Synthesis and preclinical evaluation of [11C]EAI045 as a PET tracer for imaging tumors expressing mutated epidermal growth factor receptor.

BACKGROUND: Mutations in the epidermal growth factor receptor (EGFR) kinase domain are common in non-small cell lung cancer. Conventional tyrosine kinase inhibitors target the mutation site in the ATP binding pocket, thereby inhibiting the receptor's function. However, subsequent treatment resistance mutations in the ATP binding site are common. The EGFR allosteric inhibitor, EAI045, is proposed to have an alternative mechanism of action, disrupting receptor signaling independent of the ATP-binding site. The antibody cetuximab is hypothesized to increase the number of accessible allosteric pockets for EAI045, thus increasing the potency of the inhibitor. This work aimed to gain further knowledge on pharmacokinetics, the EGFR mutation-targeting potential, and the influence of cetuximab on the uptake by radiolabeling EAI045 with carbon-11 and tritium. RESULTS: 2-(5-fluoro-2-hydroxyphenyl)-2-((2-iodobenzyl)amino)-N-(thiazol-2-yl)acetamide and 2-(5-fluoro-2-hydroxyphenyl)-N-(5-iodothiazol-2-yl)-2-(1-oxoisoindolin-2-yl)acetamide were synthesized as precursors for the carbon-11 and tritium labeling of EAI045, respectively. [11C]EAI045 was synthesized using [11C]CO in a palladium-catalyzed ring closure in a 10 ± 1% radiochemical yield (decay corrected to end of [11C]CO2 production), > 97% radiochemical purity and 26 ± 1 GBq/µmol molar activity (determined at end of synthesis) in 51 min. [3H]EAI045 was synthesized by a tritium-halogen exchange in a 0.2% radiochemical yield, 98% radiochemical purity, and 763 kBq/nmol molar activity. The ability of [11C]EAI045 to differentiate between L858R/T790M mutated EGFR expressing H1975 xenografts and wild-type EGFR expressing A549 xenografts was evaluated in female nu/nu mice. The uptake was statistically significantly higher in H1975 xenografts compared to A549 xenografts (0.45 ± 0.07%ID/g vs. 0.31 ± 0.10%ID/g, P = 0.0166). The synergy in inhibition between EAI045 and cetuximab was evaluated in vivo and in vitro. While there was some indication that cetuximab influenced the uptake of [3H]EAI045 in vitro, this could not be confirmed in vivo when tumor-bearing mice were administered cetuximab (0.5 mg), 24 h prior to injection of [11C]EAI045. CONCLUSIONS: EAI045 was successfully labeled with tritium and carbon-11, and the in vivo results indicated [11C]EAI045 may be able to distinguish between mutated and non-mutated EGFR in non-small cell lung cancer mouse models. Cetuximab was hypothesized to increase EAI045 uptake; however, no significant effect was observed on the uptake of [11C]EAI045 in vivo or [3H]EAI045 in vitro in H1975 xenografts and cells.

Psychoeducation for breast cancer: A systematic review and meta-analysis.

BACKGROUND: Psychoeducation has emerged as an intervention for women with breast cancer (BC). This meta-analysis evaluated the effectiveness of psychoeducation on adherence to diagnostic procedures and medical treatment, anxiety, depression, quality of life (QoL), and BC knowledge among patients with BC symptoms or diagnosis and BC survivors. METHODS: A systematic literature search (in PubMed, Embase, PsycINFO and Cochrane) for randomised controlled trials (RCTs) comparing the effects of psychoeducation to control among patients with BC symptoms or diagnosis and BC survivors. Effects were expressed as relative risks (RRs) and standardized mean differences (SMDs) with their 95% confidence intervals. RESULTS: Twenty-seven RCTs (7742 participants; 3880 psychoeducation and 3862 controls) were included. Compared with controls, psychoeducation had no significant effect on adherence to diagnostic procedures and medical treatment (RR 1.553; 95% CI 0.733 to 3.290, p = .16), but it significantly decreased anxiety (SMD -0.710, 95% CI -1.395 to -0.027, p = .04) and improved QoL with (SMD 0.509; 95% CI 0.096 to 0.923, p < .01). No effects were found for psychoeducation on depression (SMD -0.243, 95% CI -0.580 to 0.091, p = .14), or BC knowledge (SMD 0.718, 95% CI -0.800 to 2.236, p = .23). CONCLUSION: We demonstrated that psychoeducation did not improve adherence to diagnostic procedures and treatment, depression and BC knowledge but was valuable for reducing anxiety and improving QoL. Future studies may explore the effectiveness of psychoeducation in promoting adherence across various types of cancer.

