Search

This study investigated the effect of combining radiation with an angiogenesis inhibitor and vascular disrupting agent on tumor response and systemic toxicity. CDF1 mice with 200 mm3 foot implanted C3H mammary carcinomas were treated with TNP-470 (100 mg/kg every second day for 2 weeks; s.c.) and combretastatin A-4 phosphate (CA4P; 1 × 250 mg/kg, i.p.). Radiation (230-kV X-rays) was locally administered to tumors of restrained non-anesthetized mice. Response was tumor growth delay and change in mouse body weight. Radiation induced changes in serum levels of 10 cytokines up to 72-h after irradiation were measured using a Luminex assay. The results showed that TNP-470 (100 mg/kg × 7) or CA4P (250 mg/kg × 1) significantly (Student’s t-test; p < 0.05) inhibited tumor growth; the greatest effect when these two drugs were combined. TNP-470 and CA4P, alone or together, also significantly enhanced tumor response to radiation. No systemic toxicity occurred with drugs administered alone or in combination, but toxicity was observed when TNP-470 was combined with radiation. Serum cytokine levels only showed a significant transient increase in IL-6 1-h after irradiating. In conclusion, combining different acting vascular targeting agents with radiation increased anti-tumor activity. However, this benefit may sometimes be associated with a radiation-induced inflammatory response increasing systemic toxicity. more...

Large donor–acceptor scaffolds derived from polycyclic aromatic hydrocarbons (PAHs) with tunable HOMO and LUMO energies are important for several applications, such as organic photovoltaics. Here, we present a large selection of PAHs based on central indenofluorene (IF) or fluorene cores and containing various dithiafulvene (DTF) donor units that gain aromaticity upon oxidation and a variety of acceptor units, such as vinylic diesters, enediynes, and cross-conjugated radiaannulenes (RAs) that gain aromaticity upon reduction. In some cases, the DTF units are expanded by pyrrolo annelation. The optical and redox properties of these compounds, in some cases carbon-rich, were studied by UV–vis absorption spectroscopy and cyclic voltammetry. Synthetically, the work explores IF diones or fluorenone as central building blocks by subjecting the carbonyl groups to a variety of reactions; that are, phosphite- or Lawesson’s reagent-mediated olefination reactions (to introduce DTF motifs), Ramirez/Corey–Fuchs dibromo-olefinations followed by Sonogashira couplings (to introduce enediynes motifs), and Knoevenagel condensations (to introduce the vinylic diester motif). By a subsequent Glaser–Hay coupling reaction, a RA acceptor unit was introduced to provide a DTF-IF-RA donor–acceptor scaffold with a low-energy charge-transfer absorption and multi-redox behavior. more...

Abstract A comprehensive literature reports on the correlation between elevated levels of urokinase-type plasminogen activator receptor (uPAR) and the severity of diseases with chronic inflammation including solid cancers. Molecular imaging is widely used as a non-invasive method to locate disease dissemination via full body scans and to stratify patients for targeted treatment. To date, the only imaging probe targeting uPAR that has reached clinical phase-II testing relies on a high-affinity 9-mer peptide (AE105), and several studies by positron emission tomography (PET) scanning or near-infra red (NIR) fluorescence imaging have validated its utility and specificity in vivo. While our previous studies focused on applying various reporter groups, the current study aims to improve uPAR-targeting properties of AE105. We successfully stabilized the small uPAR-targeting core of AE105 by constraining its conformational landscape by disulfide-mediated cyclization. Importantly, this modification mitigated the penalty on uPAR-affinity typically observed after conjugation to macrocyclic chelators. Cyclization did not impair tumor targeting efficiency of AE105 in vivo as assessed by PET imaging and a trend towards increased tracer uptake was observed. In future studies, we predict that this knowledge will aid development of new fluorescent AE105 derivatives with a view to optical imaging of uPAR to assist precision guided cancer surgery. more...

Abstract Background Literacy is one of the most important skills a students can achieve, as it provides access to information and communication. Unfortunately, literacy skills are not easily acquired, especially for students with intellectual disabilities who require augmentative and alternative communication (AAC). There are many barriers to literacy acquisition, some due to low expectations from parents and teachers and lack of evidence-based reading programs and reading materials adapted for AAC. Barriers as a result of extensive support needs is also a real factor. This trial aims to deliver reading instructions to 40 students with intellectual disabilities who require AAC and contribute in the debate on how to best support this population through reading instructions to maximizes their reading skills. Methodology Forty non-verbal or minimally verbal students (age 6–14) with intellectual disabilities who require AAC will be part of a reading intervention with a multiple single-case design with four randomized baselines. The intervention period will last for 18 months and will commence in March 2023. The students will receive the intervention in a one-to-one format, working systematically with a reading material that contains phonological awareness and decoding tasks based on the Accessible Literacy Learning (ALL) developed by Janice Light and David McNaughton. All the teachers will be trained to deliver the reading intervention. Discussion The reading material “Lesing for alle” (Reading for all) is based on and follow the strategies behind the research of ALL. The current trial will through a reading intervention contribute to move beyond only teaching sight words and combine several reading components such as sound blending, letter-sound correspondence, phoneme segmentation, shared reading, recognition of sight words, and decoding. The strategies and methods in use is built on the existing science of reading, especially what has been effective in teaching reading for students with intellectual disabilities who require AAC. There is limited generalizability of prior findings in reading-related phonological processing interventions to different populations of them who use AAC specially outside of the USA. More research is needed to understand how programs designed to improve reading skills across other settings understand the program’s long-term effects and to study the effectiveness when delivered by educators who are not speech language therapists or researchers. Trial registration NCT05709405 . Registered 23 January 2023. more...

