Adina Weinerman

Increased plasma vascular endothelial growth factor (VEGF) as a surrogate marker for optimal therapeutic dosing of VEGF receptor-2 monoclonal antibodies

A major obstacle compromising the successful application of many of the new targeted anticancer drugs, including angiogenesis inhibitors, is the empiricism associated with determining an effective biological/therapeutic dose because many of these drugs express optimum therapeutic activity below the maximum tolerated dose, if such a dose can be defined. Hence, surrogate markers are needed to help determine optimal dosing. Here we describe such a molecular marker, increased plasma levels of vascular endothelial growth factor (VEGF), in normal or tumor-bearing mice that received injections of an anti-VEGF receptor (VEGFR)-2 monoclonal antibody, such as DC101. Rapid increases of mouse VEGF (e.g., within 24 hours) up to 1 order of magnitude were observed after single injections of DC101 in non–tumor-bearing severe combined immunodeficient or nude mice; similar increases in human plasma VEGF were detected in human tumor-bearing mice. RAFL-1, another anti-VEGFR-2 antibody, also caused a significant increase in plasma VEGF. In contrast, increases in mouse VEGF levels were not seen when small molecule VEGFR-2 inhibitors were tested in normal mice. Most importantly, the increases in plasma VEGF were induced in a dose-dependent manner, with the maximum values peaking when doses previously determined to be optimally therapeutic were used. Plasma VEGF should be considered as a possible surrogate pharmacodynamic marker for determining the optimal biological dose of antibody drugs that block VEGFR-2 (KDR) activity in a clinical setting.

Low-Dose Metronomic Daily Cyclophosphamide and Weekly Tirapazamine: A Well-Tolerated Combination Regimen with Enhanced Efficacy That Exploits Tumor Hypoxia

The recent clinical successes of antiangiogenic drug-based therapies have also served to highlight the problem of acquired resistance because, similar to other types of cancer therapy, tumors that initially respond eventually stop doing so. Consequently, strategies designed to delay resistance or treat resistant subpopulations when they arise have assumed considerable importance. This requires a better understanding of the various possible mechanisms for resistance. In this regard, reduced oxygenation is thought to be a key mediator of the antitumor effects of antiangiogenic therapies; accordingly, increased hypoxia tolerance of the tumor cells presents a potential mechanism of resistance. However, hypoxia can also be exploited therapeutically through the use of hypoxic cell cytotoxins, such as tirapazamine. With this in mind, we measured the oxygenation of PC-3 human prostate cancer xenografts subjected to chronic low-dose metronomic (LDM) antiangiogenic chemotherapy using cyclophosphamide given through the drinking water. We found that LDM cyclophosphamide impairs the oxygenation of PC-3 xenografts even during relapse, coinciding with reduced microvessel density. Combination of LDM cyclophosphamide with tirapazamine results in significantly improved tumor control in the PC-3, HT-29 colon adenocarcinoma, and MDA-MB-231 breast cancer human xenograft models without having a negative effect on the favorable toxicity profile of LDM cyclophosphamide. These results provide further evidence that reduced vascular dependence/increased hypoxia tolerance may be a basis for eventual resistance of tumors exposed to long-term LDM chemotherapy.

Down-regulation of DNA mismatch repair proteins in human and murine tumor spheroids: implications for multicellular resistance to alkylating agents.

Similar to other anticancer agents, intrinsic or acquired resistance to DNA-damaging chemotherapeutics is a major obstacle for cancer therapy. Current strategies aimed at overcoming this problem are mostly based on the premise that tumor cells acquire heritable genetic mutations that contribute to drug resistance. Here, we present evidence for an epigenetic, tumor cell adhesion–mediated, and reversible form of drug resistance that is associated with a reduction of DNA mismatch repair proteins PMS2 and/or MLH1 as well as other members of this DNA repair process. Growth of human breast cancer, human melanoma, and murine EMT-6 breast cancer cell lines as multicellular spheroids in vitro, which is associated with increased resistance to many chemotherapeutic drugs, including alkylating agents, is shown to lead to a reproducible down-regulation of PMS2, MLH1, or, in some cases, both as well as MHS6, MSH3, and MSH2. The observed down-regulation is in part reversible by treatment of tumor spheroids with the DNA-demethylating agent, 5-azacytidine. Thus, treatment of EMT-6 mouse mammary carcinoma spheroids with 5-azacytidine resulted in reduced and/or disrupted cell-cell adhesion, which in turn sensitized tumor spheroids to cisplatin-mediated killing in vitro. Our results suggest that antiadhesive agents might sensitize tumor spheroids to alkylating agents in part by reversing or preventing reduced DNA mismatch repair activity and that the chemosensitization properties of 5-azacytidine may conceivably reflect its role as a potential antiadhesive agent as well as reversal agent for MLH1 gene silencing in human tumors.