Preclinical evaluation of [18F]FB-A20FMDV2 as a selective marker for measuring αVß6 integrin occupancy using positron emission tomography in rodent lung.

PURPOSE: Integrin αvß6 belongs to the RGD subset of the integrin family, and its expression levels are a prognostic and theranostic factor in some types of cancer and pulmonary fibrosis. This paper describes the GMP radiolabelling of the synthetic 20 amino acid peptide A20FMDV2 (NAVPNLRGDLQVLAQKVART), derived from the foot-and-mouth disease virus, and characterises the use of [18F]FB-A20FMDV2 as a high affinity, specific and selective PET radioligand for the quantitation and visualisation of αvß6 in rodent lung to support human translational studies. METHODS: The synthesis of [18F]FB-A20FMDV2 was performed using a fully automated and GMP-compliant process. Sprague-Dawley rats were used to perform homologous (unlabelled FB-A20FMDV2) and heterologous (anti-αvß6 antibody 8G6) blocking studies. In order to generate a dosimetry estimate, tissue residence times were generated, and associated tissue exposure and effective dose were calculated using the Organ Level Internal Dose Assessment/Exponential Modelling (OLINDA/EXM) software. RESULTS: [18F]FB-A20FMDV2 synthesis was accomplished in 180 min providing ~800 MBq of [18F]FB-A20FMDV2 with a molar activity of up to 150 GBq/µmol and high radiochemical purity (> 97%). Following i.v. administration to rats, [18F]FB-A20FMDV2 was rapidly metabolised with intact radiotracer representing 5% of the total radioactivity present in rat plasma at 30 min. For the homologous and heterologous block in rats, lung-to-heart SUV ratios at 30-60 min post-administration of [18F]FB-A20FMDV2 were reduced by 38.9 ± 6.9% and 56 ± 19.2% for homologous and heterologous block, respectively. Rodent biodistribution and dosimetry calculations using OLINDA/EXM provided a whole body effective dose in humans 33.5 µSv/MBq. CONCLUSION: [18F]FB-A20FMDV2 represents a specific and selective PET ligand to measure drug-associated αvß6 integrin occupancy in lung. The effective dose, extrapolated from rodent data, is in line with typical values for compounds labelled with fluorine-18 and combined with the novel fully automated and GMP-compliant synthesis and allows for clinical use in translational studies.

18F-Trifluoromethanesulfinate Enables Direct C-H 18F-Trifluoromethylation of Native Aromatic Residues in Peptides.

18F labeling strategies for unmodified peptides with [18F]fluoride require 18F-labeled prosthetics for bioconjugation more often with cysteine thiols or lysine amines. Here we explore selective radical chemistry to target aromatic residues applying C-H 18F-trifluoromethylation. We report a one-step route to [18F]CF3SO2NH4 from [18F]fluoride and its application to direct [18F]CF3 incorporation at tryptophan or tyrosine residues using unmodified peptides as complex as recombinant human insulin. The fully automated radiosynthesis of octreotide[Trp(2-CF218F)] enables in vivo positron emission tomography imaging.

Clinical quantification of the integrin αvß6 by [18F]FB-A20FMDV2 positron emission tomography in healthy and fibrotic human lung (PETAL Study).