IntroductionEarly intervention may significantly improve the prognosis associated with psychotic disorders in adulthood.MethodsThe present study examined the acceptability and effectiveness of a standalone intensive, in-home, mentalization-based treatment (MBT) for extremely high-risk, non-help-seeking youth on the psychotic spectrum [Equipo Clínico de Intervención a Domicilio (ECID), Home Intervention Clinical Team].ResultsDespite previously being unable to participate in treatment, more than 90% of youth engaged and those on the psychotic spectrum demonstrated slightly higher engagement than the general high-risk group (95% and 85%, respectively, X1 = 4.218, p = 0.049). Generalized estimating equation (GEE) models revealed no main group effect on the likelihood of reengaging with school over the first 12 months of treatment (X1 = 1.015, p = 0.314) when controlling for the duration of school absenteeism at intake. Overall, the percentage of school engagement rose from 12 to 55 over this period, more than 40% of the total sample experienced clinically reliable change and an additional 50% appeared clinically stable. No statistically significant difference was observed between the groups in the average change in HoNOSCA total severity score (X1 = 0.249, p = 0.618) or the distribution of youth into categories of clinical change during the first year of treatment (X1 = 0.068, p = 0.795).DiscussionThe present findings suggest that a mentalization based intervention may be able to engage extremely high-risk youth in treatment and have clinically meaningful impact on symptom severity and functioning after 12 months. more...

Background: The focus on hand hygiene during the pandemic has been reported to increase the hand eczema (HE) prevalence in health care workers (HCWs); however, detailed prospective data are missing. Objective: To evaluate changes in HE prevalence, exposures, and health-related quality of life among HCWs during the COVID-19 pandemic. Methods: In this prospective cohort study, HCWs employed at the hospitals in Copenhagen responded to a digital questionnaire at the beginning of the pandemic and 11 months thereafter. Results: A total of 795 HCWs responded to both questionnaires (83.4% women). The calculated 1-year HE prevalence decreased from 16.0% at baseline to 13.0% at follow-up. The number of hand washings decreased significantly, whereas the use of alcohol-based hand rubs on wet skin increased significantly. In a logistic regression model, increased use of alcohol-based hand rubs on wet skin was associated with HE at follow-up (odds ratio, 1.78; 95% CI, 1.11-2.87). Health-related quality of life worsened slightly at follow-up, with HE severity and frequent flareups being risk factors for a reduced health-related quality of life. Limitations: Sample size. Conclusion: In contrast to previous studies undertaken during the pandemic, we found a relatively low and stable HE prevalence. Our findings suggest that the interaction between changed exposures and HE is complex and cannot be linked to a single factor. more...

IntroductionNo evidence of disease activity with three components (NEDA-3) is achieved if the person with MS (pwMS) has no new MRI lesions, no new relapses and no change in Expanded disability status scale (EDSS) over 1 year. Whether NEDA-3 is a good tool in measuring disease activity is up for discussion, but it is superior to the individual parameters separately and user-friendly. There is disagreement on whether NEDA-3 is a good predictor of long-term disability.MethodsThis is a retrospective cohort study using real-world data with limited selection bias from the complete MS population at two hospitals in the southeast of Norway. We included pwMS diagnosed between 2006 and 2017 who had enough information to determine time to failure of NEDA-3 after diagnosis.ResultsOf 536 pwMS, only 38% achieved NEDA 1 year after diagnosis. PwMS achieving NEDA were more likely to be started on a high efficacy drug as the initial drug, but there were no demographic differences. Mean time to NEDA failure was 3.3 (95% CI 2.9–3.7) years. Starting a high efficiacy therapy was associated with an increased risk of sustaining NEDA as compared to those receiving moderate efficacy therapy. PwMS who achieved NEDA at year one had a mean time to EDSS 6 of 33.8 (95% CI 30.9–36.8) years vs. 30.8 (95% CI 25.0–36.6) years in pwMS who did not achieve NEDA, p < 0.001. When rebaselining NEDA 1 year after diagnosis, 52.2% achieved NEDA in the 1st year after rebaseline, mean time to NEDA failure was 3.4 (95% CI 3.0–3.7) years and mean time to EDSS 6 was 44.5 (95% CI 40.4–48.5) years in pwMS achieving NEDA vs. 29.6 (95% CI 24.2–35.0) years in pwMS not achieving NEDA, p < 0.001. After rebaseline, pwMS with a high efficacy therapy as the initial drug had a mean time from diagnosis to NEDA fail of 4.8 years (95% CI 3.9–5.8) vs. 3.1 years (95% CI 2.7–3.5) in pwMS started on a moderate efficacy therapy, p < 0.001. In pwMS with NEDA failure at year one, 70% failed one, 28% failed two and 2% failed three components. New MRI lesions were the most common cause of NEDA failure (63%), followed by new relapses (50%) and EDSS change (25%).ConclusionNEDA-3 from rebaseline after 1 year, once treatment is stabilized, can predict the long-term disease course in MS. Starting a high efficacy DMT is associated with longer time to NEDA failure than moderate therapies. Finally, most pwMS only fail one component and new MRI lesions are the most likely cause of NEDA failure. more...

