Unusual Pheochromocytoma Presentation: From Dysuria to Catecholamine Crisis.

Pheochromocytomas are catecholamine-secreting tumors that can present as a surgical emergency, with a mortality rate as high as 15%. When these lesions present as a crisis, diagnosis and management can be very challenging, given the profound physiologic consequences, such as cardiovascular collapse or multiple organ failure, occurring over a rapid time frame. We describe an unusual case of a pheochromocytoma presenting with urinary frequency and subsequent shock and tumor hemorrhage following a urological procedure. Our patient was successfully managed with resuscitation and appropriate blood pressure control to stabilize hemodynamics prior to proceeding with open adrenalectomy. Furthermore, our patient presented initially with urinary symptoms, which has not been described as an initial presentation of pheochromocytoma. This case brings important learning points regarding unusually presenting pheochromocytomas and emergency management to improve patient survival.

A phase I, first-in-human study to evaluate the safety and tolerability, pharmacokinetics, and pharmacodynamics of MRG-001 in healthy subjects.

Preclinical studies demonstrate that pharmacological mobilization and recruitment of endogenous bone marrow stem cells and immunoregulatory cells by a fixed-dose drug combination (MRG-001) improves wound healing, promotes tissue regeneration, and prevents allograft rejection. In this phase I, first-in-human study, three cohorts receive subcutaneous MRG-001 or placebo, every other day for 5 days. The primary outcome is safety and tolerability of MRG-001. Fourteen subjects received MRG-001 and seven received a placebo. MRG-001 is safe over the selected dose range. There are no clinically significant laboratory changes. The intermediate dose group demonstrates the most significant white blood cell, stem cell, and immunoregulatory cell mobilization. PBMC RNA sequencing and gene set enrichment analysis reveal 31 down-regulated pathways in the intermediate MRG-001 dose group compared with no changes in the placebo group. MRG-001 is safe across all dose ranges. MRG-001 may be a clinically useful therapy for immunoregulation and tissue regeneration (ClinicalTrials.gov: NCT04646603).

Effect of Physical Therapy and Rehabilitation Timing on Rotator Cuff Repair Revisions and Capsulitis.

INTRODUCTION: One variable that could potentially affect failure of a rotator cuff repair (RCR) is the timing of beginning physical therapy (PT) after the procedure. Although many studies have demonstrated decreased stiffness with beginning PT early, studies have also demonstrated that early PT increases repair failure. The goal of this study was to identify revision surgery and capsulitis rates after RCRs from an available database and determine whether an association was present with the timing of PT post-RCR. METHODS: Medicare patients within the PearlDiver database who underwent RCR were stratified based on the timing of their first PT session postoperatively, and revision surgery and capsulitis rates were determined among the groups for both open and arthroscopic RCR. Demographics and comorbidities of the cohort were also used to formulate a multivariate analysis for revision surgery rate. RESULTS: The cohort consisted of 64,842 patients who underwent RCR and started PT within 13 weeks of surgery. Starting PT within 1 week postoperatively resulted in a significantly higher revision surgery rate compared with starting PT in weeks 2 to 5, 6 to 9, or 10 to 13 (6.9% vs. 3.6% among all other groups, P = <0.001). The multivariate analysis for revision surgery further demonstrated that starting PT within 1 week postoperatively was associated with a significantly higher rate of revision surgery compared with beginning PT after 1 week (OR = 2.086, P < 0.001). No association was found between timing of beginning PT and capsulitis rates. CONCLUSION: In the Medicare patient cohort, beginning PT within 1 week postoperatively was associated with a significantly higher revision surgery rate; however, no associated benefit was noted in capsulitis rates for beginning PT early. This calls into question the use of an early passive range of motion protocol for older patient cohort; however, further studies should be completed to conclusively determine the most efficacious time to begin rehabilitation post-RCR. LEVEL OF EVIDENCE: Level III.

