Quantitative [18F]-Naf-PET-MRI Analysis for the Evaluation of Dynamic Bone Turnover in a Patient with Facetogenic Low Back Pain.

Imaging techniques that reflect dynamic bone turnover may aid in characterizing a wide range of bone pathologies. Bone is a dynamic tissue undergoing continuous remodeling with the competing activity of osteoblasts, which produce the new bone matrix, and osteoclasts, whose function is to eliminate mineralized bone. [18F]-NaF is a positron emission tomography (PET) radiotracer that enables visualization of bone metabolism. [18F]-NaF is chemically absorbed into hydroxyapatite in the bone matrix by osteoblasts and can thus noninvasively detect osteoblastic activity, which is occult to conventional imaging techniques. Kinetic modeling of dynamic [18F]-NaF-PET data provides detailed quantitative measures of bone metabolism. Conventional semi-quantitative PET data, which utilizes standardized uptake values (SUVs) as a measure of radiotracer activity, is referred to as a static technique due to its snapshot of tracer uptake in time.  Kinetic modeling, however, utilizes dynamic image data where tracer levels are continuously acquired providing tracer uptake temporal resolution. From the kinetic modeling of dynamic data, quantitative values like blood flow and metabolic rate (i.e., potentially informative metrics of tracer dynamics) can be extracted, all with respect to the measured activity in the image data. When combined with dual modality PET-MRI, region-specific kinetic data can be correlated with anatomically registered high-resolution structural and pathologic information afforded by MRI. The goal of this methodological manuscript is to outline detailed techniques for performing and analyzing dynamic [18F]-NaF-PET-MRI data. The lumbar facet joint is a common site of degenerative arthritis disease and a common cause for axial low back pain.  Recent studies suggest [18F]-NaF-PET may serve as a useful biomarker of painful facetogenic disease.  The human lumbar facet joint will, therefore, be used as a prototypical region of interest for dynamic [18F]-NaF-PET-MRI analysis in this manuscript.

A Patient-derived Xenograft Model of Pancreatic Neuroendocrine Tumors Identifies Sapanisertib as a Possible New Treatment for Everolimus-resistant Tumors.

Patients with pancreatic neuroendocrine tumors (PNET) commonly develop advanced disease and require systemic therapy. However, treatment options remain limited, in part, because experimental models that reliably emulate PNET disease are lacking. We therefore developed a patient-derived xenograft model of PNET (PDX-PNET), which we then used to evaluate two mTOR inhibitor drugs: FDA-approved everolimus and the investigational new drug sapanisertib. PDX-PNETs maintained a PNET morphology and PNET-specific gene expression signature with serial passage. PDX-PNETs also harbored mutations in genes previously associated with PNETs (such as MEN1 and PTEN), displayed activation of the mTOR pathway, and could be detected by Gallium-68 DOTATATE PET-CT. Treatment of PDX-PNETs with either everolimus or sapanisertib strongly inhibited growth. As seen in patients, some PDX-PNETs developed resistance to everolimus. However, sapanisertib, a more potent inhibitor of the mTOR pathway, caused tumor shrinkage in most everolimus-resistant tumors. Our PDX-PNET model is the first available, validated PDX model for PNET, and preclinical data from the use of this model suggest that sapanisertib may be an effective new treatment option for patients with PNET or everolimus-resistant PNET.

Biodistribution of Antibody-MS2 Viral Capsid Conjugates in Breast Cancer Models.

A variety of nanoscale scaffolds, including virus-like particles (VLPs), are being developed for biomedical applications; however, little information is available about their in vivo behavior. Targeted nanoparticles are particularly valuable as diagnostic and therapeutic carriers because they can increase the signal-to-background ratio of imaging agents, improve the efficacy of drugs, and reduce adverse effects by concentrating the therapeutic molecule in the region of interest. The genome-free capsid of bacteriophage MS2 has several features that make it well-suited for use in delivery applications, such as facile production and modification, the ability to display multiple copies of targeting ligands, and the capacity to deliver large payloads. Anti-EGFR antibodies were conjugated to MS2 capsids to construct nanoparticles targeted toward receptors overexpressed on breast cancer cells. The MS2 agents showed good stability in physiological conditions up to 2 days and specific binding to the targeted receptors in in vitro experiments. Capsids radiolabeled with 64Cu isotopes were injected into mice possessing tumor xenografts, and both positron emission tomography-computed tomography (PET/CT) and scintillation counting of the organs ex vivo were used to determine the localization of the agents. The capsids exhibit surprisingly long circulation times (10-15% ID/g in blood at 24 h) and moderate tumor uptake (2-5% ID/g). However, the targeting antibodies did not lead to increased uptake in vivo despite in vitro enhancements, suggesting that extravasation is a limiting factor for delivery to tumors by these particles.