Abstract The purpose of this study was to assess the clinical value of a deep learning (DL) model for automatic detection and segmentation of brain metastases, in which a neural network is trained on four distinct MRI sequences using an input-level dropout layer, thus simulating the scenario of missing MRI sequences by training on the full set and all possible subsets of the input data. This retrospective, multicenter study, evaluated 165 patients with brain metastases. The proposed input-level dropout (ILD) model was trained on multisequence MRI from 100 patients and validated/tested on 10/55 patients, in which the test set was missing one of the four MRI sequences used for training. The segmentation results were compared with the performance of a state-of-the-art DeepLab V3 model. The MR sequences in the training set included pre-gadolinium and post-gadolinium (Gd) T1-weighted 3D fast spin echo, post-Gd T1-weighted inversion recovery (IR) prepped fast spoiled gradient echo, and 3D fluid attenuated inversion recovery (FLAIR), whereas the test set did not include the IR prepped image-series. The ground truth segmentations were established by experienced neuroradiologists. The results were evaluated using precision, recall, Intersection over union (IoU)-score and Dice score, and receiver operating characteristics (ROC) curve statistics, while the Wilcoxon rank sum test was used to compare the performance of the two neural networks. The area under the ROC curve (AUC), averaged across all test cases, was 0.989 ± 0.029 for the ILD-model and 0.989 ± 0.023 for the DeepLab V3 model (p = 0.62). The ILD-model showed a significantly higher Dice score (0.795 ± 0.104 vs. 0.774 ± 0.104, p = 0.017), and IoU-score (0.561 ± 0.225 vs. 0.492 ± 0.186, p more...

The human skin is a highly complex organ comprising multiple tissue layers and diverse cell types. Here, the authors present a spatially-resolved quantitative proteomic atlas of the healthy human skin, characterizing the protein profiles of four skin layers and nine cell types. more...

BackgroundUp to half of patients with localized prostate cancer experience biochemical relapse within 10 years after definitive radiotherapy. The aim of this prospective study was to investigate the toxicity, dose to the organs at risk (OARs), and efficacy of dose-intensified focal salvage radiotherapy.Methods and MaterialThirty-three patients (median age 68.8 years) with histologically confirmed relapse after primary definitive radiotherapy were enrolled between 2012 and 2019. No patients had metastases at imaging or in bone marrow aspiration. Twenty-three patients were treated with high dose-rate brachytherapy to the recurrent tumor, defined at multiparametric MRI, with 3 fractions of 10 Gy with two weeks interval, and 10 patients by stereotactic body radiotherapy with 35 Gy to the local recurrence and 25 Gy to the whole prostate in 5 fractions. We used the RTOG-scoring system to grade genitourinary (GU) and gastrointestinal toxicity (GI) at three months (acute), and at 12, 24, and 36 months (late). Dose-volume histogram parameters to the local recurrence and the OARs were obtained and 2 Gy equivalent (EQD2) total dose was calculated using the linear-quadratic model with α/β = 3 Gy. Efficacy was assessed by the progression-free interval and overall survival.ResultsMedian follow-up time was 81 months (range 21–115). The cumulative moderate to severe GI and GU toxicities were 3.0% (1/33) and 15.2% (5/33). Six patients had grade 1 acute GI toxicity, none had grade 2 or 3. One patient had grade 3 acute GU toxicity, two had grade 2, and fourteen had grade 1. One patient had late GI toxicity grade 2 and eight had grade 1. Four patients had late GU toxicity grade 2 and eight had grade 1. No patients had grade 3 late toxicity. The mean total D90 to the recurrent tumor was 77.7 ± 17.0 Gy. The mean total rectum D2cc was 17.0 ± 7.9 Gy and the mean total urethra D0.1cc was 29.1 ± 8.2 Gy. Twenty-eight patients had re-irradiation without androgen deprivation therapy (ADT). Nine of these are still relapse-free and 10 had a recurrence-free interval longer than 2 years.ConclusionThe toxicity of salvage radiotherapy was mild to moderate. One-third of the patients achieved long-term stable disease without ADT and one-third had a recurrence-free interval longer than 2 years. Some patients progressed rapidly and probably did not benefit from re-irradiation. more...