Heartburn Center Set-Up in a Community Setting: Engineering and Execution.

Background: Optimal management of gastroesophageal reflux disease (GERD) requires a concerted team of physicians rather than an individual approach. While an integrated approach to GERD has previously been proposed, the practical execution of such a "center of excellence" (COE) has not been described, particularly in a community setting. Ranging from initial consultation and diagnosis to surgical intervention for complex disease, such an approach is likely to provide optimal care and provide surveillance for patients with a complex disease process of GERD. Methods: We report our approach to implement an integrated heartburn center (HBC) and our experience with the first cohort of patients. Patients treated in the HBC were followed for 2 years from initial consultation to completion of their appropriate treatment plan, including anti-reflux surgery. The performance prior to the HBC set-up was compared to that post-HBC. Performance was measured in terms of volume of patients referred, referral patterns, length of stay (LOS), and patient health-related quality of life (HRQL) pre- and post-surgery. Results: Setting up the HBC resulted in referrals from multiple avenues, including primary care physicians (PCPs), emergency departments (EDs), and gastroenterologists (GIs). There was a 75% increase in referrals compared to pre-center patient volumes. Among the initial cohort of 832 patients presenting to the HBC, <10% had GERD for <1 year, ~60% had GERD for 1-11 years, and ~30% had GERD for ≥12 years. More than one-quarter had atypical GERD symptoms (27.6%). Only 6.4% had been on PPIs for <1 year and >20% had been on PPIs for ≥12 years. Thirty-eight patients were found to have Barrett's esophagus (4.6%) (up to 10 times the general population prevalence). Two patients had dysplasia. Seven patients (0.8%) received radiofrequency ablation (RFA) for Barrett's esophagus and two patients received endoscopic mucosal resection (EMR) for Barrett's esophagus-related dysplasia. The most common comorbidities were chronic pulmonary disease (16.8%) and diabetes without complications (10.6%). Patients received treatment for newly identified comorbid conditions, including early maladaptive schemas (EMS) and generalized anxiety disorder (GAD) (n = 7; 0.8%). Fifty cases required consultation with various specialists (6.0%) and 34 of those (4.1%) resulted in changes in care. Despite the significant increase in patient referrals, conversion rates from diagnosis to anti-reflux surgery remained consistent at ~25%. Overall HRQL improved year-over-year, and LOS was significantly reduced with potential cost savings for the larger institution. Conclusions: While centralization of GERD care is known to improve outcomes, in this case study we demonstrated the clinical success and commercial viability of centralizing GERD care in a community setting. The integrated GERD service line center offered a comprehensive, multi-specialty, and coordinated patient-centered approach. The approach is reproducible and may allow hospitals to set up their own heartburn COEs, strengthening patient-community relationships and establishing scientific and clinical GERD leadership.

Trends in Corticosteroid Injections for Treatment of Lateral Epicondylitis: An Analysis of 80,169 Patients.

INTRODUCTION: Corticosteroid (CS) injections are a frequently used treatment modality for lateral epicondylitis (LE) despite an increasing number of studies suggesting their lack of efficacy. The objective of this study was to review the annual utilization of CS injections for treatment of LE, as well as that of other nonsurgical treatments and surgical treatments, to understand how recent publications have affected the practice of physicians in treating LE. METHODS: Patients with LE from 2010 to 2017 were identified within a national insurance database and grouped by treatment modalities of CS injections, physical therapy, bracing treatment, and surgery. Epidemiologic and demographic data were reported using descriptive statistics. The number of patients receiving each treatment and the number of CS injections per patient were quantified for each year, and annual trends were analyzed using logistic regression. RESULTS: Among 80,169 qualifying patients, 16,476 received CS injections, 12,180 received physical therapy, 1,874 received bracing treatment, and 2,650 underwent surgery, with patients receiving multiple modalities being members of each respective group. We found a significant decrease in the proportion of patients with LE receiving CS injections from 23.3% in 2010 to 18.8% in 2017 (R2 = 0.956, P < 0.001). Interestingly, the number of CS injections per patient increased during this period from 1.33 to 1.83 (R2 = 0.843, P = 0.001). No notable changes in utilization trends for other modalities were found. DISCUSSION: Overall, our data support a decline in the use of CS injection as a treatment modality for LE from 2010 to 2017. Although correlational, this trend may reflect the increasing body of published evidence demonstrating the ineffectiveness of CS injections for the treatment of LE. In addition, the increasing number of injections per patient among those who received injections contrasts with the overall decrease in steroid utilization among all patients. Further study is needed to fully understand the mechanisms behind these trends.

