CDH patients.

Intermittent Hypoxia Impairs Endothelial Function in Early Preatherosclerosis.

Intermittent hypoxia seems to be a major pathomechanism of obstructive sleep apnea-associated progression of atherosclerosis. The goal of the present study was to assess the influence of hypoxia on endothelial function depending on the initial stage of vasculopathy. We used 16 ApoE-/- mice were exposed to a 6-week-intermittent hypoxia either immediately (early preatherosclerosis) or after 5 weeks of high-cholesterol diet (advanced preatherosclerosis). Another 16 ApoE-/- mice under normoxia served as corresponding controls. Endothelial function was measured by an organ bath technique. Blood plasma CD31+/annexin V+ endothelial microparticles as well as sca1/flk1+ endothelial progenitor cells in blood and bone marrow were analyzed by flow cytometry. The findings were that intermittent hypoxia impaired endothelial function (56.6±6.2% of maximal phenylephrine-induced vasoconstriction vs. 35.2±4.1% in control) and integrity (increased percentage of endothelial microparticles: 0.28±0.05% vs. 0.15±0.02% in control) in early preatherosclerosis. Peripheral repair capacity expressed as the number of endothelial progenitor cells in blood was attenuated under hypoxia (2.0±0.5% vs. 5.3±1.9% in control), despite the elevated number of these cells in the bone marrow (2.0±0.4% vs. 1.1±0.2% in control). In contrast, endothelial function, as well as microparticle and endothelial progenitor cell levels were similar under hypoxia vs. control in advanced preatherosclerosis. We conclude that hypoxia aggravates endothelial dysfunction and destruction in early preatherosclerosis.

Turbulent heating in galaxy clusters brightest in X-rays.

The hot (10(7) to 10(8) kelvin), X-ray-emitting intracluster medium (ICM) is the dominant baryonic constituent of clusters of galaxies. In the cores of many clusters, radiative energy losses from the ICM occur on timescales much shorter than the age of the system. Unchecked, this cooling would lead to massive accumulations of cold gas and vigorous star formation, in contradiction to observations. Various sources of energy capable of compensating for these cooling losses have been proposed, the most promising being heating by the supermassive black holes in the central galaxies, through inflation of bubbles of relativistic plasma. Regardless of the original source of energy, the question of how this energy is transferred to the ICM remains open. Here we present a plausible solution to this question based on deep X-ray data and a new data analysis method that enable us to evaluate directly the ICM heating rate from the dissipation of turbulence. We find that turbulent heating is sufficient to offset radiative cooling and indeed appears to balance it locally at each radius-it may therefore be the key element in resolving the gas cooling problem in cluster cores and, more universally, in the atmospheres of X-ray-emitting, gas-rich systems on scales from galaxy clusters to groups and elliptical galaxies.

[Current status of transcatheter aortic valve implantation (TAVI) for patients with severe symptomatic aortic stenosis]. / Perkutane Aortenklappenimplantation (TAVI) zur Behandlung schwerer symptomatischer Aortenklappenstenosen: aktueller Stand.

Percutaneous trans-catheter aortic valve implantation (TAVI) has been established as an alternative to surgical valve replacement in surgical high-risk patients. TAVI is also considered the treatment of choice for symptomatic with severe aortic stenosis who are judged to be in-operable. In current practice in Germany more than one third of all aortic valve replacement interventions are performed as a TAVI procedure. It is of crucial importance that proper selection of patients as well as the treatment modality is performed by a so called "heart team", consisting of at least a cardiologist and a cardiac surgeon.

[GeCAS registry. Sense and purpose of a carotid percutaneous transluminal angioplasty register in the era of obligatory quality assurance]. / GeCAS-Register. Sinn und Zweck eines Carotis-PTA-Registers im Zeitalter der obligaten Qualitätssicherung.

Clinical registries have become increasingly more important tools for scientists as well as for medical admission boards worldwide during recent years due to the ability to investigate the safety and efficacy of a therapeutic method in the general population under real world conditions. The clinical benefit of current registry data seems to be particularly high in a treatment method, such as carotid artery stenting (CAS) where safety and efficacy, especially in daily clinical practice, could not be totally clarified by several randomized clinical trials (RCT). For this reason the new multidisciplinary, multicenter and prospective German Carotid Artery Registry (GeCAS) was founded in January 2011 for continuing quality control in CAS in clinical practice in Germany. The GeCAS registry is a fusion of two large German CAS registries, the ALKK-CAS registry and the PROCAS registry, which were conducted by cardiologists, angiologists and radiologists and operated from 1996 until December 2010. However, a general duty of documentation (BQS) of every CAS procedure exists throughout Germany since January 2012. In contrast to optional documentation of CAS within the GeCAS registry, the nationwide and obligatory documentation is strictly focused on the main issues, such as indications and between hospital comparisons of outcome of patients. In the GeCAS registry data collection is generally more extensive and also includes a 30-day and 10-year follow-up. Compared to the BQS institute, benchmarking reports of GeCAS are more detailed and are made available to every participating hospital on a biannual basis. This generates an image of the current reality of CAS in Germany in addition to the nationwide obligatory documentation. Furthermore, data of the GeCAS registry is the basis for research work (e.g. publications and presentations), for generating new hypotheses and for technical development in CAS in Germany. Consequently, the existence of a multicenter and multidisciplinary CAS registry, such as the GeCAS registry, is considered necessary and medically useful.