The pathogenesis of chronic hand eczema remains unclear. Insights into the skin microbiome in hand eczema and its potential relevance to disease severity may help to elucidate the underlying mechanisms of hand eczema. The aim of this study was to characterize the microbiome in patients with hand eczema and healthy controls. A 5-visit prospective study was conducted over a period of 3 weeks. At each visit, bacterial swabs were taken from the hands of patients with hand eczema and controls. The microbiome was examined using DNA extraction and 16S rRNA amplicon sequencing (V3–V4 regions). Fifty patients with hand eczema and 50 controls were included (follow-up rate=100%). The baseline bacterial α-diversity was reduced on the hands of patients with hand eczema compared with controls (effect size=–0.31; 95% confidence interval (95% CI) –0.50; –0.11; p = 0.003). The dysbiosis on the patients’ hands was stable over the study period, was associated with disease severity, and was characterized by reduced bacterial diversity and different bacterial community compositions. more...

In this review we examine Nikolai Ivanovich Vavilov’s relationship to Scandinavia and the impact he and his ideas have had on Scandinavia. We trace the historical connections from Vavilov back to 18th century scientists, such as Carl Von Linneaus (Sweden) and 19th century European scientists such as Alphonse de Candolle (Switzerland), Henry de Vilmorin (France), and William Bateson (England). Vavilov has influenced the conservation work in Scandinavia resulting amongst other in the establishment of the Nordic Gene Bank in 1979 and the Svalbard Global Seed Vault which started operating in 2008. Vavilov travelled to Scandinavia in 1921 and in 1931 to give lectures and exchange ideas, especially with the breeders at the Swedish Seed Association (Svalöf) in Scania, Sweden, but also at the Copenhagen University in Denmark. Vavilov did not recognize Scandinavia as part of a center of origin of cultivated plants. It was only after World War II, when P.M. Zhukovsky, a scholar of N.I Vavilov, developed the concept of mega-centers of diversity of cultivated plants, that Scandinavia became part of what he termed the European-Siberian Region of Diversity. We list species domesticated in Scandinavia or Northern Europe, and we further discuss concepts related to crop evolution and highlight the great impact Vavilov has had by inspiring scientists across disciplines and over many decades. more...

Hand eczema is frequently colonized with Staphylococcus aureus. Some patients with hand eczema wear occlusive gloves regularly; however, the effect of this on the density of S. aureus is unexplored. The aim of this study is to examine the effect of occlusive gloves on the density of S. aureus sampled from the hands of patients with hand eczema. In an experimental set-up, patients with moderate-to-severe hand eczema wore an occlusive glove on one hand for 4 h with a 30-min break. Bacterial swabs were collected from the most severe eczema lesion on the hand before and immediately after glove exposure. S. aureus colony-forming units were counted and log-transformations used for comparison of before- and after-values. Among 30 patients, 19 (63%) were colonized with S. aureus. After glove occlusion S. aureus colony-forming units increased by a factor of 1.72 (p more...

Background: Moderate and high efficacy disease modifying therapies (DMTs) have a profound effect on disease activity. The current treatment guidelines only recommend high efficacy DMTs for patients with highly active MS. The objective was to examine the impact of initial treatment choice in achieving no evidence of disease activity (NEDA) at year 1 and 2.Methods: Using a real-world population-based registry with limited selection bias from the southeast of Norway, we determined how many patients achieved NEDA on moderate and high efficacy DMTs.Results: 68.0% of patients who started a high efficacy DMT as the first drug achieved NEDA at year 1 and 52.4% at year 2 as compared to 36.0 and 19.4% of patients who started a moderate efficacy DMT as a first drug. The odds ratio (OR) of achieving NEDA on high efficacy drugs compared to moderate efficacy drugs as a first drug at year 1 was 3.9 (95% CI 2.4–6.1, p < 0.001). The OR for high efficacy DMT as the second drug was 2.5 (95% CI 1.7–3.9, p < 0.001), and was not significant for the third drug. Patients with a medium or high risk of disease activity were significantly more likely to achieve NEDA on a high efficacy therapy as a first drug compared to moderate efficacy therapy as a first drug.Conclusions: Achieving NEDA at year 1 and 2 is significantly more likely in patients on high-efficacy disease modifying therapies than on moderate efficacy therapies, and the first choice of treatment is the most important. The immunomodulatory treatment guidelines should be updated to ensure early, high efficacy therapy for the majority of patients diagnosed with MS. more...

