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• NGS access enables patient identification for tumor-agnostic therapies. • Different tumor-agnostic therapeutics have been approved based on response rate. • Multiple challenges lay ahead to expand the number of tumor-agnostic drugs. • Unveiling mechanisms of resistance to different targeted agents will be key. • Implementing tumor-agnostic therapies requires histology-specific contextualization. The advent of molecular profiling and the generalization of next generation sequencing in oncology has enabled the identification of patients who could benefit from targeted agents. Since the tumor-agnostic approval of pembrolizumab for patients with MSI-High tumors in 2017, different molecularly-guided therapeutics have been awarded approvals and progressively incorporated in the treatment landscape across multiple tumor types. As the number of tumor-agnostic targets considered druggable expands in the clinic, novel challenges will reshape the drug development field involving all the stakeholders in oncology. In this review, we provide an overview of current tumor-agnostic approvals and discuss promising candidate therapeutics for tumor-agnostic designation and challenges for their broad implementation. [ABSTRACT FROM AUTHOR]

Tumor organoids have been proposed as a model system for precision medicine. The ability of tumor organoids to retain characteristics of the original tumor makes them unique for cancer research on an individual patient level. Hence, the idea to use tumor organoids for clinical decision making and optimize patient outcome is tempting. In vitro responses of tumor organoids to a wide array of drugs have been positively correlated to patient responses. However, substantial challenges remain and prospective studies with large cohorts are highly needed before implementation in clinical cancer care can be considered. Because of their personalized characteristics and the immediate link with patient data, tumor organoids also have great potential in preclinical research. Here, we provide a critical overview of both clinical and preclinical advances using tumor organoids. [ABSTRACT FROM AUTHOR]

Summary The therapeutic landscape of melanoma is improving rapidly. Targeted inhibitors show promising results, but drug resistance often limits durable clinical responses. There is a need for in vivo systems that allow for mechanistic drug resistance studies and (combinatorial) treatment optimization. Therefore, we established a large collection of patient-derived xenografts (PDXs), derived from BRAF V600E , NRAS Q61 , or BRAF WT /NRAS WT melanoma metastases prior to treatment with BRAF inhibitor and after resistance had occurred. Taking advantage of PDXs as a limitless source, we screened tumor lysates for resistance mechanisms. We identified a BRAF V600E protein harboring a kinase domain duplication (BRAF V600E/DK ) in ∼10% of the cases, both in PDXs and in an independent patient cohort. While BRAF V600E/DK depletion restored sensitivity to BRAF inhibition, a pan-RAF dimerization inhibitor effectively eliminated BRAF V600E/DK -expressing cells. These results illustrate the utility of this PDX platform and warrant clinical validation of BRAF dimerization inhibitors for this group of melanoma patients. [ABSTRACT FROM AUTHOR]

Summary Forced overexpression and/or downregulation of proteins regulating epithelial-to-mesenchymal transition (EMT) has been reported to alter metastasis by changing migration and stem cell capacity of tumor cells. However, these manipulations artificially keep cells in fixed states, while in vivo cells may adapt transient and reversible states. Here, we have tested the existence and role of epithelial-mesenchymal plasticity in metastasis of mammary tumors without artificially modifying EMT regulators. In these tumors, we found by intravital microscopy that the motile tumor cells have undergone EMT, while their epithelial counterparts were not migratory. Moreover, we found that epithelial-mesenchymal plasticity renders any EMT-induced stemness differences, as reported previously, irrelevant for metastatic outgrowth, because mesenchymal cells that arrive at secondary sites convert to the epithelial state within one or two divisions, thereby obtaining the same stem cell potential as their arrived epithelial counterparts. We conclude that epithelial-mesenchymal plasticity supports migration but additionally eliminates stemness-enhanced metastatic outgrowth differences. [ABSTRACT FROM AUTHOR]

Abstract: Circulating tumor cells (CTCs) have received a lot of attention from both researchers and clinicians because of their prognostic value for progression-free and overall survival in selected tumor types. CTCs are readily available by single venipuncture, thereby posing little burden on the patient and allowing for repeated, sequential sampling during therapy. Nowadays, the sensitivity of several CTC detection and capture techniques allow for further characterization and analysis of specific targets of interest on the CTC itself. These techniques have given CTCs the potential to be used as a pharmacodynamic read-out in drug development. In this review, we explore the utility of CTCs as a pharmacodynamic biomarker in early clinical oncological trials. We present an overview of current literature on assays for CTCs as pharmacodynamic biomarker, their different targets of interest and their level of validation, followed by discussion of their limitations. [Copyright &y& Elsevier]

