Realizing better doctor-patient dialogue about choices in palliative care and early phase clinical trial participation: towards an online value clarification tool (OnVaCT)

Background: Patients with advanced cancer for whom standard systemic treatment is no longer available may be offered participation in early phase clinical trials. In the decision making process, both medical-technical information and patient values and preferences are important. Since patients report decisional conflict after deciding on participation in these trials, improving the decision making process is essential. We aim to develop and evaluate an Online Value Clarification Tool (OnVaCT) to assist patients in clarifying their values around this end-of-life decision. This improved sharing of values is hypothesized to support medical oncologists in tailoring their information to individual patients’ needs and, consequently, to support patients in taking decisions in line with their values and reduce decisional conflict. Methods: In the first part, patients’ values and preferences and medical oncologists’ views hereupon will be explored in interviews and focus groups to build a first prototype OnVaCT using digital communication (serious gaming). Next, we will test feasibility during think aloud sessions, to deliver a ready-to-implement OnVaCT. In the second part, the OnVaCT, with accompanied training module, will be evaluated in a pre-test (12–18 months before implementation) post-test (12–18 months after implementation) study in three major Dutch cancer centres. We will include 276 patients (> 18 years) with advanced cancer for whom standard systemic therapy is no longer available, and who are referred for participation in early phase clinical trials. The first consultation will be recorded to analyse patient-physician communication regarding the discussion of patients’ values and the decision making process. Three weeks afterwards, decisional conflict will be measured. Discussion: This project aims to support the discussion of patient values when considering participation in early phase clinical trials. By including patients before their first appointment with the medical oncologist and record

Risk profiles and one-year outcomes of patients with newly diagnosed atrial fibrillation in India: Insights from the GARFIELD-AF Registry.

BACKGROUND: The Global Anticoagulant Registry in the FIELD-Atrial Fibrillation (GARFIELD-AF) is an ongoing prospective noninterventional registry, which is providing important information on the baseline characteristics, treatment patterns, and 1-year outcomes in patients with newly diagnosed non-valvular atrial fibrillation (NVAF). This report describes data from Indian patients recruited in this registry. METHODS AND RESULTS: A total of 52,014 patients with newly diagnosed AF were enrolled globally; of these, 1388 patients were recruited from 26 sites within India (2012-2016). In India, the mean age was 65.8 years at diagnosis of NVAF. Hypertension was the most prevalent risk factor for AF, present in 68.5% of patients from India and in 76.3% of patients globally (P < 0.001). Diabetes and coronary artery disease (CAD) were prevalent in 36.2% and 28.1% of patients as compared with global prevalence of 22.2% and 21.6%, respectively (P < 0.001 for both). Antiplatelet therapy was the most common antithrombotic treatment in India. With increasing stroke risk, however, patients were more likely to receive oral anticoagulant therapy [mainly vitamin K antagonist (VKA)], but average international normalized ratio (INR) was lower among Indian patients [median INR value 1.6 (interquartile range {IQR}: 1.3-2.3) versus 2.3 (IQR 1.8-2.8) (P < 0.001)]. Compared with other countries, patients from India had markedly higher rates of all-cause mortality [7.68 per 100 person-years (95% confidence interval 6.32-9.35) vs 4.34 (4.16-4.53), P < 0.0001], while rates of stroke/systemic embolism and major bleeding were lower after 1 year of follow-up. CONCLUSION: Compared to previously published registries from India, the GARFIELD-AF registry describes clinical profiles and outcomes in Indian patients with AF of a different etiology. The registry data show that compared to the rest of the world, Indian AF patients are younger in age and have more diabetes and CAD. Patients with a higher stroke risk are more likely to receive anticoagulation therapy with VKA but are underdosed compared with the global average in the GARFIELD-AF. CLINICAL TRIAL REGISTRATION-URL: http://www.clinicaltrials.gov. Unique identifier: NCT01090362