Linear structures in the core of the Coma cluster of galaxies.

The hot x-ray-emitting plasma in galaxy clusters is predicted to have turbulent motion, which can contribute around 10% of the cluster's central energy density. We report deep Chandra X-ray Observatory observations of the Coma cluster core, showing the presence of quasi-linear high-density arms spanning 150 kiloparsecs, consisting of low-entropy material that was probably stripped from merging subclusters. Two appear to be connected with a subgroup of galaxies at a 650-kiloparsec radius that is merging into the cluster, implying coherence over several hundred million years. Such a long lifetime implies that strong isotropic turbulence and conduction are suppressed in the core, despite the unrelaxed state of the cluster. Magnetic fields are presumably responsible. The structures seen in Coma present insight into the past billion years of subcluster merger activity.

Innovations and novel technologies in TAVI. Second generation transcatheter heart valves.

Transcatheter aortic valve implantation (TAVI) is the new standard-of-care for inoperable patients with superior outcome compared to conservative management including balloon valvuloplasty. In high-risk patients, TAVI has shown non-inferiority compared with surgical aortic valve replacement. Although data from national multi-centre registries are very encouraging and use of TAVI in intermediate risk patients has been discussed, it is of note that the commercially available and currently used transcatheter heart valves (THV) have not yet been assessed by randomized clinical trials in those patients. New technology advances promise to simplify TAVI and to improve outcome by reducing the rate of TAVI-specific issues such as paravalvular aortic regurgitation (PAR), annular rupture, and conduction disturbances. A reduction in the incidence and severity of PAR represents an obvious target for technical improvements in the design of upcoming "next generation" THVs and of implantation techniques including repositioning/recapturing features, paravalvular sealing techniques, and precise peri-interventional imaging modalities.

Biomarkers of anti-angiogenic therapy in metastatic colorectal cancer (mCRC): original data and review of the literature.

INTRODUCTION: Tumour angiogenesis via vascular endothelial growth factor (VEGF) is essential for promoting tumour progression and is overexpressed in colorectal cancer. The humanised monoclonal anti-VEGF antibody bevacizumab (Avastin®, Genentech Inc., South San Francisco, CA) has shown activity in metastatic colorectal cancer (mCRC) combined with conventional chemotherapy. The search for biomarkers to predict response to anti-angiogenic therapy in mCRC is of great interest. We investigated several potential predictive anti-angiogenic markers including circulating endothelial progenitor cells (EPC) in patients with mCRC receiving bevacizumab containing treatment within a randomised multicenter phase 2 study of the German AIO GI tumour study group. METHODS: We collected sequential blood samples and tumour tissues from patients participating in a clinical trial for patients with mCRC. We performed flow cytometry of mononuclear cells isolated from peripheral blood to assess CD 133 + or CD 34 + /KDR + EPC before the first bevacizumab containing chemotherapy and after 21 days. Circulating VEGF blood levels before a bevacizumab containing chemotherapy regimen and after 21 days and VEGF expression in tumour tissue were examined. RESULTS: Patients with mCRC and a partial remission after six months of immuno-chemotherapy containing bevacizumab showed a reduction of CD 34 negative KDR positive cells as early as 3 weeks after start of therapy. In contrast, no remarkable change in the number of CD 34 /KDR positive or CD 34 /CD133 positive cells was seen. Furthermore, there was no correlation between treatment response and VEGF expression within the tumour tissue. The mAb bevacizumab reduced serum-VEGF levels in patients independent of their treatment response to bevacizumab. DISCUSSION: We examined circulating endothelial progenitor cells (EPC), serum-VEGF levels and the tumour tissue VEGF expression of patients with mCRC under a bevacizumab containing chemotherapy. The patients with a partial remission after six months of immuno-chemotherapy showed a reduction of CD 34 negative KDR positive cells as early as 3 weeks after start of therapy. Neither serum nor tissue markers were of significant predictive value in our pilot study. Furthermore, we review the current data on biomarkers for anti-angiogenic therapy of mCRC.