Aim: Cediranib is a highly potent inhibitor of vascular endothelial growth factor receptor (VEGFR) signalling. Preclinical and clinical data suggest that inhibition of the VEGFR and epidermal growth factor receptor (EGFR) pathways may be synergistic. Combination treatment with cediranib and gefitinib, an EGFR signalling inhibitor, was evaluated in patients with advanced solid tumours. Patients and methods: Ninety patients received treatment in this four-part, open-label study (NCT00502060). The patients received once-daily oral doses of cediranib (20–45mg) and gefitinib 250mg (part A1; n =16) or 500mg (part B1; n =44). A cohort expansion phase investigated the potential pharmacokinetic interaction of cediranib 30mg with gefitinib 250mg (part A2; n =15) or 500mg (part B2; n =15). The primary objective was to assess the safety and tolerability of cediranib with gefitinib. Secondary assessments included pharmacokinetics, efficacy and pharmacodynamics. Results: Combination treatment was generally well tolerated; the protocol-defined maximum-tolerated dose of cediranib was 30mg/day with gefitinib 250mg/day (part A1) and cediranib 45mg/day was the maximum dose investigated with gefitinib 500mg/day (part B1). The most common adverse events were diarrhoea (84 [93%]), anorexia (63 [70%]) and fatigue (60 [67%]). Cediranib pharmacokinetic parameters were not substantially different when given alone or in combination with gefitinib. Gefitinib pharmacokinetic parameters were similar to those seen previously with gefitinib monotherapy. Efficacy results included eight (9%) confirmed partial responses (6 renal; 1 lung; 1 osteosarcoma) and 38 (42%) patients with stable disease. Pharmacodynamic assessments demonstrated changes in levels of VEGF and soluble VEGFR-2 following treatment. Conclusions: Combination treatment was generally well tolerated and showed encouraging antitumour activity in patients with advanced solid tumours. These results merit further exploration. [Copyright &y& Elsevier]

In 2–5% of patients with colorectal cancer (CRC), human epidermal growth factor 2 (HER2) is amplified or overexpressed. Despite prior evidence that anti-HER2 therapy confers clinical benefit (CB) in one-third of these patients, it is not approved for this indication in Europe. In the Drug Rediscovery Protocol (DRUP), patients are treated with off-label drugs based on their molecular profile. Here, we present the results of the cohort 'trastuzumab/pertuzumab for treatment-refractory patients with RAS/BRAF -wild-type HER2 amplified metastatic CRC (HER2+ mCRC)'. Patients with progressive treatment-refractory RAS/BRAF -wild-type HER2+ mCRC with measurable disease were included for trastuzumab plus pertuzumab treatment. Primary endpoints of DRUP are CB (defined as confirmed objective response (OR) or stable disease (SD) ≥ 16 weeks) and safety. Patients were enrolled using a Simon-like 2-stage model, with 8 patients in stage 1 and 24 patients in stage 2 if at least 1/8 patients had CB. To identify biomarkers for response, whole genome sequencing (WGS) was performed on pre-treatment biopsies. CB was observed in 11/24 evaluable patients (46%) with HER2+ mCRC, seven patients achieved an OR (29%). Median duration of response was 8.4 months. Patients had undergone a median of 3 prior treatment lines. Median progression-free survival and overall survival were 4.3 months (95% CI 1.9–10.3) and 8.2 months (95% CI 7.2–14.7), respectively. No unexpected toxicities were observed. WGS provided potential explanations for resistance in 3/10 patients without CB, for whom WGS was available. The results of this study confirm a clinically significant benefit of trastuzumab plus pertuzumab treatment in patients with HER2 +mCRC. • In 2-5% of patients with colorectal cancer HER2 is amplified or overexpressed. • Trastuzumab/pertuzumab treatment confers clinical benefit in almost half of HER2+ mCRC patients. • Treatment with trastuzumab plus pertuzumab was well tolerated. • Whole genome sequencing data may reveal potential resistance mechanisms to trastuzumab/pertuzumab treatment. [ABSTRACT FROM AUTHOR]