Epigenetic down-regulation of microRNA-126 in scleroderma endothelial cells is associated with impaired responses to VEGF and defective angiogenesis.

Impaired angiogenesis in scleroderma (SSc) is a critical component of SSc pathology. MicroRNA-126 (miR-126) is expressed in endothelial cells (MVECs) where it regulates VEGF responses by repressing the negative regulators of VEGF, including the sprouty-related protein-1 (SPRED1), and phosphoinositide-3 kinase regulatory subunit 2 (PIK3R2). MVECs were isolated from SSc skin and matched subjects (n = 6). MiR-126 expression was measured by qPCR and in situ hybridization. Matrigel-based tube assembly was used to test angiogenesis. MiR-126 expression was inhibited by hsa-miR-126 inhibitor and enhanced by hsa-miR-126 Mimic. Epigenetic regulation of miR-126 expression was examined by the addition of epigenetic inhibitors (Aza and TSA) to MVECs and by bisulphite genomic sequencing of DNA methylation of the miR-126 promoter region. MiR-126 expression, as well as EGFL7 (miR-126 host gene), in SSc-MVECs and skin, was significantly down-regulated in association with increased expression of SPRED1 and PIK3R2 and diminished response to VEGF. Inhibition of miR-126 in NL-MVECs resulted in reduced angiogenic capacity, whereas overexpression of miR-126 in SSc-MVECs resulted in enhanced tube assembly. Addition of Aza and TSA normalized miR-126 and EGFL7 expression levels in SSc-MVECs. Heavy methylation in miR-126/EGFL7 gene was noted. In conclusion, these results demonstrate that the down-regulation of miR-126 results in impaired VEGF responses.

An Innovative Ventricular Assist Device Strategy as a Bridge-to-Recovery in an Infant with Glenn Physiology.

Mechanical circulatory support for infants with single ventricle physiology remains challenging. Utilization of a ventricular assist device (VAD) has potential advantages over extracorporeal circulatory membrane oxygenation. As such, VAD utilization in single ventricle patients with refractory heart failure continues to be explored. Herein, we describe a novel VAD strategy to support an infant with Glenn physiology who presented in cardiogenic shock related to myocardial depression of unknown etiology. This VAD configuration supported the systemic circulation independent of the Glenn circulation. Seven days of VAD support resulted in recovery of myocardial and end-organ function leading to VAD removal. The patient remains alive and free from transplantation 16 months post VAD explantation.

Ondansetron does not prevent physical dependence in patients taking opioid medications chronically for pain control.

OBJECTIVES: In this study, we investigated the co-administration of ondansetron with morphine, and whether it could prevent the development of physical dependence in patients taking opioids for the treatment of chronic pain. METHODS: A total of 48 chronic back pain patients (N = 48) participated in this double-blinded, placebo-controlled, randomized study. Patients were titrated onto sustained-release oral morphine and randomized to take 8 mg ondansetron or placebo three times daily concurrently with morphine during the 30-day titration. Following titration, patients underwent Naloxone induced opioid withdrawal. Opioid withdrawal signs and symptoms were then assessed by a blinded research assistant (objective opioid withdrawal score: OOWS) and by the research participant (subjective opioid withdrawal score: SOWS). RESULTS: We observed clinically significant signs of naloxone-precipitated opioid withdrawal in all participants (ΔOOWS = 4.3 ±â€¯2.4, p < 0.0001; ΔSOWS = 14.1 ±â€¯11.7, p < 0.0001), however no significant differences in withdrawal scores were detected between treatment groups. CONCLUSION: We hypothesized that ondansetron would prevent the development of physical dependence in human subjects when co-administered with opioids, but found no difference in naloxone-precipitated opioid withdrawal scores between ondansetron and placebo treatment groups. These results suggest that further studies are needed to determine if 5HT3 receptor antagonists are useful in preventing opioid physical dependence.

