Making connections: using anatomy to guide tissue engineering approaches at the enthesis.

The enthesis demonstrates a distinct highly ordered zonal microanatomy at the osteotendinous/osteoligamentous tissue connection that allows for the smooth transmission of mechanical forces between tissues. Interfacial tissue engineering (ITE), a subset of the interdisciplinary field of tissue engineering, is directed at replicating this complex transitional anatomy of the enthesis in vitro. Yet, the limited understanding of tissue boundaries, gradients and structural relationships at specific anatomical locations hampers the development of novel therapeutic strategies for bespoke enthesis regeneration, thus reducing their direct clinical applicability. This review provides an overview of ITE approaches for repair of the osteotendinous/osteoligamentous junction and highlights the importance of complementary inclusion of direct anatomical research. The cross-disciplinary collaboration across an array of experts, including anatomists, involved in the design, development and utilisation of bioengineered tissues will enhance the properties of such tissues and improve their clinical relevance. More specifically, a detailed anatomical analysis of the region of interest should drive the in vitro design and enable researchers to develop anatomically and clinically relevant tissue-engineered replacement tissues for human implantation. Finally, the present review discusses the challenges and future directions of the ITE field and highlights the importance of anatomically driven tissue engineering as an emerging tool in clinical translational research.

Production of clovamide and its analogues in Saccharomyces cerevisiae and Lactococcus lactis.

Clovamide and its analogues are N-hydroxycinnamoyl-L-amino acids (HAA) that exhibit antioxidant activities. For environmental and economic reasons, biological synthesis of these plant-derived metabolites has garnered interest. In this study, we exploited HDT1, a BAHD acyltransferase recently isolated from red clover, for the production of clovamide and derivatives in S. cerevisiae and L. lactis. HDT1 catalyses the transfer of hydroxycinnamoyl-coenzyme A (CoA) onto aromatic amino acids. Therefore, by heterologously co-expressing HDT1 with 4-coumarate:CoA ligase (4CL), we succeeded in the biological production of clovamide and more than 20 other HAA, including halogenated ones, upon feeding the engineered micro-organisms with various combinations of cinnamates and amino acids. To the best of our knowledge, this is the first report on the biological synthesis of HAA and, more generally, on the synthesis of plant-derived antioxidant phenolic compounds in L. lactis. The production of these health beneficial metabolites in Generally Recognized As Safe (GRAS) micro-organisms such as S. cerevisiae and L. lactis provides new options for their delivery as therapeutics. SIGNIFICANCE AND IMPACT OF THE STUDY: N-hydroxycinnamoyl-L-amino acids such as clovamide are bioactive plant-derived phenolic compounds with health beneficial effects. Relying on chemical synthesis or direct extraction from plant sources for the supply of these valuable molecules poses challenges to environmental sustainability. As an alternative route, this work demonstrates the potential for biological synthesis of N-hydroxycinnamoyl-L-amino acids using engineered microbial hosts such as Saccharomyces cerevisiae and Lactococcus lactis. Besides being more eco-friendly, this approach should also provide more structurally diverse compounds and offer new methods for their delivery to the human body.

Phase I study of the halichondrin B analogue eribulin mesylate in combination with cisplatin in advanced solid tumors.

BACKGROUND: Eribulin mesylate is a synthetic macrocyclic ketone analogue of Halichondrin B that has demonstrated high antitumor activity in preclinical and clinical settings. This phase I study aimed to determine the maximum tolerated dose (MTD), dose-limiting toxicities (DLTs), and pharmacokinetics in combination with cisplatin (CP) in patients with advanced solid tumours. METHODS: Thirty-six patients with advanced solid tumours received eribulin mesylate 0.7-1.4 mg m(-2) and CP 60-75 mg m(-2). Eribulin mesylate was administered on days 1, 8, and 15 in combination with CP day 1 every 28-day cycle. The protocol was amended after dose level 4 (eribulin mesylate 1.4 mg m(-2), CP 60 mg m(-2)) when it was not feasible to administer eribulin mesylate on day 15 because of neutropenia; the treatment schedule was changed to eribulin mesylate on days 1 and 8 and CP on day 1 every 21 days. RESULTS: On the 28-day schedule, three patients had DLT during the first cycle: grade (G) 4 febrile neutropenia (1.0 mg m(-2), 60 mg m(-2)); G 3 anorexia/fatigue/hypokalemia (1.2 mg m(-2), 60 mg m(-2)); and G 3 stomatitis/nausea/vomiting/fatigue (1.4 mg m(-2), 60 mg m(-2)). On the 21-day schedule, three patients had DLT during the first cycle: G 3 hypokalemia/hyponatremia (1.4 mg m(-2), 60 mg m(-2)); G 4 mucositis (1.4 mg m(-2), 60 mg m(-2)); and G 3 hypokalemia (1.2 mg m(-2), 75 mg m(-2)). The MTD and recommended phase II dose was determined as eribulin mesylate 1.2 mg m(-2) (days 1, 8) and CP 75 mg m(-2) (day 1), on a 21-day cycle. Two patients had unconfirmed partial responses (PR) (pancreatic and breast cancers) and two had PR (oesophageal and bladder cancers). CONCLUSIONS: On the 21-day cycle, eribulin mesylate 1.2 mg m(-2), administered on days 1 and 8, in combination with CP 75 mg m(-2), administered on day 1 is well tolerated and showed preliminary anticancer activity.