Abstract: Purpose: To determine the prognostic meaning of symptoms in patients with advanced cancer. Design: Medline, Embase, Cochrane and Cinahl databases were systematically explored. The predicting symptoms were also evaluated in the three stages of palliative care: disease-directed palliation, symptom-oriented palliation and palliation in the terminal stage. Results: Out of 3167 papers, forty-four papers satisfied all criteria. Confusion, anorexia, fatigue, cachexia, weight loss, cognitive impairment, drowsiness, dyspnea, dysphagia, dry mouth and depressed mood were associated with survival in ≥50% of the studies evaluating these symptoms. Multivariate analysis showed confusion, anorexia, fatigue, cachexia, weight loss, dyspnea and dysphagia as independent prognostic factors in 30–56% of the studies. In the stage of disease-directed palliation anorexia, cachexia, weight loss, dysphagia and pain and in the stage of symptom-oriented palliation confusion, fatigue, cachexia, weight loss, dyspnea, dysphagia and nausea were shown to be independent predictors of survival in >30% of the studies. Conclusion: Symptoms with independent predictive value are confusion, anorexia, fatigue, cachexia, weight loss, dyspnea and dysphagia. New insights are added by the variance between the three palliative stages. [Copyright &y& Elsevier]

Abstract: Purpose: To assess whether age has an impact on symptoms, problems and needs of hospitalized advanced cancer patients. Patients and methods: A prospective analysis of 181 patients referred to a Palliative Care Team was done using a standardized list of symptoms, problems and needs. Differences between 3 age groups (<60; 60–70; ≥70) were analyzed. Results: Patients ≥70 years had a significantly different prevalence of depressed mood (48% versus 13% of patients 60–70 years and 24% of patients <60 years, p =0.002), urinary tract problems (20% versus 3% versus 8%, p =0.024) and drowsiness (18% versus 42% versus 25%, p =0.039). They expressed more problems with a shortage of informal caregivers (45% versus 42% versus 17%, p <0.001) and less need for support in coping (40% versus 61% versus 63%, p =0.043), relational support (3% versus 8% versus 14%, p =0.019) and support in communication (0% versus 8% versus 11%, p =0.013). Conclusion: Fewer differences than expected were found. Elderly cancer patients admitted to a hospital have more or less the same symptoms, problems and needs as their younger counterparts. Despite these findings, age-specific assessment of symptoms, problems and needs ought to be part of optimal symptom management. [Copyright &y& Elsevier]

Owing to clinical success of immune-checkpoint blockade, immunotherapy is becoming a cornerstone of modern oncology, and immuno-oncology is at the forefront of basic cancer research. This commentary outlines future opportunities for immuno-oncology modeling. [ABSTRACT FROM AUTHOR]

Academic, industry, regulatory leaders and patient advocates in cancer clinical research met in November 2018 at the Innovation and Biomarkers in Cancer Drug Development meeting in Brussels to address the existing dichotomy between increasing calls for personalised oncology approaches based on individual molecular profiles and the need to make resource and regulatory decisions at the societal level in differing health-care delivery systems around the globe. Novel clinical trial designs, the utility and limitations of real-world evidence (RWE) and emerging technologies for profiling patient tumours and tumour-derived DNA in plasma were discussed. While randomised clinical trials remain the gold standard approach to defining clinical utility of local and systemic therapeutic interventions, the broader adoption of comprehensive tumour profiling and novel trial designs coupled with RWE may allow patient and physician autonomy to be appropriately balanced with broader assessments of safety and overall societal benefit. • Develop biomarkers using rigorous methodology, rationality in clinical context, not limited to drug development. • Standardise biomarker testing seeking equivalence between Companion Diagnostics and Laboratory-Developed Tests. • Improve clinical study designs to include patient-centred end-points and core outcome sets. • Bridge the gap between individualised and population-based oncology using real-world evidence. [ABSTRACT FROM AUTHOR]