Structure-Activity Relationship of (18)F-Labeled Phosphoramidate Peptidomimetic Prostate-Specific Membrane Antigen (PSMA)-Targeted Inhibitor Analogues for PET Imaging of Prostate Cancer.

A series of phosphoramidate-based prostate specific membrane antigen (PSMA) inhibitors of increasing lipophilicity were synthesized (4, 5, and 6), and their fluorine-18 analogs were evaluated for use as positron emission tomography (PET) imaging agents for prostate cancer. To gain insight into their modes of binding, they were also cocrystallized with the extracellular domain of PSMA. All analogs exhibited irreversible binding to PSMA with IC50 values ranging from 0.4 to 1.3 nM. In vitro assays showed binding and rapid internalization (80-95%, 2 h) of the radiolabeled ligands in PSMA(+) cells. In vivo distribution demonstrated significant uptake in CWR22Rv1 (PSMA(+)) tumor, with tumor to blood ratios of 25.6:1, 63.6:1, and 69.6:1 for [(18)F]4, [(18)F]5, and [(18)F]6, respectively, at 2 h postinjection. Installation of aminohexanoic acid (AH) linkers in the phosphoramidate scaffold improved their PSMA binding and inhibition and was critical for achieving suitable in vivo imaging properties, positioning [(18)F]5 and [(18)F]6 as favorable candidates for future prostate cancer imaging clinical trials.

Caged [(18)F]FDG Glycosylamines for Imaging Acidic Tumor Microenvironments Using Positron Emission Tomography.

Solid tumors are hypoxic with altered metabolism, resulting in secretion of acids into the extracellular matrix and lower relative pH, a feature associated with local invasion and metastasis. Therapeutic and diagnostic agents responsive to this microenvironment may improve tumor-specific delivery. Therefore, we pursued a general strategy whereby caged small-molecule drugs or imaging agents liberate their parent compounds in regions of low interstitial pH. In this manuscript, we present a new acid-labile prodrug method based on the glycosylamine linkage, and its application to a class of positron emission tomography (PET) imaging tracers, termed [(18)F]FDG amines. [(18)F]FDG amines operate via a proposed two-step mechanism, in which an acid-labile precursor decomposes to form the common radiotracer 2-deoxy-2-[(18)F]fluoro-d-glucose, which is subsequently accumulated by glucose avid cells. The rate of decomposition of [(18)F]FDG amines is tunable in a systematic fashion, tracking the pKa of the parent amine. In vivo, a 4-phenylbenzylamine [(18)F]FDG amine congener showed greater relative accumulation in tumors over benign tissue, which could be attenuated upon tumor alkalinization using previously validated models, including sodium bicarbonate treatment, or overexpression of carbonic anhydrase. This new class of PET tracer represents a viable approach for imaging acidic interstitial pH with potential for clinical translation.

Synthesis and evaluation of constrained phosphoramidate inhibitors of prostate-specific membrane antigen.

Prostate-specific membrane antigen (PSMA) is a cell-surface enzyme-biomarker that is actively pursued for targeted delivery of imaging and therapeutic agents for prostate cancer. Our lab has developed PSMA inhibitors based on a phosphoramidate scaffold, which has shown both high selectivity for PSMA-positive tumors and rapid clearance in vivo when radiolabeled with (18)F. However, this scaffold exhibits hydrolytic instability under low pH and high temperature conditions, barring the use of other imaging or therapeutic radionuclides such as (68)Ga or (177)Lu. Previous studies in our lab have shown a trend in increasing acid stability as the distance between the phosphoramidate core and the α-carboxylate of the P1 residue is increased. Therefore, a new generation of phosphoramidate inhibitors was developed based on trans-4-hydroxyproline as the P1 residue to restrict the interaction of the α-carboxylate to the phosphoramidate core. These hydroxyproline inhibitors demonstrated comparable IC50 values to earlier generations as well as enhanced thermal and acid stability.