PURPOSE: The RGD-integrin, αvß6, plays a role in the pathogenesis of pulmonary fibrosis through activation of transforming growth factor beta (TGFß). This study sought to quantify expression of αvß6 in the lungs of healthy humans and subjects with pulmonary fibrosis using the αvß6-selective [18F]FB-A20FMDV2 PET ligand. METHODS: [18F]FB-A20FMDV2 PET/CT scans were performed in healthy subjects and those with fibrotic lung disease. Standard uptake values (SUV) and volume of distribution (VT) were used to quantify αvß6 expression. In subjects with fibrotic lung disease, qualitative assessment of the relationship between αvß6 expression and the distribution of fibrosis on high resolution computed tomography was conducted. RESULTS: A total of 15 participants (6 healthy, 7 with idiopathic pulmonary fibrosis (IPF) and 2 with connective tissue disease (CTD) associated PF) were enrolled. VT and SUV of [18F]FB-A20FMDV2 were increased in the lungs of subjects with pulmonary fibrosis (PF) compared with healthy subjects. Geometric mean VT (95% CI) was 0.88 (0.60, 1.29) mL/cm3 for healthy subjects, and 1.40 (1.22, 1.61) mL/cm3 for subjects with IPF; and SUV was 0.54 (0.36, 0.81) g/mL for healthy subjects and 1.03 (0.86, 1.22) g/mL for subjects with IPF. The IPF/healthy VT ratio (geometric mean, (95% CI of ratio)) was 1.59 (1.09, 2.32) (probability ratio > 1 = 0.988)) and the SUV ratio was 1.91 (1.27, 2.87) (probability ratio > 1 = 0.996). Increased uptake of [18F]FB-A20FMDV2 in PF was predominantly confined to fibrotic areas. [18F]FB-A20FMDV2 measurements were reproducible at an interval of 2 weeks. [18F]FB-A20FMDV2 was safe and well tolerated. CONCLUSIONS: Lung uptake of [18F]FB-A20FMDV2, a measure of expression of the integrin αvß6, was markedly increased in subjects with PF compared with healthy subjects.

A self-help intervention for reducing time to diagnosis in Indonesian women with breast cancer symptoms.

OBJECTIVE: We investigated the effectiveness of a self-help intervention named PERANTARA, which aims to improve adherence to diagnostic procedures among women with breast cancer (BC) symptoms to reduce the time to a definitive diagnosis. METHODS: With a cluster randomized crossover design across four hospitals, PERANTARA and treatment as usual (TAU) or TAU only was provided at successive periods in a randomly determined order. The main outcome was the time between the first medical consultation and the definitive diagnosis. Secondary outcomes were BC knowledge, measured by the Breast Cancer Knowledge Test (BCKT); symptoms of anxiety and depression, measured by the Hospital Anxiety and Depression Scale (HADS); quality of life, measured by the World Health Organization Quality of Life-BREF (WHOQOL-BREF); and health status, measured by the EQ-5D-5L. A linear mixed model analysis was conducted to analyse the outcomes. RESULTS: We recruited 132 women with BC symptoms from four hospitals; 67 participants were in the intervention group, and 65 participants were in the control group. PERANTARA reduced the time to definitive diagnosis by 13.3 days (M [SD]: 25.90 [23.20] in the intervention group vs 39.29 [35.10] in the control group; mean difference = -13.26, 95% CI = -24.51 to -2.00, P = .02). No significant difference was found between the groups in BC knowledge, symptoms of anxiety, depression, quality of life, or health status. CONCLUSIONS: PERANTARA reduced the time to definitive diagnosis among Indonesian women with BC symptoms. Psychoeducation may be an important addition to regular BC care to prevent undue delays in diagnostic procedures.

A Self-Help Guided Psychoeducational Intervention for Indonesian Women with Breast Cancer Symptoms: Development and Pilot Feasibility Study