Abstract Translational cancer research covers the whole cancer research continuum from basic to preclinical to early clinical, late clinical and outcomes research. Basic-preclinical research is the "engine" for early clinical research bridging the early translational research gap. Cancer Core Europe has been created to construct a sustainable, high level, shared research infrastructure platform with research collaborations and taskforces (data sharing, clinical trials, genomics, immunotherapy, imaging, legal & ethical problems, and education & training) having representatives from all seven member centres, in a controlled expansion model. In parallel, a consortium of ten cancer prevention centres was established, Cancer Prevention Europe, to support the complete cancer prevention research continuum. Cancer Core Europe is launching at present the Basket of Baskets trial, which is the largest personalized cancer medicine trial effort in Europe. At present, Cancer Core Europe and Cancer Prevention Europe are in the process of integrating therapeutics and prevention strategies to address in partnership the increasing cancer problem. By offering innovative approaches for cancer research, links to the healthcare systems, development of quality-assured multidisciplinary cancer care, as well as the assessment of long-term outcomes, the infrastructure is expected to serve as a hub to connect with other centres in Europe as well as on other continents. In this manner Cancer Core Europe and Cancer Prevention Europe prepare to tackle the "Mission on Cancer", with infrastructure and proofs of concept for therapeutics and prevention, research for assessment of effectiveness, health economics and added value for patients and the healthcare systems. [ABSTRACT FROM AUTHOR]

Should professionals systematically screen whole-genome sequencing (WGS) data to check for life-threatening mutations? Alternatively, should genome analysis focus on the primary reason for testing – that is, aiming to achieve precision medicine? We present an ethical review of the arguments and compare the act of searching for mutations with disclosing mutations that are discovered incidentally. [ABSTRACT FROM AUTHOR]

Drug resistance is a perpetual problem in cancer therapy with many underlying mechanisms. Alterations in drug transport over the cancer cell membrane can severely alter intratumoral drug exposure, contributing to resistance. Here, we present the somatic mutational landscape of 48 ATP-binding cassette and 416 solute carrier transporter genes in a cohort (CPCT-02; NCT01855477) of 3290 patients with different types of advanced and metastasized cancer through analysis of whole genome and transcriptome sequencing. In order to identify potential stressor mechanisms, we stratified patients based on previous systemic therapies and subsequently investigated the enrichment of mutations and copy-number alterations of transporter genes. In tumors from patients pretreated with protein kinase inhibitors (PKIs), genes encoding for specific copper (SLC31A1 and SLC31A2, χ 2 -test adjusted p -values: 6.9e-09 and 2.5e-09) and nucleoside transporters (SLC28A2 and SLC28A3, χ 2 -test adjusted p -values: 3.5e-06 and 6.8e-07) were deleted significantly more frequently than in patients pretreated with chemotherapy. Moreover, we detected 16 transporters that were differentially expressed at RNA level between these treatment groups. These findings contradict mechanisms of selective pressure, as they would be expected to originate during treatment with chemotherapy rather than with PKIs. Hence, they might constitute primary drug resistance mechanisms and, therefore, warrant further study. • Drug transporters are vital in the kinetics of anti-cancer drugs into the tumor. • We studied somatic changes in transporter genes in a large cancer patient cohort. • We found potential resistance mechanisms against platins / nucleoside analogues. • The functional implications of these findings need to be studied prospectively. [ABSTRACT FROM AUTHOR]

Interferon-γ (IFN-γ) signaling mediates host responses to infection, inflammation and anti-tumor immunity. Mutations in the IFN-γ signaling pathway cause immunological disorders, hematological malignancies, and resistance to immune checkpoint blockade (ICB) in cancer; however, the function of most clinically observed variants remains unknown. Here, we systematically investigate the genetic determinants of IFN-γ response in colorectal cancer cells using CRISPR-Cas9 screens and base editing mutagenesis. Deep mutagenesis of JAK1 with cytidine and adenine base editors, combined with pathway-wide screens, reveal loss-of-function and gain-of-function mutations, including causal variants in hematological malignancies and mutations detected in patients refractory to ICB. We functionally validate variants of uncertain significance in primary tumor organoids, where engineering missense mutations in JAK1 enhanced or reduced sensitivity to autologous tumor-reactive T cells. We identify more than 300 predicted missense mutations altering IFN-γ pathway activity, generating a valuable resource for interpreting gene variant function. [Display omitted] • Systematic base editing mutagenesis of the IFN-γ pathway in colorectal cancer cells • Functional assessment of variants relevant to cancer and immune disorders • Mutagenesis highlights functional protein domains and interaction interfaces • Missense mutations in JAK1 alter sensitivity of tumor organoids to T cells Coelho et al. use functional genomics to systematically analyze the genetic determinants of IFN-γ response in colorectal cancer cells. Base editing mutagenesis of key signaling components facilitates the parallel assessment of gene variant function at scale, relevant for understanding IFN-γ signaling in cancer immune surveillance and immune disorders. [ABSTRACT FROM AUTHOR]