Physical activity, and likely the motivation for it, varies throughout the day. The aim of this investigation was to create a short assessment (CRAVE: Cravings for Rest and Volitional Energy Expenditure) to measure motivation states (wants, desires, urges) for physical activity and sedentary behaviors. Five studies were conducted to develop and evaluate the construct validity and reliability of the scale, with 1,035 participants completing the scale a total of 1,697 times. In Study 1, 402 university students completed a questionnaire inquiring about the want or desire to perform behaviors “at the present moment (right now).” Items related to physical activity (e.g., “move my body”) and sedentary behaviors (e.g., “do nothing active”). An exploratory structural equation model (ESEM) revealed that 10 items should be retained, loading onto two factors (5 each for Move and Rest). In Study 2, an independent sample (n = 444) confirmed these results and found that Move and Rest desires were associated with stage-of-change for exercise behavior. In Study 3, 127 community-residing participants completed the CRAVE at 6-month intervals over two years- two times each session. Across-session interclass correlations (ICC) for Move (ICC = 0.72–0.95) and Rest (ICC = 0.69–0.88) were higher than when they were measured across 24-months (Move: ICC = 0.53; Rest: ICC = 0.49), indicating wants/desires have state-like qualities. In Study 4, a maximal treadmill test was completed by 21 university students. The CRAVE was completed immediately pre and post. Move desires decreased 26% and Rest increased 74%. Changes in Move and Rest desires were moderately associated with changes in perceived physical fatigue and energy. In Study 5, 41 university students sat quietly during a 50-min lecture. They completed the CRAVE at 3 time points. Move increased 19.6% and Rest decreased 16.7%. Small correlations were detected between move and both perceived energy and tiredness, but not calmness or tension. In conclusion, the CRAVE scale has good psychometric properties. These data also support tenets of the WANT model of motivation states for movement and rest (Stults-Kolehmainen et al., 2020a). Future studies need to explore how desires to move/rest relate to dynamic changes in physical activity and sedentarism. more...

Positron emission tomography (PET) has an established role in the diagnosis, staging, and restaging of esophageal carcinoma. The authors illustrate the additional value of hybrid PET/computed tomography (CT) imaging to improve the accuracy of PET in distinguishing recurrent disease from benign posttherapy changes, delineating the anatomic location of metastatic disease, and monitoring therapy response. [ABSTRACT FROM AUTHOR] more...

[This corrects the article DOI: 10.1371/journal.pone.0141881.].

Background: Blood-based protein biomarkers can be a useful tool as pre-treatment prognostic markers, as they can reflect both variations in the tumor microenvironment and the host immune response. We investigated the influence of a panel of plasma proteins for the development of any failure defined as recurrent disease in the T-, N-, or M-site in HNSCC. Methods: We used a multiplex bead-based approach to analyze 19 proteins in 86 HNSCC patients and 15 healthy controls. We evaluated the associations between the biomarkers, loco-regional failure, failure in the T-, N-, or M-site, overall survival (OS), p16 status, and hypoxia. Results: In 41 p16 positive oropharynx cancer patients we identified a profile of biomarkers consisting of upregulation of IL-2, IL-4, IL-6, IL-8, eotaxin, GRO-a, and VEGF and downregulation of VEGFR-1 and VEGFR-2 with a significantly reduced risk of failure (p more...

The skin microbiota of atopic dermatitis (AD) patients is characterized by increased Staphylococcus aureus colonization, which exacerbates disease symptoms and has been linked to reduced bacterial diversity. Skin bacterial communities in AD patients have mostly been described at family and genus levels, while species-level characterization has been limited. In this study, we investigated the role of the bacteria belonging to the Staphylococcus genus using targeted sequencing of the tuf gene with genus-specific primers. We compared staphylococcal communities on lesional and non-lesional skin of AD patients, as well as AD patients with healthy controls, and determined the absolute abundance of bacteria present at each site. We observed that the staphylococcal community, bacterial alpha diversity, and bacterial densities were similar on lesional and non-lesional skin, whereas AD severity was associated with significant changes in staphylococcal composition. Increased S. aureus, Staphylococcus capitis, and Staphylococcus lugdunensis abundances were correlated with increased severity. Conversely, Staphylococcus hominis abundance was negatively correlated with severity. Furthermore, S. hominis relative abundance was reduced on AD skin compared to healthy skin. In conclusion, various staphylococcal species appear to be important for skin health. more...