Background: Delay in the diagnosis of breast cancer (BC) may lead to an advanced stage of the disease and a poor prognosis. A psychoeducational intervention can be crucial in helping women with BC symptoms complete the examination procedures and reduce diagnosis delay of BC. Objective: To develop a psychoeducational intervention to reduce the delay of BC diagnosis among Indonesian women with BC symptoms. Methods: The development of the intervention included an inventory of crucial elements in developing psychoeducation through literature review as well as consultation with BC patients and healthcare providers. Additionally, we developed PERANTARA as the first pilot version of the self-help guided psychoeducational intervention. PERANTARA is an abbreviation for "Pengantar Perawatan Kesehatan Payadura", which means an introduction to breast health treatment. The pilot feasibility study combined an expert review and a pilot testing in hospital settings. A semi-structured interview and the client satisfaction inventory were utilized to measure feasibility and acceptability of the intervention for Indonesian women with BC symptoms. Results: PERANTARA contained an oncologist's explanation about BC and the BC survivors' testimony to reduce the time to diagnosis. The pilot study results showed that most patients were satisfied with and trusted on PERANTARA. Conclusion: PERANTARA was feasible and acceptable for Indonesian patients with BC symptoms. The development framework suggested in this study can be applied to develop psychoeducational packages for other patients group, in particular, those interventional packages aimed at reducing diagnosis and treatment delays and nonadherence.

First evaluation of PET-based human biodistribution and radiation dosimetry of 11C-BU99008, a tracer for imaging the imidazoline2 binding site.

BACKGROUND: We measured whole body distribution of 11C-BU99008, a new PET biomarker for non-invasive identification of the imidazoline2 binding site. The purpose of this phase I study was to evaluate the biodistribution and radiation dosimetry of 11C-BU99008 in healthy human subjects. METHODS: A single bolus injection of 11C-BU99008 (296 ± 10.5 MBq) was administered to four healthy subjects who underwent whole-body PET/CT over 120 min from the cranial vertex to the mid-thigh. Volumes of interest were drawn around visually identifiable source organs to generate time-activity curves (TAC). Residence times were determined from time-activity curves. Absorbed doses to individual organs and the whole body effective dose were calculated using OLINDA/EXM 1.1 for each subject. RESULTS: The highest measured activity concentration was in the kidney and spleen. The longest residence time was in the muscle at 0.100 ± 0.023 h, followed by the liver at 0.067 ± 0.015 h and lungs at 0.052 ± 0.010 h. The highest mean organ absorbed dose was within the heart wall (0.028 ± 0.002 mGy/MBq), followed by the kidneys (0.026 ± 0.005 mGy/MBq). The critical organ was the heart wall. The total mean effective dose averaged over subjects was estimated to be 0.0056 ± 0.0004 mSv/MBq for an injection of 11C-BU99008. CONCLUSIONS: The biodistribution of 11C-BU99008 has been shown here for the first time in humans. Our dosimetry data showed the total mean effective dose over all subjects was 0.0056 ± 0.0004 mSv/MBq, which would result in a total effective dose of 1.96 mSv for a typical injection of 350 MBq of 11C-BU99008. The effective dose is not appreciably different from those obtained with other 11C tracers.

Disease-related patterns of in vivo pathology in Corticobasal syndrome.

PURPOSE: To assess disease-related patterns of in vivo pathology in 11 patients with Corticobasal Syndrome (CBS) compared to 20 healthy controls and 33 mild cognitive impairment (MCI) patients due to Alzheimer's disease. METHODS: We assessed tau aggregates with [18F]AV1451 PET, amyloid-ß depositions with [18F]AV45 PET, and volumetric microstructural changes with MRI. We validated for [18F]AV1451 standardised uptake value ratio (SUVRs) against input functions from arterial metabolites and found that SUVRs and arterial-derived distribution volume ratio (DVRs) provide equally robust measures of [18F]AV1451 binding. RESULTS: CBS patients showed increases in [18F]AV1451 SUVRs in parietal (P < 0.05) and frontal (P < 0.05) cortices in the affected hemisphere compared to healthy controls and in precentral (P = 0.008) and postcentral (P = 0.034) gyrus in the affected hemisphere compared to MCI patients. Our data were confirmed at the histopathological level in one CBS patient who underwent brain biopsy and showed sparse tau pathology in the parietal cortex co-localizing with increased [18F]AV1451 signal. Cortical and subcortical [18F]AV45 uptake was within normal levels in CBS patients. In parietal and frontal cortices of the most affected hemisphere we found also grey matter loss (P < 0.05), increased mean diffusivity (P < 0.05) and decreased fractional anisotropy (P < 0.05) in CBS patients compared to healthy controls and MCI patients. Grey matter loss and white matter changes in the precentral gyrus of CBS patients were associated with worse motor symptoms. CONCLUSIONS: Our findings demonstrate disease-related patterns of in vivo tau and microstructural pathology in the absence of amyloid-ß, which distinguish CBS from non-affected individuals and MCI patients.