Sport stacking in auditory and visual attention of grade 3 learners.

The effect of sport stacking on auditory and visual attention in 32 Grade 3 children was examined using a randomised, cross-over design. Children were randomly assigned to a sport stacking (n=16) or arts/crafts group (n=16) with these activities performed over 3 wk. (12 30-min. sessions, 4 per week). This was followed by a 3-wk. wash-out period after which there was a cross-over and the 3-wk. intervention repeated, with the sports stacking group performing arts/crafts and the arts/crafts group performing sports stacking. Performance on the Integrated Visual and Auditory Continuous Performance Test, a measure of auditory and visual attention, was assessed before and after each of the 3-wk. interventions for each group. Comparisons indicated that sport stacking resulted in significant improvement in high demand function and fine motor regulation, while it caused a significant reduction in low demand function. Auditory and visual attention adaptations to sport stacking may be specific to the high demand nature of the task.

Hip surgery and radiology reporting for children with cerebral palsy prior to initiation of a hip surveillance program.

PURPOSE: Hip displacement impacts quality of life for many children with cerebral palsy (CP). While early detection can help avoid dislocation and late-stage surgery, formalized surveillance programs are not ubiquitous. This study aimed to examine: 1) surgical practices around pediatric hip displacement for children with CP in a region without formalized hip surveillance; and 2) utility of MP compared to traditional radiology reporting for quantifying displacement. METHODS: A retrospective chart review examined hip displacement surgeries performed on children with CP between 2007-2016. Surgeries were classified as preventative, reconstructive, or salvage. Pre- and post-operative migration percentage (MP) was calculated for available radiographs using a mobile application and compared using Wilcoxon Signed Ranks test. MPs were also compared with descriptions in the corresponding radiology reports using directed and conventional content analyses. RESULTS: Data from 67 children (115 surgical hips) were included. Primary surgery types included preventative (63.5% hips), reconstructive (36.5%), or salvage (0%). For the 92 hips with both radiology reports and radiographs available, reports contained a range of descriptors that inconsistently reflected the retrospectively-calculated MPs. CONCLUSION: Current radiology reporting practices do not appear to effectively describe hip displacement for children with CP. Therefore, standardized reporting of MP is recommended.

Perceptions and work-readiness of Australian physiotherapists in cancer care: a national evaluation.

OBJECTIVES: Physiotherapy interventions can improve health outcomes for people across the cancer continuum yet little is known of the work-readiness and perceptions of physiotherapists working in cancer care. This study described perceptions of Australian physiotherapists. DESIGN: Electronic, national cross-sectional survey. SETTING: One hundred nineteen Australian hospitals and 35 rehabilitation programmes in July 2019 were invited. PARTICIPANTS: Clinical physiotherapists responsible for the provision of cancer care. MAIN OUTCOME MEASURES: Custom-designed survey targeted clinical knowledge, physiotherapy management, physical activity/exercise, and learning/preparedness. Relationships between domains and demographic characteristics eg: clinical experience and work setting, were analysed. RESULTS: One hundred twenty eight surveys were completed. Median [IQR] experience was 8 [4 to 19] years (2 [0.5 to 5] years specifically in oncology). Most participants (99/128, 77%) felt poorly prepared to commence work in oncology. Confidence was consistently lower among physiotherapists in their first year compared to others. Confidence and knowledge was rated high for people with early stage cancers (median 4 [3 to 5]) and lower for prescribing exercise for patients with cardiotoxicity and knowledge of precautions/contraindications regarding hormone and targeted therapies (median 2 [1 to 3]). High importance ratings (Likert scores 4 or 5) were reported for exercise (115/127, 91%) and physical activity (120/126, 95%). Learning needs were identified for medical management, treatment side-effects/precautions and management of cancer-related pain and fatigue. CONCLUSION: Australian physiotherapists feel underprepared to work in cancer care, but report good confidence and knowledge. Professional development opportunities appear indicated.