Design and methods of the Echo WISELY (Will Inappropriate Scenarios for Echocardiography Lessen SignificantlY) study: An investigator-blinded randomized controlled trial of education and feedback intervention to reduce inappropriate echocardiograms

BACKGROUND Appropriate use criteria (AUC) for transthoracic echocardiography (TTE) were developed to address concerns regarding inappropriate use of TTE. A previous pilot study suggests that an educational and feedback intervention can reduce inappropriate TTEs ordered by physicians in training. It is unknown if this type of intervention will be effective when targeted at attending level physicians in a variety of clinical settings. AIMS The aim of this international, multicenter study is to evaluate the hypothesis that an AUC-based educational and feedback intervention will reduce the proportion of inappropriate echocardiograms ordered by attending physicians in the ambulatory environment. METHODS In an ongoing multicentered, investigator-blinded, randomized controlled trial across Canada and the United States, cardiologists and primary care physicians practicing in the ambulatory setting will be enrolled. The intervention arm will receive (1) a lecture outlining the AUC and most recent available evidence highlighting appropriate use of TTE, (2) access to the American Society of Echocardiography mobile phone app, and (3) individualized feedback reports e-mailed monthly summarizing TTE ordering behavior including information on inappropriate TTEs and brief explanations of the inappropriate designation. The control group will receive no education on TTE appropriate use and order TTEs as usual practice. CONCLUSIONS The Echo WISELY (Will Inappropriate Scenarios for Echocardiography Lessen Significantly in an education RCT) study is the first multicenter randomized trial of an AUC-based educational intervention. The study will examine whether an education and feedback intervention will reduce the rate of outpatient inappropriate TTEs ordered by attending level cardiologists and primary care physicians (www.clinicaltrials.gov identifier NCT02038101).

Prevalence and Costs of Discharge Diagnoses in Inpatient General Internal Medicine: a Multi-center Cross-sectional Study

BackgroundUnderstanding the most common and costly conditions treated by inpatient general medical services is important for implementing quality improvement, developing health policy, conducting research, and designing medical education.ObjectiveTo determine the prevalence and cost of conditions treated on general internal medicine (GIM) inpatient services.DesignRetrospective cross-sectional study involving 7 hospital sites in Toronto, Canada.ParticipantsAll patients discharged between April 1, 2010 and March 31, 2015 who were admitted to or discharged from an inpatient GIM service.Main MeasuresHospital administrative data were used to identify diagnoses and costs associated with admissions. The primary discharge diagnosis was identified for each admission and categorized into clinically relevant and mutually exclusive categories using the Clinical Classifications Software (CCS) tool.Key ResultsAmong 148,442 admissions, the most common primary discharge diagnoses were heart failure (5.1%), pneumonia (5.0%), urinary tract infection (4.6%), chronic obstructive pulmonary disease (4.5%), and stroke (4.4%). The prevalence of the 20 most common conditions was significantly correlated across hospitals (correlation coefficients ranging from 0.55 to 0.95, p ≤ 0.01 for all comparisons). No single condition represented more than 5.1% of all admissions or more than 7.9% of admissions at any hospital site. The costliest conditions were stroke (median cost

Patient characteristics, resource use and outcomes associated with general internal medicine hospital care: the General Medicine Inpatient Initiative (GEMINI) retrospective cohort study

7122, interquartile range 5587–12,354, total cost

Communicating wisely: teaching residents to communicate effectively with patients and caregivers about unnecessary tests

94,199,422, representing 6.0% of all costs) and the group of delirium, dementia, and cognitive disorders (median cost

A two-site survey of clinicians to identify practices and preferences of intensive care unit transfers to general medical wards

12,831, IQR 9539–17,509, total cost

Improving the Appropriate Use of Transthoracic Echocardiography: The Echo WISELY Trial

77,372,541, representing 4.9% of all costs). The 10 most common conditions accounted for only 36.2% of hospitalizations and 36.8% of total costs. The remaining hospitalizations included 223 different CCS conditions.ConclusionsGIM services care for a markedly heterogeneous population but the most common conditions were similar across 7 hospitals. The diversity of conditions cared for in GIM may be challenging for healthcare delivery and quality improvement. Initiatives that cut across individual diseases to address processes of care, patient experience, and functional outcomes may be more relevant to a greater proportion of the GIM population than disease-specific efforts.

Frequency and clinical relevance of inconsistent code status documentation

BACKGROUND The precise scope of hospital care delivered under general internal medicine services remains poorly quantified. The purpose of this study was to describe the demographic characteristics, medical conditions, health outcomes and resource use of patients admitted to general internal medicine at 7 hospital sites in the Greater Toronto Area. METHODS This was a retrospective cohort study involving all patients who were admitted to or discharged from general internal medicine at the study sites between Apr. 1, 2010, and Mar. 31, 2015. Clinical data from hospital electronic information systems were linked to administrative data from each hospital. We examined trends in resource use and patient characteristics over the study period. RESULTS There were 136 208 admissions to general internal medicine involving 88 121 unique patients over the study period. General internal medicine admissions accounted for 38.8% of all admissions from the emergency department and 23.7% of all hospital bed-days. Over the study period, the number of admissions to general internal medicine increased by 32.4%; there was no meaningful change in the median length of stay or cost per hospital stay. The median patient age was 73 (interquartile range [IQR] 57-84) years, and the median number of coexisting conditions was 6 (IQR 3-9). The median acute length of stay was 4.6 (IQR 2.5-8.6) days, and the median total cost per hospital stay was