Quality of life and health status of Indonesian women with breast cancer symptoms before the definitive diagnosis: A comparison with Indonesian women in general.

OBJECTIVES: Breast cancer (BC) is prevalent in low and middle-income countries (LMICs) where the majority of cases are diagnosed in late stages. The aims of this study were: (1) to assess quality of life (QOL) and health status of Indonesian women with BC symptoms before definitive diagnosis; (2) to compare QOL and health status between women with BC symptoms before definitive diagnosis and Indonesian women in general; (3) to evaluate the association between demographic variables (age, residence, social economic status and education level) and QOL within the Indonesian women with BC symptoms before definitive diagnosis. METHODS: We used WHOQOL-BREF to measure QOL and EQ-5D-5L for health status. Multivariate analysis of covariance (MANCOVA) was used to compare QOL and health status between women with BC symptoms and women from the general Indonesian population in order to control for confounders. Regression analyses were used for testing the association between the demographic variables, QOL, and health status. RESULTS: In comparison with the data from the women from the general population (n = 471), the women with BC symptoms (n = 132) reported lower QOL, especially in physical and psychological domains. They also reported more problems in all dimensions of health status. Higher education and monthly income were positively associated with QOL and health status among the women with BC symptoms. CONCLUSION: Before receiving a definitive diagnosis, women who visit hospitals with symptoms of BC, report a lower QOL and health status than women in general. Our results suggest that healthcare providers should provide targeted strategies for women with BC symptoms to improve their QOL.

A Microdose PET Study of the Safety, Immunogenicity, Biodistribution, and Radiation Dosimetry of 18F-FB-A20FMDV2 for Imaging the Integrin αvß6.

The αvß6 integrin is involved in the pathogenesis of cancer and fibrosis. A radiolabeled 20-amino-acid αvß6-binding peptide, derived from the foot and mouth virus (NAVPNLRGDLQVLAQKVART [A20FMDV2]), has been developed to image αvß6 levels preclinically. This study was designed to translate these findings into a clinical PET imaging protocol to measure the expression of αvß6 in humans. Methods: Preclinical toxicology was undertaken, and a direct immunoassay was developed for 4-fluorobenzamide (FB)-A20FMDV2. Four healthy human subjects (2 male and 2 female) received a single microdose of 18F-FB-A20FMDV2 followed by a multibed PET scan of the whole body over more than 3 h. Results: There were no findings in the preclinical toxicology assessments, and no anti-A20FMDV2 antibodies were detected before or after dosing with the PET ligand. The mean and SD of the administered mass of 18F-FB-A20FMDV2 was 8.7 ± 4.4 µg (range, 2.7-13.0 µg). The mean administered activity was 124 ± 20 MBq (range, 98-145 MBq). There were no adverse or clinically detectable pharmacologic effects in any of the subjects. No significant changes in vital signs, laboratory study results, or electrocardiography results were observed. Uptake of radioactivity was observed in the thyroid, salivary glands, liver, stomach wall, spleen, kidneys, ureters, and bladder. Time-activity curves indicated that the highest activity was in the bladder content, followed by the kidneys, small intestine, stomach, liver, spleen, thyroid, and gallbladder. The largest component of the residence times was the voided urine, followed by muscle, bladder, and liver. Using the mean residence time over all subjects as input to OLINDA/EXM, the effective dose was determined to be 0.0217 mSv/MBq; using residence times from single subjects gave an SD of 0.0020 mSv/MBq from the mean. The critical organ was the urinary bladder, with an absorbed dose of 0.18 mGy/MBq. Conclusion:18F-FB-A20FMDV2 successfully passed toxicology criteria, showed no adverse effects in this first-in-humans study, and has an effective dose that enables multiple scans in a single subject.

A protocol for a cluster-randomized controlled trial of a self-help psycho-education programme to reduce diagnosis delay in women with breast cancer symptoms in Indonesia.