Abstract: Background: We recently identified apolipoprotein A2 (ApoA2) and serum amyloid α (SAA) as independent prognosticators in metastatic renal cell carcinoma (mRCC) patients, thereby improving the accuracy of the Memorial-Sloan Kettering Cancer Center (MSKCC) model. Objective: Validate these results prospectively in a separate cohort of mRCC patients treated with tyrosine kinase inhibitors (TKIs). Design, setting, and participants: For training we used 114 interferon-treated mRCC patients (inclusion 2001–2006). For validation we studied 151 TKI-treated mRCC patients (inclusion 2003–2009). Measurements: Using Cox proportional hazards regression analysis, SAA and ApoA2 were associated with progression-free survival (PFS) and overall survival (OS). In 72 TKI-treated patients, SAA levels were analyzed longitudinally as a potential early marker for treatment effect. Results and limitations: Baseline ApoA2 and SAA levels significantly predicted PFS and OS in the training and validation cohorts. Multivariate analysis identified SAA in both separate patient sets as a robust and independent prognosticator for PFS and OS. In contrast to our previous findings, ApoA2 interacted with SAA in the validation cohort and did not contribute to a better predictive accuracy than SAA alone and was therefore excluded from further analysis. According to the tertiles of SAA levels, patients were categorized in three risk groups, demonstrating accurate risk prognostication. SAA as a single biomarker showed equal prognostic accuracy when compared with the multifactorial MSKCC risk mode. Using receiver operating characteristic analysis, SAA levels >71 ng/ml were designated as the optimal cut-off value in the training cohort, which was confirmed for its significant sensitivity and specificity in the validation cohort. Applying SAA >71 ng/ml as an additional risk factor significantly improved the predictive accuracy of the MSKCC model in both independent cohorts. Changes in SAA levels after 6–8 wk of TKI treatment had no value in predicting treatment outcome. Conclusions: SAA but not ApoA2 was shown to be a robust and independent prognosticator for PFS and OS in mRCC patients. When incorporated in the MSKCC model, SAA showed additional prognostic value for patient management. [Copyright &y& Elsevier]

Summary: The development of resistance to chemotherapy is a major obstacle for lasting effective treatment of cancer. Here, we demonstrate that endogenous mesenchymal stem cells (MSCs) become activated during treatment with platinum analogs and secrete factors that protect tumor cells against a range of chemotherapeutics. Through a metabolomics approach, we identified two distinct platinum-induced polyunsaturated fatty acids (PIFAs), 12-oxo-5,8,10-heptadecatrienoic acid (KHT) and hexadeca-4,7,10,13-tetraenoic acid (16:4(n-3)), that in minute quantities induce resistance to a broad spectrum of chemotherapeutic agents. Interestingly, blocking central enzymes involved in the production of these PIFAs (cyclooxygenase-1 and thromboxane synthase) prevents MSC-induced resistance. Our findings show that MSCs are potent mediators of resistance to chemotherapy and reveal targets to enhance chemotherapy efficacy in patients. [Copyright &y& Elsevier]