Molecular Response to Hypoxia; from C. elegans to cancer

Oncogenesis is governed by genetic and epigenetic events that co-opt to malignant progression. The role of the microenvironment in tumorigenesis and maintenance is increasingly appreciated. Oxygen supply is one of the rate limiting microenvironmental factors. Like healthy cells, cancer cells rely on oxygen. Hypoxia is the condition in which the partial oxygen pressure has dropped to levels that are no longer sufficient to sustain normal cellular function. Hypoxic cells alter metabolism and growth rate and produce angiogenic factors. This ultimately promotes tumor progression. The hypoxia-inducible factor (HIF) transcription factors account for a major part of this response. The HIF transcription factor is a heterodimer composed of a constitutively expressed beta subunit and a hypoxia-regulated alpha subunit. There are three distinct alpha subunits, HIF-1alpha, -2alpha and -3alpha. At physiological oxygen tensions (normoxia), the alpha subunits are continuously degraded upon synthesis, which is dependent on the Von Hippel Lindau tumorsuppressor protein. In the absense of oxygen (hypoxia), the alpha subunits stabilize and constitute the HIF transcription factor after dimerisation with the beta subunit. The HIF trancription factor is involved in the regulation of genes involved in angiogenesis, energy metabolism, cell survival and metastasis. In multiple solid cancer types, expression of HIFalpha subunits has been associated with poor prognosis. Understanding the molecular pathways triggered by hypoxia will enhance insight into the pathological mechanism that underlies hypoxia-associated poor prognosis of cancer. This thesis addresses two main questions: i. how is HIF-1alpha regulated, and ii. how does hypoxia, and particularly HIFalpha overexpression, result in a poor prognosis? Studies concerning the first research question have provided insights into regulation of the HIF pathway and these are presented in this thesis. First of all, experiments in a cell culture model mimicking the serum- and oxygen-deprived microenvironment of solid cancers indicate a crosstalk between oncogenic pathways like the PI 3-kinase pathway and the HIF pathway. This was confirmed in specimen from breast cancer patients. Furthermore, genetic screening has resulted in the identification of multiple genes potentially involved in regulation of the HIF pathway. The second research question has been addressed in multiple chapters of this thesis. In endometrium cancer the HIF pathway induces expression of the cell cycle regulator p27. Subsequent induction of cell cycle arrest might promote hypoxic cancer cell survival. Importantly, this thesis describes the identification of TWIST1 as a HIF-2alpha target gene by genetic screening in the nematode C. elegans. The HIF pathway has been conserved in the evolution, which allows usage of these model organisms. The TWIST1 gene has previously been shown to be a key molecule in metastasis formation in breast cancer. Therefore, the expression profiles of TWIST1 in breast cancer and relation to promotor methylation are also presented. Hypoxic regulation of TWIST1 might explain the association between hypoxia and metastasis formation in human cancer. In addition to the novel results on hypoxic regulation of TWIST1, this thesis also includes a current review on the latest insights in HIF-mediated regulation of metastasis

Identification by phage display of single-domain antibody fragments specific for the ODD domain in hypoxia-inducible factor 1alpha

Hypoxia triggers the transcription of genes responsible for cell survival via the key player transcription factor hypoxia-inducible factor 1alpha (HIF-1a). Overexpression of this protein has been implicated in cardiovascular disorders, carcinogenesis and cancer progression. For functional and diagnostic studies on the HIF-1a protein, we have identified single-domain antibody fragments directed against this protein by using a llama-derived nonimmune phage display library. This library displays the variable domains of the heavy-chain antibody subclass, found in these animals. Phage display selection with six recombinant HIF-1a proteins yielded five different antibody fragments. By epitope-mapping, we show that all five antibody fragments bind within the functionally important oxygen-dependent degradation domain of the HIF-1a protein. Two of these antibody fragments were engineered into bivalent antibodies that were able to detect human HIF-1a by immunohistochemistry, Western blotting and immunoprecipitation, and mouse HIF-1a by immunofluorescence and immunoprecipitation. These are the first single-domain antibody fragments that may be used in exploration of HIF-1a as a possible therapeutic target through molecular applications

Hypoxia-inducible factor-1α expression requires PI 3-kinase activity and correlates with Akt1 phosphorylation in invasive breast carcinomas

Hypoxia-inducible factor-1 alpha (HIF-1a) is the regulatory subunit of the heterodimeric transcription factor HIF-1 and the key factor in cellular response to low oxygen tension. Expression of HIF-1a protein is associated with poor patient survival and therapy resistance in many types of solid tumors. Insight into HIF-1a regulation in solid tumors is important for therapeutic strategies. In this study, we determined the pathophysiological relevance of HIF-1a regulation by the oncogenic phosphatidylinositol 30-kinase (PI 3-kinase)/Akt signaling pathway. We modeled the physiology of hypoxic tumor regions by culturing carcinoma cells under low oxygen tension in the absence of serum. We observed that hypoxic induction of HIF-1a protein was decreased by serum deprivation. Overexpression of dominant-active Akt1 restored HIF-1a expression, whereas inhibition of PI 3-kinase activity reduced hypoxic HIF-1a protein levels to a similar extent as serum deprivation. Immunohistochemical analysis of 95 human breast cancers revealed that lack of Akt1 phosphorylation correlates with low HIF-1a levels. To our knowledge, this is the first reported comparison between HIF-1a expression and Akt phosphorylation in human carcinomas. We conclude that Akt activity is physiologically relevant for HIF-1a expression in breast cancer. This implies that HIF-1a function might be therapeutically targeted by inhibition of the PI 3-kinase/ Akt pathway