The Biplanar Effect of the Medial Cuneiform Osteotomy.

Background. The "foot-CORA" (center of rotation of angulation) method confirms the medial cuneiform as the site of deformity in most forefoot/midfoot deformities and is therefore the ideal location to correct those deformities. It has been consistently observed intraoperatively by the senior author that there is a secondary, unintentional deformity created in the transverse plane when dorsiflexion and plantar flexion osteotomies of the medial cuneiform are performed to correct pronation and supination forefoot deformities, respectively. These effects may not be desirable. This biplanar effect of medial cuneiform osteotomies has been observed but not studied. The purpose of this study was to perform the 4 commonly used medial cuneiform osteotomy techniques on cadaveric feet to demonstrate their biplanar effects. Methods. Four formaldehyde preserved cadaveric feet were used to perform 4 techniques of medial cuneiform osteotomy: dorsiflexion plantar-based opening wedge, plantar flexion dorsal-based opening wedge, dorsiflexion dorsal-based closing wedge, and plantar flexion plantar-based closing wedge. Photographs and fluoroscopy were used to assess the angular changes in the sagittal and transverse planes. Angular measurements were made using OsiriX software on fluoroscopic images. Results. The medial cuneiform opening wedge osteotomies produced midfoot abduction in addition to the desired dorsiflexion and plantar flexion. The medial cuneiform closing wedge osteotomies produced midfoot adduction in addition to the desired dorsiflexion and plantar flexion. Conclusion. We confirm that intentional sagittal uniplanar osteotomies of the medial cuneiform create obligate biplanar effects. This is likely a result of tethering by ligaments and the joint capsules on the lateral border of the medial cuneiform. The obligate transverse plane effect can be used to one's advantage or result in an undesired effect if not considered during surgical planning and execution. We propose a simple treatment algorithm for selecting the appropriate medial cuneiform osteotomy for forefoot/midfoot deformities. Levels of Evidence: Level V.

Generation of unidirectionally propagated action potentials in a peripheral nerve by brief stimuli.

Single, unidirectionally propagated action potentials can be elicited in peripheral nerves by electrical stimuli of short duration. Propagation in one direction is blocked anodically by means of a quasi-trapezoidal stimulus wave form and a modified tripolar electrode configuration. Propagation in the other direction proceeds unhindered. This technique may be applicable to collision blocking of motor nerves for neural prostheses.

Electron transfer processes occurring on platinum neural stimulating electrodes: pulsing experiments for cathodic-first, charge-imbalanced, biphasic pulses for 0.566 ⩽ k ⩽ 2.3 in rat subcutaneous tissues.

OBJECTIVE: Charge injection through platinum neural stimulation electrodes is often constrained by the Shannon limit (Shannon 1992 IEEE Trans. Biomed. Eng. 39 424-6) of k = 1.75. By leveraging the tools of electrochemistry to better understand the reactions at electrode-tissue interface, we endeavor to find a way to safely inject more charge than allowed if the traditional Shannon limit were followed. APPROACH: In previous studies on platinum electrodes using charge-balanced, cathodic-first, biphasic pulses, we noted that during the secondary anodic phase, the electrode potential moves into a range where platinum dissolution is possible when charge injection is greater than k = 1.75. Platinum dissolution products are known to be toxic to brain tissues. We hypothesize that by injecting less charge in the anodic phase than the cathodic phase, the anodic potential excursions will decrease, thereby avoiding potentials where platinum dissolution is more likely. MAIN RESULTS: Our findings show that using these charge-imbalanced pulses decreases the anodic potential excursions to a level where platinum oxidation and dissolution are less likely, and aligns the anodic potentials with those observed with charge-balanced stimulation at k < 1.75-a range widely accepted as safe for stimulation with platinum. SIGNIFICANCE: From these results, we further hypothesize that charge-imbalanced biphasic stimulation would permit more charge to be safely injected through platinum electrodes than would be permitted if the dogma of charge-balanced biphasic stimuli were followed. Testing this hypothesis in cat brain in the same manner as the experiments that formed the basis for the Shannon plot could open the door for safe charge injection through platinum electrodes at levels greater than k = 1.75.