Aim: The hypoxia inducible factor (HIF) pathway plays an important role in sporadic clear cell renal cell carcinoma (ccRCC) by stimulating processes of angiogenesis, cell proliferation, cell survival and metastases formation. Herein, we evaluate the significance of upstream proteins directly regulating the HIF pathway; the prolyl hydroxylases domain proteins (PHD)1, 2 and 3 and factor-inhibiting HIF (FIH), as prognostic markers for ccRCC. Methods: Immunohistochemical marker expression was examined on a tissue microarray containing tumour tissue derived from 100 patients who underwent nephrectomy for ccRCC. Expression levels of HIF, FIH and PHD1, 2 and 3 were correlated with overall survival (OS) and clinicopathological prognostic factors. Results: HIF-1α was positively correlated with HIF-2α (p <0.0001), PHD1 (p =0.024), PHD2 (p <0.0001), PHD3 (p =0.004), FIH (p <0.0001) and VHL (p =0.031). HIF-2α levels were significantly associated with FIH (p <0.0001) and PHD2 (p =0.0155). Mutations in the VHL gene, expression variations of HIF-1α, HIF-2α and PHD1, 2, 3 did not show a correlation to OS or clinicopathological prognostic factors. Tumour stage, grade, diameter, metastastic disease and intensity of nuclear FIH were significantly correlated to OS in univariable analysis (p =0.023). Low nuclear FIH levels remained a strong independent prognostic factor in multivariable analysis (p =0.009). Conclusion: These results show that low nuclear expression of FIH is a strong independent prognostic factor for a poor overall survival in ccRCC. [Copyright &y& Elsevier]

BACKGROUND: Ovarian cancer overexpresses ET-1, and in vitro studies have shown that ET-1 confers resistance to anthracycline-containing chemotherapy. Atrasentan has been developed as an oral selective endothelin-A receptor antagonist. The objective of the study was to investigate the feasibility and toxicity of adding increasing doses of atrasentan (to a maximum of 10mg/d) and liposomal doxorubicin in patients with progressive ovarian cancer, refractory for platinum and paclitaxel. METHODS: Patients with platinum-resistant ovarian cancer were treated with pegylated liposomal doxorubicin (PLD) 50 mg/m² on day 1 (and repeated every 4 weeks) in combination with escalating doses of atrasentan once daily. The starting dose was 2.5 mg and escalated in cohorts of three patients from 5 to 10 mg. RESULTS: Twenty-six patients (mean age = 60 years, range = 42-74 years) were treated at the three dose levels. Atrasentan could be safely administered in combination at a dose of 10 mg. All patients were evaluable for toxicity, and 19 patients, included in the phase 2 period, were evaluable for response. Adverse events included nausea, vomiting, mucositis, skin toxicity, and rhinitis. Clinical cardiac toxicity, intensively monitored, was not observed, although two patients had a decrease in cardiac ejection fraction. Three objective responses were observed and another six patients had stable disease with a median time to progression of 14 weeks and an overall survival of 13.1 months. CONCLUSIONS: The addition of atrasentan to standard dose PLD in platinum-resistant ovarian cancer is feasible with some suggestion of prolonged survival. [ABSTRACT FROM AUTHOR]

INTRODUCTION: PTK/ZK is a small-molecule inhibitor of all three vascular endothelial growth factor (VEGF) receptors, platelet-derived growth factor receptor, colony-stimulating factor 1 receptor, and cytokine stem cell factor receptor. Cetuximab is a monoclonal antibody against epidermal growth factor (EGF) receptor. Combining inhibition of VEGF and EGF signaling might act additive or synergistically. METHODS: In phase 1 design, patients with advanced solid tumors were treated with PTK/ZK daily (cohort 1, 750 mg once daily; cohort 2, 1250 mg once daily; cohort 3, 250 mg [morning] and 500 mg [evening]; and cohort 4, 500 mg [morning] and 750 mg [evening]) in combination with cetuximab 250 mg/m² weekly in cycles of 28 days in cohorts of three patients. Toxicity was evaluated conform the Common Terminology Criteria for Adverse Events classification 3.0. Pharmacokinetics and pharmacodynamics consisting of circulating endothelial (progenitor) cell (CE[P]C) analysis by flow cytometry were performed. RESULTS: Safety and tolerability was evaluated in 16 patients. The most frequently reported adverse events were acne, dry skin, fatigue, nausea, dizziness, vomiting, headache, and diarrhea. One dose-limiting toxicity occurred in cohort 3 consisting of a grade 3 transaminitis. Pharmacokinetic analysis revealed no significant changes in PTK/ZK exposure on coadministration with cetuximab and in bioavailability at equivalent total daily doses. Biomarker analysis showed no significant change in the number of CE(P)Cs during treatment. One of 14 evaluable patients showed a partial response for at least 11.5 months, and 7 patients (50%) stable disease for at least 2 months. CONCLUSIONS: This study shows that the combination of PTK/ZK and cetuximab is well tolerated with only slightly overlapping toxicity profiles and has antitumor activity. [ABSTRACT FROM AUTHOR]