Ondansetron Does Not Reduce Withdrawal in Patients With Physical Dependence on Chronic Opioid Therapy.

OBJECTIVES: Individuals taking opioids for an extended period of time may become physically dependent, and will therefore experience opioid withdrawal should they stop taking the medication. Previous work in animal and human models has shown that the serotonin (5-HT3) receptor may be implicated in opioid withdrawal. In this study, we investigated if ondansetron, a 5-HT3-receptor antagonist, could reduce the symptoms of opioid withdrawal after chronic opioid exposure in humans. METHODS: In this double-blinded, randomized, crossover study, 33 chronic back pain patients (N = 33) were titrated onto sustained-release oral morphine for 30 days. After titration, participants attended 2 study sessions, 1 week apart, in which opioid withdrawal was induced with intravenous naloxone, with or without 8 mg intravenous ondansetron pretreatment. Opioid withdrawal symptoms were assessed by a blinded research assistant (objective opioid withdrawal score [OOWS]) and by the research participant (subjective opioid withdrawal score [SOWS]). RESULTS: Clinically significant signs of withdrawal were observed during both the ondansetron (ΔOOWS = 3.58 ±â€Š2.22, P < 0.0001; ΔSOWS = 12.48 ±â€Š11.18, P < 0.0001) and placebo sessions (ΔOOWS = 3.55 ±â€Š2.39, P < 0.0001; ΔSOWS = 12.21 ±â€Š10.72, P < 0.0001), but no significant differences were seen between the treatment sessions in either the OOWS or SOWS scores. CONCLUSION: We hypothesized that ondansetron would reduce opioid withdrawal symptoms in human subjects, but found no difference in withdrawal severity between ondansetron and placebo sessions. These findings suggest that more investigation may be necessary to determine if 5-HT3-receptor antagonists are suitable treatment options for opioid withdrawal.

One Month of Oral Morphine Decreases Gray Matter Volume in the Right Amygdala of Individuals with Low Back Pain: Confirmation of Previously Reported Magnetic Resonance Imaging Results.

OBJECTIVE: Prolonged exposure to opioids is known to produce neuroplastic changes in animals; however, few studies have investigated the effects of short-term prescription opioid use in humans. A previous study from our laboratory demonstrated a dosage-correlated volumetric decrease in the right amygdala of participants administered oral morphine daily for 1 month. The purpose of this current study was to replicate and extend the initial findings. METHODS: Twenty-one participants with chronic low back pain were enrolled in this double-blind, placebo-controlled study. Participants were randomized to receive daily morphine (n = 11) or a matched placebo (n = 10) for 1 month. High-resolution anatomical images were acquired immediately before and after the treatment administration period. Morphological gray matter changes were investigated using tensor-based morphometry, and significant regions were subsequently tested for correlation with morphine dosage. RESULTS: Decreased gray matter volume was observed in several reward- and pain-related regions in the morphine group, including the bilateral amygdala, left inferior orbitofrontal cortex, and bilateral pre-supplementary motor areas. Morphine administration was also associated with significant gray matter increases in cingulate regions, including the mid cingulate, dorsal anterior cingulate, and ventral posterior cingulate. CONCLUSIONS: Many of the volumetric increases and decreases overlapped spatially with the previously reported changes. Individuals taking placebo for 1 month showed neither gray matter increases nor decreases. The results corroborate previous reports that rapid alterations occur in reward-related networks following short-term prescription opioid use.