Decisional Conflict after Deciding on Potential Participation in Early Phase Clinical Cancer Trials: Dependent on Global Health Status, Satisfaction with Communication, and Timing

When standard treatment options are not available anymore, patients with advanced cancer may participate in early phase clinical trials. Improving this complex decision-making process may improve their quality of life. Therefore, this prospective multicenter study with questionnaires untangles several contributing factors to decisional conflict (which reflects the quality of decision-making) in patients with advanced cancer who recently decided upon early phase clinical trial participation (phase I or I/II). We hypothesized that health-related quality of life, health literacy, sense of hope, satisfaction with the consultation, timing of the decision, and the decision explain decisional conflict. Mean decisional conflict in 116 patients was 30.0 (SD = 16.9). Multivariate regression analysis showed that less decisional conflict was reported by patients with better global health status (β = -0.185, p = 0.018), higher satisfaction (β = -0.246, p = 0.002), and who made the decision before (β = -0.543, p &lt; 0.001) or within a week after the consultation (β = -0.427, p &lt; 0.001). These variables explained 37% of the variance in decisional conflict. Healthcare professionals should realize that patients with lower global health status and who need more time to decide may require additional support. Although altering such patient intrinsic characteristics is difficult, oncologists can impact the satisfaction with the consultation. Future research should verify whether effective patient-centered communication could prevent decisional conflict

The TWIST1 oncogene is a direct target of hypoxia-inducible factor-2alpha.

Hypoxia-inducible factors (HIFs) are highly conserved transcription factors that play a crucial role in oxygen homeostasis. Intratumoral hypoxia and genetic alterations lead to HIF activity, which is a hallmark of solid cancer and is associated with poor clinical outcome. HIF activity is regulated by an evolutionary conserved mechanism involving oxygen-dependent HIFalpha protein degradation. To identify novel components of the HIF pathway, we performed a genome-wide RNA interference screen in Caenorhabditis elegans, to suppress HIF-dependent phenotypes, like egg-laying defects and hypoxia survival. In addition to hif-1 (HIFalpha) and aha-1 (HIFbeta), we identified hlh-8, gska-3 and spe-8. The hlh-8 gene is homologous to the human oncogene TWIST1. We show that TWIST1 expression in human cancer cells is enhanced by hypoxia in a HIF-2alpha-dependent manner. Furthermore, intronic hypoxia response elements of TWIST1 are regulated by HIF-2alpha, but not HIF-1alpha. These results identify TWIST1 as a direct target gene of HIF-2alpha, which may provide insight into the acquired metastatic capacity of hypoxic tumors

Patients with Rare Cancers in the Drug Rediscovery Protocol (DRUP) Benefit from Genomics-Guided Treatment

Purpose: Patients with rare cancers (incidence less than 6 cases per 100,000 persons per year) commonly have less treatment opportunities and are understudied at the level of genomic targets. We hypothesized that patients with rare cancer benefit from approved anticancer drugs outside their label similar to common cancers.Experimental Design: In the Drug Rediscovery Protocol (DRUP), patients with therapy-refractory metastatic cancers harboring an actionable molecular profile are matched to FDA/European Medicines Agency-approved targeted therapy or immunotherapy. Patients are enrolled in parallel cohorts based on the histologic tumor type, molecular profile and study drug. Primary endpoint is clinical benefit (complete response, partial response, stable disease >= 16 weeks).Results: Of 1,145 submitted cases, 500 patients, including 164 patients with rare cancers, started one of the 25 available drugs and were evaluable for treatment outcome. The overall clinical benefit rate was 33% in both the rare cancer and nonrare cancer subgroup. Inactivating alterations of CDKN2A and activating BRAF aberrations were overrepresented in patients with rare cancer compared with nonrare cancers, resulting in more matches to CDK4/6 inhibitors (14% vs. 4%; P <= 0.001) or BRAF inhibitors (9% vs. 1%; P <= 0.001). Patients with rare cancer treated with small-molecule inhibitors targeting BRAF experienced higher rates of clinical benefit (75%) than the nonrare cancer subgroup.Conclusions: Comprehensive molecular testing in patients with rare cancers may identify treatment opportunities and clinical benefit similar to patients with common cancers. Our findings highlight the importance of access to broad molecular diagnostics to ensure equal treatment opportunities for all patients with cancer.Experimentele farmacotherapi