We and others have previously demonstrated that the acute release of progenitor cells in response to chemotherapy actually reduces the efficacy of the chemotherapy. Here, we take these data further and investigate the clinical relevance of circulating endothelial (progenitor) cells (CE(P)Cs) and modulatory cytokines in patients after chemotherapy with relation to progression-free and overall survival (PFS/OS). Patients treated with various chemotherapeutics were included. Blood sampling was performed at baseline, 4 hours, and 7 and 21 days after chemotherapy. The mononuclear cell fraction was analyzed for CE(P)C by FACS analysis. Plasma was analyzed for cytokines by ELISA or Luminex technique. CE(P)Cs were correlated with response and PFS/OS using Cox proportional hazard regression analysis. We measured CE(P)Cs and cytokines in 71 patients. Only patients treated with paclitaxel showed an immediate increase in endothelial progenitor cell 4 hours after start of treatment. These immediate changes did not correlate with response or survival. After 7 and 21 days of chemotherapy, a large and consistent increase in CE(P)C was found (P < .01), independent of the type of chemotherapy. Changes in CE(P)C levels at day 7 correlated with an increase in tumor volume after three cycles of chemotherapy and predicted PFS/OS, regardless of the tumor type or chemotherapy. These findings indicate that the late release of CE(P)C is a common phenomenon after chemotherapeutic treatment. The correlation with a clinical response and survival provides further support for the biologic relevance of these cells in patients' prognosis and stresses their possible use as a therapeutic target. [ABSTRACT FROM AUTHOR]

Summary: Several hypotheses have been proposed to explain how antiangiogenic drugs enhance the treatment efficacy of cytotoxic chemotherapy, including impairing the ability of chemotherapy-responsive tumors to regrow after therapy. With respect to the latter, we show that certain chemotherapy drugs, e.g., paclitaxel, can rapidly induce proangiogenic bone marrow-derived circulating endothelial progenitor (CEP) mobilization and subsequent tumor homing, whereas others, e.g., gemcitabine, do not. Acute CEP mobilization was mediated, at least in part, by systemic induction of SDF-1α and could be prevented by various procedures such as treatment with anti-VEGFR2 blocking antibodies or paclitaxel treatment in CEP-deficient Id mutant mice, both of which resulted in enhanced antitumor effects mediated by paclitaxel, but not by gemcitabine. [Copyright &y& Elsevier]

Abstract: The suffering of patients with incurable cancer is determined to a large degree by the presence and intensity of the symptoms of their disease. Knowledge of symptom prevalence is important for clinical practice. The main aim of this study was to obtain a reliable estimation of symptom prevalence in patients with incurable cancer by performing a systematic review of studies assessing this topic. We included 44 studies (including 25,074 patients) on overall symptom prevalence (Group 1) and six studies (including 2,219 patients) on symptom prevalence during the last one to two weeks of life (Group 2). In these studies, symptom prevalence was assessed by a questionnaire, a standardized interview, or the medical record. We identified 37 symptoms assessed in at least five studies. Almost all symptoms occurred in more than 10% of the patients. Five symptoms (fatigue, pain, lack of energy, weakness, and appetite loss) occurred in more than 50% of the patients of Group 1. Weight loss occurred significantly more often in Group 2 compared to Group 1, and pain, nausea, and urinary symptoms occurred significantly less often. Generally, symptom prevalence was highest if assessed by a questionnaire. The results of this study should be used to guide doctors and nurses in symptom management. Proper attention to symptom burden and suffering should be the basis for individually tailored treatment aimed at improving or maintaining quality of life of patients in their last period of life. [Copyright &y& Elsevier]