Acute opioid withdrawal is associated with increased neural activity in reward-processing centers in healthy men: A functional magnetic resonance imaging study.

BACKGROUND: Opioid analgesics are frequently prescribed for chronic pain. One expected consequence of long-term opioid use is the development of physical dependence. Although previous resting state functional magnetic resonance imaging (fMRI) studies have demonstrated signal changes in reward-associated areas following morphine administration, the effects of acute withdrawal on the human brain have been less well-investigated. In an earlier study by our laboratory, ondansetron was shown to be effective in preventing symptoms associated with opioid withdrawal. The purpose of this current study was to characterize neural activity associated with acute opioid withdrawal and examine whether these changes are modified by ondansetron. METHODS: Ten participants were enrolled in this placebo-controlled, randomized, double-blind, crossover study and attended three acute opioid withdrawal sessions. Participants received either placebo or ondansetron (8Ymg IV) before morphine administration (10Ymg/70Ykg IV). Participants then underwent acute naloxone-precipitated withdrawal during a resting state fMRI scan. Objective and subjective opioid withdrawal symptoms were assessed. RESULTS: Imaging results showed that naloxone-precipitated opioid withdrawal was associated with increased neural activity in several reward processing regions, including the right pregenual cingulate, putamen, and bilateral caudate, and decreased neural activity in networks involved in sensorimotor integration. Ondansetron pretreatment did not have a significant effect on the imaging correlates of opioid withdrawal. CONCLUSIONS: This study presents a preliminary investigation of the regional changes in neural activity during acute opioid withdrawal. The fMRI acute opioid withdrawal model may serve as a tool for studying opioid dependence and withdrawal in human participants.

Multimodal ultrasound-photoacoustic imaging of tissue engineering scaffolds and blood oxygen saturation in and around the scaffolds.

Preclinical, noninvasive imaging of tissue engineering polymeric scaffold structure and/or the physiological processes such as blood oxygenation remains a challenge. In vitro or ex vivo, the widely used scaffold characterization modalities such as porosimetry, electron or optical microscopy, and X-ray microcomputed tomography have limitations or disadvantages-some are invasive or destructive, others have limited tissue penetration (few hundred micrometers) and/or show poor contrast under physiological conditions. Postmortem histological analysis, the most robust technique for the evaluation of neovascularization is obviously not appropriate for acquiring physiological or longitudinal data. In this study, we have explored the potential of ultrasound (US)-coregistered photoacoustic (PA) imaging as a noninvasive multimodal imaging modality to overcome some of the above challenges and/or provide complementary information. US-PA imaging was employed to characterize poly(lactic-co-glycolic acid) (PLGA) polymer scaffolds or single-walled carbon nanotube (SWCNT)-incorporated PLGA (SWCNT-PLGA) polymer scaffolds as well as blood oxygen saturation within and around the scaffolds. Ex vivo, PLGA and SWCNT-PLGA scaffolds were placed at 0.5, 2, and 6 mm depths in chicken breast tissues. PLGA scaffolds could be localized with US imaging, but generate no PA signal (excitation wavelengths 680 and 780 nm). SWCNT-PLGA scaffolds generated strong PA signals at both wavelengths due to the presence of the SWCNTs and could be localized with both US and PA imaging depths between 0.5-6 mm (lateral resolution = 90 µm, axial resolution = 40 µm). In vivo, PLGA and SWCNT-PLGA scaffolds were implanted in subcutaneous pockets at 2 mm depth in rats, and imaged at 7 and 14 days postsurgery. The anatomical position of both the scaffolds could be determined from the US images. Only SWCNT-PLGA scaffolds could be easily detected in the US-PA images. SWCNT-PLGA scaffolds had significant four times higher PA signal intensity compared with the surrounding tissue and PLGA scaffolds. In vivo blood oxygen saturation maps around and within the PLGA scaffolds could be obtained by PA imaging. There was no significant difference in oxygen saturation for the PLGA scaffolds at the two time points. The blood oxygen saturation maps complemented the histological analysis of neovascularization of the PLGA scaffolds.