Cancer patient and clinician acceptability and feasibility of a supportive care screening and referral process.

BACKGROUND: Incorporating supportive care into routine cancer care is an increasing priority for the multi-disciplinary team with growing evidence of its importance to patient-centred care. How to design and deliver a process which is appropriate for patients, clinicians and health services in rural areas needs further investigation. OBJECTIVE: To (i) examine the patient and clinician acceptability and feasibility of incorporating a supportive care screening and referral process into routine cancer care in a rural setting, and (ii) explore any potential influences of patient variables on the acceptability of the process. METHODS: A total of 154 cancer patients and 36 cancer clinicians across two rural areas of Victoria, Australia participated. During treatment visits, patients and clinicians participated in a supportive care process involving screening, discussion of problems, and provision of information and referrals. Structured questionnaires with open and closed questions were used to measure patient and clinician acceptability and feasibility. RESULTS: Patients and clinicians found the supportive care process highly acceptable. Screening identified relevant patient problems (90%) and problems that may not have otherwise been identified (83%). The patient-clinician discussion helped patients realize help was available (87%) and enhanced clinician-patient rapport (72%). Patients received useful referrals to services (76%). Feasibility issues included timing of screening for newly diagnosed patients, privacy in discussing problems, clinician time and availability of referral options. No patient demographic or disease factors influenced acceptability or feasibility. CONCLUSIONS: Patients and clinicians reported high acceptability for the supportive care process, although mechanisms for incorporating the process into health care need to be further developed.

A qualitative study of rural women's views for the treatment of early breast cancer.

AIM: Identify what factors rural women perceived to influence their surgical choice for EBC. BACKGROUND: Higher rates of mastectomy still remain for women with early breast cancer (EBC) in rural areas. While access to radiotherapy is a commonly identified barrier, there is growing debate around other factors which are also important influences on surgical choice. METHODS: Qualitative study with 70 interviews with women diagnosed with EBC in rural Gippsland, Australia. Twenty-nine women had a mastectomy and 41 had breast conserving surgery (BCS). RESULTS: Patient led psychosocial and surgeon led factors influenced surgical choice. Psychosocial factors were a greater influence for the mastectomy group. These included a high fear of cancer recurrence and radiotherapy, negative views of the body and breast, a family history of cancer, wanting to avoid the negative treatment experiences they had seen significant others go through, and not wanting to travel for treatment. Surgeon led factors were a greater influence for the BCS group, in particular, the direct recommendation made by the surgeon for BCS. For both groups, urgency to act was a shared psychosocial factor. Trust and confidence in the expertise and reputation of the surgeon and their consultation style were surgeon led factors shared by the groups. CONCLUSIONS: To ensure women achieve the best treatment outcome, patients and clinicians need to work together to identify how important and influential the various factors are for the women and, if necessary, to seek support to ensure informed decisions are made.

Communicating about breast cancer: rural women's experience of interacting with their surgeon.

OBJECTIVE: This study examined rural women's satisfaction with the interaction and communication with their surgeon during diagnosis and treatment planning for early breast cancer. Differences in satisfaction were investigated between treatment groups (mastectomy and breast conservation surgery) and demographic variables (age, marital status, education level, employment status and place of residence). Practice was compared with clinical practice guidelines. DESIGN: The study was designed as a cross-sectional survey. SETTING: The study was set in Eastern regional Victoria, Australia. PARTICIPANTS: Seventy women diagnosed with early breast cancer participated in the study. MAIN OUTCOME MEASURES: The main outcome measures used by the study were satisfaction in three areas of practice: (i) telling a woman she has breast cancer; (ii) providing information and involving the woman in the decision-making; and (iii) preparing the woman for specific management. RESULTS: No differences in satisfaction were found between treatment groups and demographic variables. Overall, women in this study were highly satisfied (>93%) with the interaction and communication with their surgeon. Women reported that the surgeon created a supportive environment for discussion, that they were provided with adequate information and referrals, and that they were actively involved in the decision-making. Practice could have been improved for women who were alone at diagnosis as women without a partner made a quicker decision about treatment. CONCLUSION: Rural women in Victoria Australia were largely satisfied with the interaction and communication with their surgeon during diagnosis and treatment planning for early breast cancer. Current practice was predominately in line with clinical practice guidelines.