Music and language share the property of being rhythmic signifying behaviours. In singing, and in poetry, the musical beats and the metric units of the text, plus the prosodic accents, are coordinated to form often complex rhythms. However, dancing is probably even more fundamental than singing as an indicator of musical meaning. In the bodily behaviour of dancing, the rhythmic patterns are expressed through gestures that communicate from body to body and directly signify emotional states — gestures and states which are subsequently mirrored mentally by an audience. Dance is therefore determined by contexts, and as contexts are determined by the domains of meaning in the human lifeworld, different forms of dancing unfold in different semantic domains. This article discusses examples of such differences in the domain-dependent meaning of dance, in particular by comparing tango to capoeira. By analyzing current discourse on these genres, it furthermore examines the conceptual contents of a number of metaphors linking dance to dialogue, thereby highlighting the communicative role of the fundamental triad: music, language, and dance. more...

The impact of children's interactions with parents in the context of out-of-home placements is receiving much-needed cross-disciplinary attention. However, the paucity of instruments that can reliably represent young children's experiences of such interactions precludes a nuanced evaluation of their impact on wellbeing and development. In response to this empirical gap, the present study investigates children's relational withdrawal as a clinically salient, easily observable and conceptually valid measure of infants' and toddlers' responses to parents. Relational withdrawal, challenging behaviors and salivary cortisol were assessed before, during and after parental visits. Conceptually, the findings suggest that observations of relational withdrawal correlate meaningfully with measure of neurobiological reactivity. Clinically, three profiles of cross-variable responses in children appeared, distinguishing between groups that experience increased, decreased or unchanged levels of stress in response to parental visits. Taken together, the findings lend empirical support to systematic observations of relational withdrawal to bolster evaluations of young children's experience of parental visitation during out-of-home placements. more...

Agricultural diversification is one way of meeting the future challenges associated with climate change and population growth, making farmers’ access to a diversity of high-yielding, good quality cultivars critical. In this paper we provide an overview of the seed system in the Nordic region from the 1950 to the present. The emphasis is on breeding businesses and their production of cultivars. Key primary sources have been the national variety lists, other written sources on plant breeding, and a survey. We document how enterprises have merged and how this consolidation process has affected the production of new cultivars and led to an emphasis on major crops, resulting in the abandonment of breeding activities for several other crops. The results are discussed in relation to structures and in the broader context of agrobiodiversity issues in peripheral regions of the world. more...

BackgroundMothers' stress in pregnancy is considered an environmental risk factor in child development. Multiple stressors may combine to increase risk, and maternal personal characteristics may offset the effects of stress. This study aimed to test the effect of 1) multifactorial prenatal stress, integrating objective "stressors" and subjective "distress" and 2) the moderating effects of maternal characteristics (perceived social support, self-esteem and specific personality traits) on infant birthweight.MethodHierarchical regression modeling was used to examine cross-sectional data on 403 birth mothers and their newborns from an adoption study.ResultsDistress during pregnancy showed a statistically significant association with birthweight (R2 = 0.032, F(2, 398) = 6.782, p = .001). The hierarchical regression model revealed an almost two-fold increase in variance of birthweight predicted by stressors as compared with distress measures (R2Δ = 0.049, F(4, 394) = 5.339, p < .001). Further, maternal characteristics moderated this association (R2Δ = 0.031, F(4, 389) = 3.413, p = .009). Specifically, the expected benefit to birthweight as a function of higher SES was observed only for mothers with lower levels of harm-avoidance and higher levels of perceived social support. Importantly, the results were not better explained by prematurity, pregnancy complications, exposure to drugs, alcohol or environmental toxins.ConclusionsThe findings support multidimensional theoretical models of prenatal stress. Although both objective stressors and subjectively measured distress predict birthweight, they should be considered distinct and cumulative components of stress. This study further highlights that jointly considering risk factors and protective factors in pregnancy improves the ability to predict birthweight. more...

A 73-year-old woman was referred to the hospital due to a pigmented, asymptomatic nevus on her right arm that had changed in size and color. The histopathological examination showed a superficial spreading malignant melanoma, Clark level III, 2.26 mm in thickness. Two years later, the patient presented a 10 cm rapidly growing mass in her right axilla. The mass in the axilla measured 12.5 ΄ 9 ΄ cm. It revealed a lymph node metastases with a tumor growth composed of two different contiguous morphological and immunohistochemical components, respectively, melanosomes and leiomyosarcoma. The combination of a melanocytic nevus with other tumor of epidermal or adnexal origin has been described before, but still the co-existence of two different neoplasms within a lesion is still uncommon. The most common combination is basal cell carcinoma and melanocytic nevus or one of them together with a seborrheic keratosis. There have also been occasional reports of rhabdomyosarcomatous differentiation. However, mesenchymal differentiation, and in this case leiomysarcoma, with formation of heterologous elements in melanocytic tumor is very rare. Another plausible explanation may be that malignant melanoma cells could have transdifferentiated into a leiomyosarcomatoid phenotype with resulting metastases of either type. Malignant melanomas have shown a wide variety of cytological changes and can mimic carcinomas, lymphomas, and sarcomas. Spindle cell melanomas commonly simulate spindle cell carcinomas. It has also been documented that desmoplastic melanomas can change into fibroblastic, Schwannian, and myofibroblastic differentiation. more...