Development and initial application of a fully integrated photoacoustic micro-ultrasound system.

Photoacoustic (PA) imaging for biomedical applications has been under development for many years. Based on the many advances over the past decade, a new photoacoustic imaging system has been integrated into a micro-ultrasound platform for co-registered PA-ultrasound (US) imaging. The design and implementation of the new scanner is described and its performance quantified. Beamforming techniques and signal processing are described, in conjunction with in vivo PA images of normal subcutaneous mouse tissue and selected tumor models. In particular, the use of the system to estimate the spatial distribution of oxygen saturation (sO2) in blood and co-registered with B-mode images of the surrounding anatomy are investigated. The system was validated in vivo against a complementary technique for measuring partial pressure of oxygen in blood (pO2). The pO2 estimates were converted to sO2 values based on a standard dissociation curve found in the literature. Preliminary studies of oxygenation effects were performed in a mouse model of breast cancer (MDA-MB-231) in which control mice were compared with mice treated with a targeted antiangiogenic agent over a 3 d period. Treated mice exhibited a >90% decrease in blood volume, an 85% reduction in blood wash-in rate, and a 60% decrease in relative tissue oxygenation.

The modulation of endothelial cell morphology, function, and survival using anisotropic nanofibrillar collagen scaffolds.

Endothelial cells (ECs) are aligned longitudinally under laminar flow, whereas they are polygonal and poorly aligned in regions of disturbed flow. The unaligned ECs in disturbed flow fields manifest altered function and reduced survival that promote lesion formation. We demonstrate that the alignment of the ECs may directly influence their biology, independent of fluid flow. We developed aligned nanofibrillar collagen scaffolds that mimic the structure of collagen bundles in blood vessels, and examined the effects of these materials on EC alignment, function, and in vivo survival. ECs cultured on 30-nm diameter aligned fibrils re-organized their F-actin along the nanofibril direction, and were 50% less adhesive for monocytes than the ECs grown on randomly oriented fibrils. After EC transplantation into both subcutaneous tissue and the ischemic hindlimb, EC viability was enhanced when ECs were cultured and implanted on aligned nanofibrillar scaffolds, in contrast to non-patterned scaffolds. ECs derived from human induced pluripotent stem cells and cultured on aligned scaffolds also persisted for over 28 days, as assessed by bioluminescence imaging, when implanted in ischemic tissue. By contrast, ECs implanted on scaffolds without nanopatterning generated no detectable bioluminescent signal by day 4 in either normal or ischemic tissues. We demonstrate that 30-nm aligned nanofibrillar collagen scaffolds guide cellular organization, modulate endothelial inflammatory response, and enhance cell survival after implantation in normal and ischemic tissues.

PU.1-dependent transcriptional regulation of miR-142 contributes to its hematopoietic cell-specific expression and modulation of IL-6.

MicroRNAs (miRs) have emerged as critical modulators of immune responses, but little is known about their transcriptional regulation and tissue specificity. miR-142 is specifically expressed in hematopoietic tissues and plays an important role in regulating immunity. In this study we identified the key transcriptional elements for regulation of miR-142 and its impact on TLR4-mediated expression of IL-6. The PU.1, C/EBPß, and Runx1 transcription factor binding sites are conserved and constitutively occupied by the respective transcription factors in the miR-142 gene promoter only in the hematopoietic cells. Specific knockdown experiments in hematopoietic cells and rescue experiments in nonhematopoietic cells show that PU.1 is critical for miR-142 gene expression and that it synergizes with Runx1, C/EBPß, and CBFß. Furthermore, TLR4 stimulation enhanced miR-155 whereas experiments with knockdown and mimic expression of miR-155 demonstrated that miR-155 negatively regulates miR-142-3p expression by targeting PU.1. Thus, TLR4 stimulation represses PU.1, resulting in downregulation of miR-142 and increased expression of IL-6. These results collectively reveal the direct cis-acting sequences of miR-142 specific promoter and that transcription factor PU.1 is necessary for its exclusive expression in hematopoietic cells and regulation of IL-6.