BACKGROUND: Breast cancer (BC) is the most frequent cancer occurring in women across the world. Its mortality rate in low-middle income countries (LMICs) is higher than in high-income countries (HICs), and in Indonesia BC is the leading cause of cancer deaths among women. Delay in breast cancer diagnosis negatively impacts cancer prognosis. Only about 30% of patients who come to the hospital to check on their breast abnormalities, continue thorough examination to biopsy to get a diagnosis based on the results of anatomical pathology. Many Indonesian women with breast cancer were already in an advanced stage when starting treatment. Therefore, delay in diagnosis is a serious problem that needs to be addressed. The present study will investigate whether our newly developed self-help psycho-educational programme, "PERANTARA", for women with breast cancer symptoms is effective to reduce patient diagnosis delay in Indonesia. METHODS: A cluster-randomized controlled trial will be conducted in 106 patients in four hospitals in Bandung, West Java, Indonesia. Data will be collected at baseline (pre-assessment), 7 days after the intervention (post-assessment), and at 3 months (follow-up assessments). The primary outcome is delay in diagnosis and treatment. Secondary outcomes are breast cancer knowledge, anxiety and depression, and quality of life. Exploratively, adherence with treatment will be measured too. Data will be analysed by hierarchical linear modelling (HLM) to assess differential change over time. DISCUSSION: If proven effective, PERANTARA will be evaluated and implemented in a diversity of settings for local cares (such as in POSYANDU, PUSKESMAS) that provide health education/psycho-education for women with breast symptoms. TRIAL REGISTRATION: ISRCTN12570738 . Date: November 19th, 2016.

Participation in a clinical trial for a child with cancer is burdensome for a minority of children.

AIM: This study explored how parents who had lost a child to cancer felt about them taking part in a clinical trial. METHODS: A retrospective questionnaire was sent to parents who had lost a child to cancer. They were asked whether their child took part in a clinical trial during their palliative phase, their motives for their child's participation, how they perceived their child's burden and whether they would, hypothetically speaking, enrol again. RESULTS: The 24 parents of 16 deceased children who had participated in a clinical trial explained their motives for their child's participation. The most common answers, with multiple responses, were treatment for future patients (n = 16), hope for a cure (n = 9) and prolonging their child's life (n = 6). Eight parents said that participating was not burdensome for their child and four said it was very burdensome, with others answering in between. None of the parents would decline participation if they would be in the same situation again. CONCLUSION: Performing clinical trials, even in a vulnerable population, such as children with cancer at the end of life, may not always lead to increased burden. None of the parents would in future, given the same circumstances, decline participation in a clinical trial.

A dual radiolabelling approach for tracking metal complexes: investigating the speciation of copper bis(thiosemicarbazonates) in vitro and in vivo.

Copper(II)bis(thiosemicarbazonato) complexes such as [(64)Cu]Cu-ATSM continue to be investigated for positron emission tomography (PET) imaging of tumour hypoxia. However, the currently proposed mechanisms for the mode of action of these complexes are unable to account fully for their observed biological behaviour. In order to examine the roles of the copper metal and the ligand, we designed a pair of (123)I/(64)Cu-copper bis(thiosemicarbazonates), radiolabelled at either the metal or at the ligand. In vitro cellular retention studies of the orthogonal pair demonstrate for the first time that retention under hypoxia involves dissociation of the copper bis(thiosemicarbazone) complex, consistent with the previously suggested mechanism of reductive trapping of copper. In contrast, in vivo biodistribution and dynamic PET/SPECT imaging of the orthogonally labelled complexes underline our previous findings for [(64)Cu]Cu-ATSM and [(64)Cu]Cu-acetate, providing further support for the important contribution of copper metabolism in the in vivo hypoxia selectivity of Cu-ATSM. This dual radiolabelling approach may find applications for determining the speciation of other metal complexes in vitro and in vivo.

Health locus of control in Indonesian women with breast cancer: a comparison with healthy women.