Background: Both small cell and non-small cell lung cancer overexpress somatostatin receptors (SSTR). P2045 peptide is an 11-amino acid somatostatin analog that binds with high affinity to SSTR and can be labeled with Tc-99m to gauge receptor prevalence or with Re-188 for 2.1 MeV beta radiotherapy. To evaluate the safety of this approach, a phase I dose-escalation study of Re-188 P2045 in SSTR-positive lung cancer was performed., Methods: Patients were required to have stage IIIb or IV or recurrent non-small cell lung cancer or extensive stage or recurrent small cell lung cancer, performance status 0 to 1, and normal organ function. There were no limitations on the number of prior therapies. Tumor SSTR was detected with Tc-99m P2045. If positive and projected renal dose of radiation from Re-188 P2045 was less than 20 Gy, treatment with escalating doses of Re-188 P2045 was instituted. Three doses were evaluated 30 mCi/m2, 60 mCi/m2, and 90 mCi/m2. A single dose of Re-188 P2045 was allowed. Dose-limiting toxicity was defined as > or = grade 3 nonhematologic toxicity or grade 4 hematologic toxicity., Results: Fifteen patients were enrolled. The median age was 61 years. Fourteen patients had > or = 2 prior chemotherapy regimens. All were imaged with Tc-99m P2045, eight patients received Re-188 P2045. The most common toxicity was mild lymphopenia. The trial was halted at the 90 mCi/m2 level when three patients were projected to have renal radiation doses above 20 Gy. The monoclonal antibody was not determined, and no responses were seen. Five of the eight patients (62.5%, 95% CI: 24-91%) had stable disease for at least 8 weeks, all of whom entered the study with progressive disease. Median overall survival was 11.5 months., Conclusions: This trial demonstrated that Re-188 P2045 was well tolerated. Tc-99m P2045 imaging allows identification of patients who may benefit from this treatment. Although responses were not seen, survival for these heavily pretreated patients is interesting and merits further research. more...

N-(2-hydroxypropyl) methacrylamide (HPMA) copolymer-RGDfK conjugates targeting the alpha(v)beta(3) integrin have shown increased accumulation in solid tumors and promise for selective delivery of radiotherapeutics to sites of angiogenesis- or tumor-expressed alpha(v)beta(3) integrin. An unresolved issue in targeting radiotherapeutics to solid tumors is toxicity to non-target organs. To reduce toxicity of radiolabeled conjugates, we have synthesized HPMA copolymer-RGDfK conjugates with varying molecular weight and charge content to help identify a polymeric structure that maximizes tumor accumulation while rapidly clearing from non-targeted organs. Endothelial cell binding studies showed that copolymer conjugates of approximately 43, 20 and 10 kD actively bind to the alpha(v)beta(3) integrin. Scintigraphic images showed rapid clearance of indium-111 ((111)In) radiolabeled conjugates from the blood pool and high kidney accumulation within 1 h in tumor bearing mice. Biodistribution data confirms images with high accumulation in kidney (max 210% ID/g for 43 kD conjugate) and lower tumor accumulation (max 1.8% ID/g for 43 kD conjugate). While actively binding to the alpha(v)beta(3) integrin in vitro, HPMA copolymer-RGDfK conjugates with increased negative charge through increased CHX-A''-DTPA chelator content in the side chains causes increased kidney accumulation with a loss of tumor accumulation in vivo. more...

Radionuclidic impurities of (210)Po prepared by neutron irradiation of (209)Bi via the (209)Bi(n,gamma)(210)Bi reaction were investigated. Following irradiation and ingrowth, a pure (210)Po solution was obtained by sublimation and dissolution. Results were obtained by liquid scintillation (LS) counting, isotope dilution alpha (alpha)-spectrometry, and high-purity germanium gamma-ray spectrometry. No alpha-emitting (3-10MeV) or gamma-emitting (30-3600keV) impurities were detected, with calculated lower limits of detection for impurities of approximately 0.01% (210)Po activity. LS spectra revealed no identifiable beta-emitting impurity. LS sources prepared using Opti-Phase 'Hi Safe' III and Opti-Fluor LS cocktails were stable over a 4-day multi-cycle counting period for (210)Po dissolved in 0.1% trifluoracetic acid (pH approximately 2, water fraction approximately 2%). The radioactivity concentration determined by LS counting was verified by isotope dilution alpha spectrometry. These results suggest that neutron irradiation of (209)Bi (followed by sublimation) can produce (210)Po in a highly pure form that is suitable for radiopharmaceutical preparations. more...