Supporting international medical graduates in rural Australia: a mixed methods evaluation.

INTRODUCTION: In Australia, international medical graduates (IMGs) make a substantial contribution to rural medical workforces. They often face significant communication, language, professional and cultural barriers, in addition to the other challenges of rural clinical practice. The Gippsland Inspiring Professional Standards among International Experts (GIPSIE) program was designed to provide educational support to IMGs across a large geographical region using innovative educational methods to ultimately build capacity in the provision of rural medical education. GIPSIE offered 5 sessions over 3 months. Simulation-based training was a prominent theme and addressed clinical knowledge, attitudes and skills and included a range of activities (eg procedural skills training with benchtop models, management of the acutely ill patient with SimMan, patient assessment skills with simulated patients). Diverse clinical communication skills were explored (eg teamwork, handover, telephone, critical information). Audiovisual review of performance was enabled through the use of iPod nano devices. GIPSIE was underpinned by a website offering diverse learning resources. Content experts were invited to lead sessions that integrated knowledge and skills reflecting local practice. METHODS: IMGs were recruited from hospitals (n = 15) and general practices (n = 2) across the region. It was aimed to evaluate the impact of GIPSIE on the clinical practice of IMG participants. Evaluation measures included pre- and post-program 15 item multisource feedback (MSF), post-program questionnaires and, in order to address retention, telephone interviews exploring participants' responses 3 months after the program finished. RESULTS: Fifteen participants completed GIPSIE and rated the program highly, especially the simulation-based activities with feedback and later audiovisual review on iPods and the GIPSIE website. Suggestions were made to improve several aspects of the program. Participants reported increased knowledge, skills and professionalism after the program. Although overall MSF scores showed no statistically significant changes, there were positive directional changes for the items 'technical skills appropriate to current practice', 'willingness and effectiveness when teaching/training colleagues' and 'communication with carers and family'. These developments were also supported in free-text comments. Learning was reported to be sustained 3 months after the program. CONCLUSIONS: GIPSIE was highly valued by participants who reported improvements in clinical knowledge and skills. A range of professional issues were raised and addressed. GIPSIE seemed to provide a platform for further development. Although new to many participants, simulation was embraced as an educational method. The relationship between regional clinicians and the medical school was pivotal to success. A feature of the study was tracking improvements in clinical practice as a consequence of participating in the GIPSIE program. Future work needs to focus on further promoting the transfer of learning to the workplace. However the sustainability of these programs requires significant commitment.

Examining the introduction of a supportive care screening and referral process for cancer patients: how does practice compare with protocols?

PURPOSE: The aim of this study was to examine the introduction of a supportive care screening and referral process into clinical practice for patients with cancer, and to determine how clinicians' actions compared to evidence-based protocols contained within the Supportive Care Resource Kit. METHODS: A Supportive Care Resource Kit was developed as a resource for clinicians to enable a systematic process of screening cancer patients for unmet supportive care needs and addressing these needs by using evidence-based protocols. Clinicians were recruited and trained in supportive care and the use of the kit. Patients were recruited and screened for their supportive care needs. Patients and clinicians undertook a problem solving discussion, which was documented and analysed using content analysis. RESULTS: In applying the screening process, clinicians undertook discussion, referral and information provision with patients. Comparison to evidence-based protocols revealed that practice was predominantly in line with protocols. Overall, clinicians' practice matched well with guidance from the protocols on discussion and referral, but less so in providing information to patients. Actions taken between supportive care domains differed with clinician preference evident for dealing with physical problems compared with practical, emotional and family problems. CONCLUSIONS: Implications for practice and research include, exploring strategies for broadening clinician confidence in dealing with all areas of supportive care needs; undertaking further research into the use of protocols in health care and incorporating strategic, multidisciplinary planning in protocol implementation schemes.