The aims of this study were to assess whether Indonesian women with breast cancer havea higher external health locus of control (HLC) than healthy women, and to explore the association between HLC and symptoms of anxiety and depression. In this study, 120 consecutive women with breast cancer were recruited at the outpatient surgical oncology clinic at the Hasan Sadikin Hospital in Bandung. One hundred and twenty two healthy women were recruited from the Bandung area as controls. A standard demographic form, Form C of the Multidimensional Health Locus of Control, as well as the Hospital Anxiety and Depression Scale and patients' medical records were used. Data were analyzed using descriptive statistics, t-test, Pearson's correlation, MANOVA and multiple linear regressions. Women with breast cancer had higher scores on all external HLC subscales, i.e. chance, doctor, powerful others and God, and lower internal HLC compared to healthy women. High God LHC scores were associated with a high level of anxiety (ß=0.21, p<0.05), whereas none of the HLC subscales were associated with depression. Our results suggest that women with breast cancer tend to have high external HLC, while healthy women tend to have high internal HLC. A strong belief in an external source of control, i.e. God, might be negatively associated with patient emotional adjustment. Further research is needed to give an insight into the direction of this association.

A localized tolerance in the substrate specificity of the fluorinase enzyme enables "last-step" 18F†fluorination of a RGD peptide under ambient aqueous conditions.

A strategy for last-step (18)F fluorination of bioconjugated peptides is reported that exploits an "Achilles heel" in the substrate specificity of the fluorinase enzyme. An acetylene functionality at the C-2 position of the adenosine substrate projects from the active site into the solvent. The fluorinase catalyzes a transhalogenation of 5'-chlorodeoxy-2-ethynyladenosine (ClDEA) to 5'-fluorodeoxy-2-ethynyladenosine (FDEA). Extending a polyethylene glycol linker from the terminus of the acetylene allows the presentation of bioconjugation cargo to the enzyme for (18)F labelling. The method uses an aqueous solution (H2(18)O) of [(18)F]fluoride generated by the cyclotron and has the capacity to isotopically label peptides of choice for positron emission tomography (PET).

Consulting a traditional healer and negative illness perceptions are associated with non-adherence to treatment in Indonesian women with breast cancer.

OBJECTIVE: The aim of the present study was to test the association between psychosocial factors and delay in uptake of treatment and treatment non-adherence in Indonesian women with breast cancer. METHODS: Seventy consecutive patients with breast cancer who were treated at the Hasan Sadikin Hospital in Indonesia were recruited. They completed a demographic form, the non-adherence questionnaire, the Breast Cancer Knowledge Test, the Brief Illness Perception Questionnaire, the Multidimensional Health Locus of Control Scales, the Satisfaction with Cancer Information Profile and the Distress Thermometer. RESULTS: Seventeen (24%) out of 70 patients reported that they had delayed initiating treatment at the hospital, and nine (13%) out of 70 patients had missed two or more consecutive treatment sessions. In the bivariate analyses, we found no significant differences on any of the psychological variables between patients who delayed initiating treatment and those patients who did not, whereas patients who had missed two or more consecutive sessions had lower satisfaction with the type and timing of information provided and more negative illness perceptions than patients who had not missed their sessions. In multivariate regression analyses, consulting a traditional healer before diagnosis was associated with treatment delay (ß = 1.27, p = 0.04). More negative illness perceptions (ß = 0.10, p = 0.02) and whether a traditional healer had been consulted after diagnosis (ß = 1.67, p = 0.03) were associated with missing treatment sessions. CONCLUSIONS: Indonesian health professionals need to be aware of patients' negative illness perceptions and their unrealistic belief in traditional healers.

Parenting stress as a mediator of parents' negative mood state and behavior problems in children with newly diagnosed cancer.