Linear summation of torque produced by selective activation of two motor fascicles.

Linear summation of torque was observed while applying selective activation to two different motor fascicles in the cat sciatic nerve. The excitatory stimulus was applied to two or more contacts housed in a four contact self-sizing spiral cuff electrode. To achieve a linear summation of torque, a delay between the two stimuli that was longer than the length of the facilitatory period but less than the length of the refractory period was used. Using a 900-micros delay between pulses, linear summation of two different torque outputs was successfully achieved in 125 out of 129 trials across five cats. These trials were performed using cuff electrodes that were in place for periods ranging up to 352 days. The results of these studies support the hypothesis that a single self-sizing spiral cuff with multiple contacts and a single lead may be used in place of several muscle-based electrodes each with its own separate lead.

Electron transfer processes occurring on platinum neural stimulating electrodes: pulsing experiments for cathodic-first, charge-balanced, biphasic pulses for 0.566 ⩽ k ⩽ 2.3 in rat subcutaneous tissues.

OBJECTIVE: Our mission is twofold: (1) find a way to safely inject more charge through platinum electrodes than the Shannon limit (k = 1.75) permits and (2) nurture an interest in the neural stimulation community to understand the electron transfer process occurring on neural stimulating electrodes. APPROACH: We report here on measurements of the electrode potential, performed on platinum neural stimulating electrodes in the subcutaneous space of an anesthetized rat under neural stimulation conditions. MAIN RESULTS: The results for six platinum electrodes with areas ranging from 0.2 mm2 to 12.7 mm2 were similar to prior results in sulfuric acid, except that the measured potentials were shifted negative 0.36 V because of the pH difference between the two media. The anodic 'end' potential, measured at t = 20 ms after the onset of the biphasic current pulse, was the primary focus of the data collected because previous results had shown that as charge injection crosses the Shannon limit (k = 1.75), this potential moves into a range where platinum surface oxidation and dissolution is likely to occur. The behavior of V e(t = 20 ms) over a range of electrode surface areas studied was consistent with our sulfuric acid study. Implicit, but little noticed, in Shannon's formulation is that small and large platinum electrodes behave the same in terms of k value; our data supports this idea. SIGNIFICANCE: We hypothesize that the k = 1.75 Shannon limit for safe stimulation designates a charge-injection boundary above which platinum toxicity becomes a relevant consideration for living cells around an electrode, a possibility that can be directly tested, and is a vital step forward in mission (1).

Electron transfer processes occurring on platinum neural stimulating electrodes: calculated charge-storage capacities are inaccessible during applied stimulation.

OBJECTIVE: Neural prostheses employing platinum electrodes are often constrained by a charge/charge-density parameter known as the Shannon limit. In examining the relationship between charge injection and observed tissue damage, the electrochemistry at the electrode-tissue interface should be considered. The charge-storage capacity (CSC) is often used as a predictor of how much charge an electrode can inject during stimulation, but calculating charge from a steady-state i-E curve (cyclic voltammogram) over the water window misrepresents how electrodes operate during stimulation. We aim to gain insight into why CSC predictions from classic i-E curves overestimate the amount of charge that can be injected during neural stimulation pulsing. APPROACH: In this study, we use a standard electrochemical technique to investigate how platinum electrochemistry depends on the potentials accessed by the electrode and on the electrolyte composition. MAIN RESULTS: The experiments indicate: (1) platinum electrodes must be subjected to a 'cleaning' procedure in order to expose the maximum number of surface platinum sites for hydrogen adsorption; (2) the 'cleaned' platinum surface will likely revert to an obstructed condition under typical neural stimulation conditions; (3) irreversible oxygen reduction may occur under neural stimulation conditions, so the consequences of this reaction should be considered; and (4) the presence of the chloride ion (Cl-) or proteins (bovine serum albumin) inhibits oxide formation and alters H adsorption. SIGNIFICANCE: These observations help explain why traditional CSC calculations overestimate the charge that can be injected during neural stimulation. The results underscore how careful electrochemical examination of the electrode-electrolyte interface can result in more accurate expectations of electrode performance during applied stimulation.

A pilot service-evaluation examining change in HbA1c related to the prescription of internet-based education films for type 2 diabetes.