Incorporating supportive care into routine cancer care: the benefits and challenges to clinicians' practice.

PURPOSE/OBJECTIVES: To investigate clinicians' experiences with supportive care screening and referral, and identify perceived barriers and benefits associated with implementation into the clinical setting. DESIGN: Qualitative, exploratory approach based on interviews. SETTING: A large regional hospital in Victoria, Australia, that provides chemotherapy and radiotherapy services to patients with cancer. SAMPLE: 5 chemotherapy nurses and 1 radiation therapist. METHODS: Semistructured interviews were conducted, documented, and analyzed with qualitative techniques. MAIN RESEARCH VARIABLES: Clinical benefits of supportive care screening and referral, and barriers to clinical implementation. FINDINGS: Clinicians perceived that supportive care screening benefited their practice by improving communication and rapport with patients. Clinicians supported each other during screening implementation, and although they initially were hesitant about the process, they ultimately endorsed screening for wider implementation. Time constraints and scope of practice were identified as significant barriers. CONCLUSIONS: Supportive care screening was endorsed as part of future clinical practice, but barriers to implementation need to be addressed. IMPLICATIONS FOR NURSING: With current psychosocial guidelines recommending routine supportive care screening of patients with cancer and statewide mandatory screening targets set in Australia, healthcare organizations need to carefully consider implementation processes. Although nurses are ideally placed to complete screening, organizations need to ensure that appropriate training and support mechanisms have been developed, as well as adequate resources, to enable integration into routine practice.

Patients' perception of communication with clinicians during screening and discussion of cancer supportive care needs.

OBJECTIVE: Effective communication between patients and clinicians is an essential aspect of supportive care for cancer patients, however many patients find this communication is inadequate. This study examined cancer patients' perception of communication with their clinician during a supportive care screening and discussion process and the ways in which this process assisted communication. METHODS: One hundred and fifty-four patients undertaking treatment for cancer in chemotherapy, radiotherapy and surgical units in six hospitals in Australia participated in a formal supportive care screening, discussion and referral process and were interviewed about their experiences. RESULTS: The majority of patients interviewed felt that the process enhanced communication by encouraging them to reflect on their needs, assisting them to initiate a discussion with the clinician, validating their needs, encouraging them to seek help and support and focusing clinician attention on unmet needs. CONCLUSION: Patients perceived the formal process of supportive care improved communication between themselves and their clinicians. PRACTICE IMPLICATIONS: Undertaking a patient-centred process of supportive care can assist clinicians to meet the unmet needs of patients with cancer and can increase patient satisfaction.

Implementation of a multi-level evaluation strategy: a case study on a program for international medical graduates.

Evaluation of educational interventions is often focused on immediate and/or short-term metrics associated with knowledge and/or skills acquisition. We developed an educational intervention to support international medical graduates working in rural Victoria. We wanted an evaluation strategy that included participants' reactions and considered transfer of learning to the workplace and retention of learning. However, with participants in distributed locations and limited program resources, this was likely to prove challenging. Elsewhere, we have reported the outcomes of this evaluation. In this educational development report, we describe our evaluation strategy as a case study, its underpinning theoretical framework, the strategy, and its benefits and challenges. The strategy sought to address issues of program structure, process, and outcomes. We used a modified version of Kirkpatrick's model as a framework to map our evaluation of participants' experiences, acquisition of knowledge and skills, and their application in the workplace. The predominant benefit was that most of the evaluation instruments allowed for personalization of the program. The baseline instruments provided a broad view of participants' expectations, needs, and current perspective on their role. Immediate evaluation instruments allowed ongoing tailoring of the program to meet learning needs. Intermediate evaluations facilitated insight on the transfer of learning. The principal challenge related to the resource intensive nature of the evaluation strategy. A dedicated program administrator was required to manage data collection. Although resource-intensive, we recommend baseline, immediate, and intermediate data collection points, with multi-source feedback being especially illuminating. We believe our experiences may be valuable to faculty involved in program evaluations.