OBJECTIVE: The aim was to investigate the influence of parents' negative mood state and parenting stress on behavior in children with newly diagnosed cancer. METHODS: A total of 123 parents (n=58 fathers, n=65 mothers) of 67 children with newly diagnosed cancer completed three questionnaires separately at the same time measuring parents' negative mood state, parenting stress, and child behavior problems. RESULTS: Parents' negative mood state was weakly correlated to more child behavior problems (r=0.31, p<0.01), and higher levels of parenting stress were strongly correlated to more child behavior problems (r=0.61, p<0.01). Mediation analyses indicated that the relationship between parents' negative mood state and child behavior problems (c=0.29, p=0.02 (fathers); c=0.25, p=0.04 (mothers)) became non-significant after mediating for parenting stress (c'=0.003, p=0.98 (fathers); c'=0.10, p=0.42 (mothers)). The indirect effect of parents' negative mood state and child behavior problems was only significant for fathers (95% CI [0.12; 0.51]), indicating that parenting stress mediates the effect between fathers' negative mood state and child behavior problems. CONCLUSIONS: This is the first study to demonstrate the mediational role of parenting stress in fathers of a child with newly diagnosed cancer.

Psychosocial and cultural reasons for delay in seeking help and nonadherence to treatment in Indonesian women with breast cancer: a qualitative study.

OBJECTIVE: The aim of this study was to explore reasons for delay in seeking medical help and nonadherence to treatment in Indonesian women with breast cancer. METHOD: Semistructured interviews were conducted by purposive sampling, using a consecutive sample of 50 breast cancer patients who were treated at the Outpatient Surgical Oncology Clinic of Hasan Sadikin Hospital in Bandung, Indonesia. Interviews were recorded, transcribed verbatim, and coded using qualitative software. Codes were merged into main themes that were subsequently mapped onto the study's aim. RESULTS: Eight main themes concerning reasons for delay in seeking medical help and treatment nonadherence emerged, namely: lack of awareness and knowledge, cancer beliefs, treatment beliefs, financial problems, emotional burden, severe side effects, paternalistic style of communication, and unmet information needs. CONCLUSION: This study has identified several modifiable psychosocial and cultural factors related to delay in seeking help and nonadherence to treatment in breast cancer patients. We suggest that the provision of extensive information through media campaigns, treatment decision aids, and caregiver and patient education are needed to change the illness behaviors of Indonesian breast cancer patients.

A comparison of the behavior of (64)Cu-acetate and (64)Cu-ATSM in vitro and in vivo.

UNLABELLED: (64)Cu-diacetyl-bis(N(4)-methylthiosemicarbazonate), (64)Cu-ATSM, continues to be investigated clinically as a PET agent both for delineation of tumor hypoxia and as an effective indicator of patient prognosis, but there are still aspects of the mechanism of action that are not fully understood. METHODS: The retention of radioactivity in tumors after administration of (64)Cu-ATSM in vivo is substantially higher for tumors with a significant hypoxic fraction. This hypoxia-dependent retention is believed to involve the reduction of Cu-ATSM, followed by the loss of copper to cellular copper processing. To shed light on a possible role of copper metabolism in hypoxia targeting, we have compared (64)Cu retention in vitro and in vivo in CaNT and EMT6 cells or cancers after the administration of (64)Cu-ATSM or (64)Cu-acetate. RESULTS: In vivo in mice bearing CaNT or EMT6 tumors, biodistributions and dynamic PET data are broadly similar for (64)Cu-ATSM and (64)Cu-acetate. Copper retention in tumors at 15 min is higher after injection of (64)Cu-acetate than (64)Cu-ATSM, but similar values result at 2 and 16 h for both. Colocalization with hypoxia as measured by EF5 immunohistochemistry is evident for both at 16 h after administration but not at 15 min or 2 h. Interestingly, at 2 h tumor retention for (64)Cu-acetate and (64)Cu-ATSM, although not colocalizing with hypoxia, is reduced by similar amounts by increased tumor oxygenation due to inhalation of increased O2. In vitro, substantially less uptake is observed for (64)Cu-acetate, although this uptake had some hypoxia selectivity. Although (64)Cu-ATSM is stable in mouse serum alone, there is rapid disappearance of intact complex from the blood in vivo and comparable amounts of serum bound activity for both (64)Cu-ATSM and (64)Cu-acetate. CONCLUSION: That in vivo, in the EMT6 and CaNT tumors studied, the distribution of radiocopper from (64)Cu-ATSM in tumors essentially mirrors that of (64)Cu-acetate suggests that copper metabolism may also play a role in the mechanism of selectivity of Cu-ATSM.