We undertook a pilot service-evaluation of prescribed internet-based patient education films for patients with type 2 diabetes. The uptake was 28% and film watching was associated with a relative mean difference in HbA1c of -9.0mmol/mol in the film watchers compared to non-watchers over a three-month period (P=0.0008).

Electron transfer processes occurring on platinum neural stimulating electrodes: pulsing experiments for cathodic-first/charge-balanced/biphasic pulses for 0.566 ≤ k ≤ 2.3 in oxygenated and deoxygenated sulfuric acid.

The application of a train of cathodic-first/charge-balanced/biphasic pulses applied to a platinum electrode resulted in a positive creep of the anodic phase potential that increases with increasing charge injection but reaches a steady-state value before 1000 pulses have been delivered. The increase follows from the fact that charge going into irreversible reactions occurring during the anodic phase must equal the charge going into irreversible reactions during the cathodic phase for charge-balanced pulses. In an oxygenated electrolyte the drift of the measured positive potential moved into the platinum oxidation region of the i(V e) profile when the charge injection level exceeds k = 1.75. Platinum dissolution may occur in this region and k = 1.75 defines a boundary between damaging and non-damaging levels on the Shannon Plot. In a very low oxygen environment, the positive potential remained below the platinum oxidation region for the highest charge injection values studied, k = 2.3. The results support the hypothesis that platinum dissolution is the defining factor for the Shannon limit, k = 1.75. Numerous instrumentation issues were encountered in the course of making measurements. The solutions to these issues are provided.

Electron transfer processes occurring on platinum neural stimulating electrodes: a tutorial on the i(V e) profile.

The aim of this tutorial is to encourage members of the neuroprosthesis community to incorporate electron transfer processes into their thinking and provide them with the tools to do so when they design and work with neurostimulating devices. The focus of this article is on platinum because it is the most used electrode metal for devices in commercial use. The i(V e) profile or cyclic voltammogram contains information about electron transfer processes that can occur when the electrode-electrolyte interface, V e, is at a specific potential, and assumed to be near steady-state conditions. For the engineer/designer this means that if the potential is not in the range of a specific electron transfer process, that process cannot occur. An i(V e) profile, recorded at sweep rates greater than 0.1 mVs(-1), approximates steady-state conditions. Rapid transient potential excursions, like that seen with neural stimulation pulses, may be too fast for the reaction to occur, however, this means that if the potential is in the range of a specific electron transfer process it may occur and should be considered. The approach described here can be used to describe the thermodynamic electron transfer processes on other candidate electrode metals, e.g. stainless steel, iridium, carbon-based, etc.

Treatment of relapsed non-Hodgkin's lymphomas with dexamethasone, high-dose cytarabine, and cisplatin before marrow transplantation.

Combination chemotherapy is capable of curing many patients with newly diagnosed intermediate- and high-grade non-Hodgkin's lymphomas (NHL), but treatment of relapsed NHL remains problematic. Bone marrow transplantation (BMT) offers the best chance for disease-free survival, but interim chemotherapy is often necessary while awaiting BMT, especially for patients with bulky disease. We report here 39 patients (median age, 44 years) who failed primary therapy with doxorubicin-based regimens and subsequently were treated with one to six cycles of dexamethasone, 40 mg intravenous (IV) every day on days 1 to 4, cisplatin 100 mg/m2 by continuous infusion on day 1, and cytarabine 2 g/m2 IV every 12 hours x two doses on day 2 (DHAP) before the planned BMT. Histologies included 16 diffuse large-cell, six diffuse mixed, five diffuse small-cleaved, four lymphoblastic, and eight other. Twenty-eight patients had stage IV disease, 13 had B symptoms, and 20 had an elevated lactate dehydrogenase (LDH). Patients had been treated with a median of three previous chemotherapy regimens. Sixty-one percent of patients had high tumor burdens according to the MD Anderson criteria. Objective responses to DHAP were seen in 26 patients (67%) including nine complete responses (CRs) (23%) and 17 partial responses (PRs) (44%), and responses lasted a median of 7.5 months. Myelosuppression was the major toxicity, but there were no treatment-related deaths. To date, 17 patients have undergone subsequent BMT with a projected 3-year disease-free survival of 15%. We conclude that the DHAP regimen is effective short-term salvage therapy for relapsed NHL patients, but the long-term prognosis of multiply relapsed patients remains poor.

Feasibility and efficacy of weekly intraarterial cisplatin in locally advanced (stage III and IV) head and neck cancers.