Mobile computing in medical education: opportunities and challenges.

PURPOSE OF REVIEW: There is an increasing importance of incorporating mobile computing into the academic medical environment. A growing majority of physicians, residents and medical students currently use mobile devices for education, access to clinical information and to facilitate bedside care. Therefore, it is important to assess the current opportunities and challenges in the use of mobile computing devices in the academic medical environment. RECENT FINDINGS: Current research has found that a majority of physicians, residents and medical students either own or use mobile devices. In addition, studies have shown that these devices are effective as educational tools, resource guides and aids in patient care. Although there are opportunities for medical education, issues of deployment must still be addressed, such as privacy, connectivity, standardization and professionalism. SUMMARY: Understanding the opportunities and challenges of using mobile computing devices in the academic medical environment can help determine the feasibility and benefits of their use for individuals and institutions.

Information technology and its role in anaesthesia training and continuing medical education.

Today's educators are faced with substantial challenges in the use of information technology for anaesthesia training and continuing medical education. Millennial learners have uniquely different learning styles than previous generations of students. These preferences distinctly incorporate the use of digital information technologies and social technologies to support learning. To be effective teachers, modern educators must be familiar with these new information technologies and understand how to use them for medical education. Examples of new information technologies include learning management systems, lecture capture, social media (YouTube, Flickr), social networking (Facebook), Web 2.0, multimedia (video learning triggers and point-of-view video) and mobile computing applications. The information technology challenges for educators in the twenty-first century include: (a) understanding how technology shapes the learning preferences of today's anaesthesia residents, (b) distinguishing between the function and properties of new learning technologies and (c) properly using these learning technologies to enhance the anaesthesia curriculum.

Low-dose metronomic oral dosing of a prodrug of gemcitabine (LY2334737) causes antitumor effects in the absence of inhibition of systemic vasculogenesis.

Metronomic chemotherapy refers to the close, regular administration of conventional chemotherapy drugs at relatively low, minimally toxic doses, with no prolonged break periods; it is now showing encouraging results in various phase II clinical trials and is currently undergoing phase III trial evaluation. It is thought to cause antitumor effects primarily by antiangiogenic mechanisms, both locally by targeting endothelial cells of the tumor neovasculature and systemically by effects on bone marrow-derived cells, including circulating endothelial progenitor cells (CEP). Previous studies have shown reduction of CEPs by metronomic administration of a number of different chemotherapeutic drugs, including vinblastine, cyclophosphamide, paclitaxel, topotecan, and tegafur plus uracil (UFT). However in addition to, or even instead of, antiangiogenic effects, metronomic chemotherapy may cause suppression of tumor growth by other mechanisms such as stimulating cytotoxic T-cell responses or by direct antitumor effects. Here we report results evaluating the properties of metronomic administration of an oral prodrug of gemcitabine LY2334737 in nontumor-bearing mice and in preclinical models of human ovarian (SKOV3-13) and breast cancer (LM2-4) xenografts. Through daily gavage (at 6 mg/kg/d), the schedules tested were devoid of toxicity and caused antitumor effects; however, a suppressive effect on CEPs was not detected. Unexpectedly, metronomic LY2334737 administration caused increased blood flow in luciferase-tagged LM2-4 tumor xenografts, and this effect, readily measured using contrast micro-ultrasound, coincided with a relative increase in tumor bioluminescence. These results highlight the possibility of significant antitumor effects mediated by metronomic administration of some chemotherapy drugs without a concomitant inhibition of systemic angiogenesis.