Abstract: Purpose: To assess the prognostic value of symptoms in hospitalised advanced cancer patients. Patients and methods: A prospective analysis was performed of 181 hospitalised patients referred to a Palliative Care Team. Comprehensive symptom questionnaire, functional status, estimated life expectancy and survival were assessed. Using a Cox regression model, a predictive survival model was built. Results: Median survival: 53d. Median number of symptoms: 4; 20 symptoms occurred in ⩾10%. Multivariate analysis showed nausea, dysphagia, dyspnoea, confusion and absence of depressed mood as independent prognostic factors for survival (p <0.05) with relative risks of dying of 1.96, 1.81, 1.79, 2.35 and 1.79, respectively. Patients with 2, 3 or 4 of these factors at the same time had a relative risk of dying of 2.7, 2.1 and 9.0, respectively. Conclusion: A cluster of factors comprising nausea, dysphagia, dyspnoea, confusion and absence of depressed mood may be used to accurately predict survival in hospitalised advanced cancer patients. [Copyright &y& Elsevier]

The tumor suppressor function of the yon Hippel-Lindau protein (pVHL) has previously been linked to its role in regulating hypoxia-inducible factor levels. However, VHL gene mutations suggest a hypoxia-inducible factor-independent function for the N-terminal acidic domain in tumor suppression. Here, we report that phosphorylation of the N-terminal acidic domain of pVHL by casein kinase-2 is essential for its tumor suppressor function. This post-translational modification did not affect the levels of hypoxia-inducible factor; however, it did change the binding of pVHL to another known binding partner, fibronectin. Cells expressing phospho-defective mutants caused improper fibronectin matrix deposition and demonstrated retarded tumor formation in mice. We propose that phosphorylation of the acidic domain plays a role in the regulation of proper fibronectin matrix deposition and that this may be relevant for the development of VHL-associated malignancies. [ABSTRACT FROM AUTHOR]

Numbers of circulating endothelial cells (CECs) are increased in cancer patients with progressive disease. Also, cancer patients have an increased risk for thrombotic events, being negatively associated with prognosis. Tissue factor (TF), the physiological initiator of coagulation, is present on the surface of many extravascular cells. In 34 samples from cancer patients and in seven from volunteers, CECs were quantified (with endothelium-specific anti-CD146 beads), and TF-activity assessed with a chromogenic assay. All samples displayed very limited TF-activity (patients: 1.6±3.1μU; volunteers: 0.94±1.7μU FXa/100 CECs, P=0.30 by Mann–Whitney test). After in vitro TNFα-stimulation, CECs from both cancer patients and volunteers showed substantially increased TF-activity (endogenous activity: 17.3±6.4μU; after TNFα-stimulation: 73.8±34.3μU FXa; P=0.028, Wilcoxon signed ranks test), reflecting the potential of CECs to generate biologically active TF. As the chromogenic assay determines a mean cellular TF-activity, we also analyzed immunohistochemical TF-antigen expression on CEC subsets. TF-antigen expression was undetectable. CECs isolated from cancer patients do not express TF. CECs can generate functional TF after stimulation and may therefore play a role in (intratumoral) coagulation induction and tumor angiogenesis. [Copyright &y& Elsevier]

Amyloid fibrils are components of proteinaceous plaques that are associated with conformational diseases such as Alzheimer's disease, transmissible spongiform encephalopathies, and familial amyloidosis. Amyloid polypeptides share a specific quarternary structure element known as cross-β structure. Commonly, fibrillar aggregates are modified by advanced glycation end products (AGE). In addition, AGE formation itself induces protein aggregation. Both amyloid proteins and protein-AGE adducts bind multiligand receptors, such as receptor for AGE, CD36, and scavenger receptors A and B type I, and the serine protease tissue-type plasminogen activator (tPA). Based on these observations, we hypothesized that glycation induces refolding of globular proteins, accompanied by formation of cross-β structure. Using transmission electron microscopy, we demonstrate here that glycated albumin condensates into fibrous or amorphous aggregates. These aggregates bind to amyloid-specific dyes Congo red and thioflavin T and to tPA. In contrast to globular albumin, glycated albumin contains amino acid residues in β-sheet conformation, as measured with circular dichroism spectropolarimetry. Moreover, it displays cross-β structure, as determined with x-ray fiber diffraction. We conclude that glycation induces refolding of initially globular albumin into amyloid fibrils comprising cross-β structure. This would explain how glycated ligands and amyloid ligands can bind to the same multiligand "cross-β structure" receptors and to tPA. [ABSTRACT FROM AUTHOR]