Thirty-five consecutive patients with primary unresectable head and neck cancers were considered eligible for protocol treatment with neoadjuvant intraarterial cisplatin. External carotid artery catheterizations were technically feasible in 29 patients (83%). Twenty-five patients with 28 primary tumors received intraarterial cisplatin, 100 mg/m2, every seven to 14 days for three cycles. The most common toxicity was nausea and vomiting. Ipsilateral hemialopecia, transient VII nerve palsy, and blurring of vision seem to be unique to this route of administration at this dose. A complete response was seen at the primary tumor site in nine of 28 (32%), with 14 of 28 partial responses (50%). In evaluating both primary tumor and nodal disease, five of 25 patients achieved a complete response and 15 of 25 a partial response. In previous reports, one complete response was observed in 74 patients with head and neck cancer treated with neoadjuvant intravenous (IV) cisplatin every 3 weeks. The overall response of 82% reported here is comparable to that reported with combination chemotherapy and suggests an advantage to the arterial administration of cisplatin when possible in the neoadjuvant setting.

Effect of tamoxifen on sexual functioning in patients with breast cancer.

PURPOSE: To define the incidence of sexual dysfunction in a population of women with breast cancer treated with tamoxifen. PATIENTS AND METHODS: Breast cancer patients with a performance status of 0 to 2 who had been treated with tamoxifen for 2 to 24 months completed the following measures: the Center for Epidemiologic Studies-Depression Scale, the Sexual History Form, and the Breast Cancer Prevention Trial Symptom Checklist. Forty-nine of the participants underwent gynecologic examinations with vaginal smears for determination of estrogen effect. RESULTS: Fifty-seven women were entered onto the trial. Sexual desire, arousal, and ability to achieve orgasm were comparable to norms established in participants in the Tamoxifen Prevention Trial (National Surgical Adjuvant Breast and Bowel Project P-01). Pain, burning, or discomfort with intercourse was reported in 54% of patients and did not correlate with age, surgical treatment of the primary cancer, or chemotherapy. Estrogen effect was seen on the vaginal smears of 34 of 49 participants and was more common in older patients (P = .054). The presence of estrogen effect correlated with negative reactions during sex (P = .02) and vaginal dryness or tightness (P = .046). CONCLUSION: Women treated with tamoxifen in the adjuvant setting experienced symptoms of sexual dysfunction. The individual contributions of chemotherapy and tamoxifen to sexual dysfunction warrant prospective study.

Metabolic flare: indicator of hormone responsiveness in advanced breast cancer.

PURPOSE: The purpose of this study was to investigate whether positron emission tomography (PET) with the glucose analog [(18)F]fluorodeoxyglucose (FDG) and the estrogen analog 16 alpha-[(18)F]fluoroestradiol-17 beta (FES), performed before and after treatment with tamoxifen, could be used to detect hormone-induced changes in tumor metabolism (metabolic flare) and changes in available levels of estrogen receptor (ER). In addition, we investigated whether these PET findings would predict hormonally responsive breast cancer. PATIENTS AND METHODS: Forty women with biopsy-proved advanced ER-positive (ER(+)) breast cancer underwent PET with FDG and FES before and 7 to 10 days after initiation of tamoxifen therapy; 70 lesions were evaluated. Tumor FDG and FES uptake were assessed semiquantitatively by the standardized uptake value (SUV) method. The PET results were correlated with response to hormonal therapy. RESULTS: In the responders, the tumor FDG uptake increased after tamoxifen by 28.4% +/- 23.3% (mean +/- SD); only five of these patients had evidence of a clinical flare reaction. In nonresponders, there was no significant change in tumor FDG uptake from baseline (mean change, 10.1% +/- 16.2%; P =.0002 v responders). Lesions of responders had higher baseline FES uptake (SUV, 4.3 +/- 2.4) than those of nonresponders (SUV, 1.8 +/- 1.3; P =.0007). All patients had evidence of blockade of the tumor ERs 7 to 10 days after initiation of tamoxifen therapy; however, the degree of ER blockade was greater in the responders (mean percentage decrease, 54.8% +/- 14.2%) than in the nonresponders (mean percentage decrease, 19.4% +/- 17.3%; P =.0003). CONCLUSION: The functional status of tumor ERs can be characterized in vivo by PET with FDG and FES. The results of PET are predictive of responsiveness to tamoxifen therapy in patients with advanced ER(+) breast cancer.