Objective: To determine the usefulness of FDG PET/CT scanning in the management and staging of myeloma and to assess its strengths and limitations., Design: FDG PET/CT scans and all other available imaging studies were reviewed retrospectively from 16 consecutive patients by two experienced musculoskeletal radiologists and two nuclear medicine physicians working in consensus., Patients: The 16 patients had undergone a total of 19 FDG PET/CT scans. Radiographs were available in all cases, including 13 skeletal surveys; 25 CT scans (16 chest, three abdominal, four pelvic, one spine, one neck) and 22 MR imaging studies (17 spine, three pelvic, two extremity) also were reviewed. Patients' records were examined for relevant clinical information. All focal areas of abnormal FDG uptake were correlated with the other imaging studies to determine clinical significance. FDG PET/CT scans also were reviewed to see if small lesions shown on the other imaging studies could be identified in retrospect., Results: The 12 men and four women had an average age of 58 years (range 30-69 years). All 16 patients had an established diagnosis of multiple myeloma, with average duration of disease, from time of initial diagnosis to review, of 30 months (range 6 months to 11+ years). The FDG PET/CT scans revealed a total of 104 sites (90 in bone, 14 soft tissue) that were suspicious for neoplastic activity based on a standardized uptake value (SUV) greater than 2.5. Fifty-seven of these sites (55%) were new or previously undetected. The other imaging studies (X-ray, CT, MR) and clinical information confirmed the other 47 areas but also revealed 133 other small skeletal lesions. Six of these 133 additional lesions showed mild FDG uptake on re-review of the PET/CT scans. The FDG PET/CT findings led to management changes in 9/16 patients. MR imaging revealed five cases of diffuse bone involvement (four spine, one scapula) that were not evident by FDG PET/CT., Conclusion: FDG PET/CT scans are useful for the management and staging of myeloma. However, if PET/CT were the sole imaging study done, it would miss many additional small lytic skeletal lesions and could miss diffuse spine involvement. more...

The alphaVbeta3 integrin plays important roles in tumor-induced angiogenesis and tumor metastasis and hence, many small molecule alphaVbeta3 ligands have been developed for cancer diagnosis and therapy. Although these show good alphaVbeta3 targeting, most have suboptimal pharmacokinetics and show rapid tumor washout. We studied the biodistribution and tumor targeting properties of N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer based conjugates of mono-(RGDfK) and doubly cyclized (RGD4C) alphaVbeta3 binding peptides. Endothelial cell adhesion studies showed similar affinity of HPMA-RGD4C and HPMA-RGDfK conjugate for alphaVbeta3 integrins. Scintigraphic images of tumor bearing mice demonstrated that both conjugates showed tumor localization at 24 h post-injection and were retained at the tumor site until 192 h, whereas the efficient background clearance was observed over time. Necropsy organ counts showed that tumor accumulation of both HPMA-RGD4C and HPMA-RGDfK conjugates increased over time with peak accumulations at 4.9 +/- 0.9% and 5.0 +/- 1.2% ID/g, respectively. In contrast the background organ distribution rapidly cleared over time resulting in significant increases of tumor-to-background ratios. The radioactive dose as indicated by the area under curve (HPMA-RGD4C: 4825.3 microCi/g h and HPMA-RGDfK: 4424.9 microCi/g h) was highest for the tumor. The polymer conjugates of RGD4C or RGDfK provide a means to enhance tumor uptake, decrease background accumulation, and enable selective delivery of therapeutic or diagnostic agents to tumor sites. more...

Introduction: New methods of delivering radiotherapy to sites of occult or disseminated cancer are needed to control the disease and address the failure of conventional therapy. Because tumor cells rely on angiogenesis for survival, we assessed the effectiveness of beta-emitter radiotherapy delivered by polymer-peptide conjugates that target tumor neovasculature. This molecularly targeted radiation is intended to damage both the endothelial bed and surrounding neoplastic cells., Methods: N-(2-Hydroxypropyl) methacrylamide (HPMA), a biocompatible and water-soluble copolymer, was derivatized to incorporate side chains for (99m)Tc and (90)Y chelation and was further conjugated to a alpha(V)beta(3) integrin-targeting peptide (RGD4C). The HPMA copolymer-RGD4C conjugate was characterized by its side-chain contents, in vitro endothelial cell adhesion assay and its biodistribution and antitumor effectiveness in a SCID mouse xenograft model of human prostate carcinoma., Results: The conjugate contained about 16 RGD4C moieties per polymer backbone. Tumor accumulation significantly increased (P < .01) over time from 1.05 +/- 0.03 % injected dose (%ID)/g tissue at 1 h to 4.32 +/-0.32% at 72 h. The activity in major normal tissues significantly decreased (P < .05) during that period. At 21 days, the control tumors increased 442% in volume from baseline. In contrast, a 7% and a 63% decrease of tumor volume were observed for the 100- and 250-microCi (90)Y treatment groups, respectively. Histopathological examination revealed increased apoptosis in the treated tumors with no acute signs of radiation-induced toxicity to other organs., Conclusion: This copolymer-peptide conjugate targets tumor angiogenic vessels and delivers sufficient radiotherapy to arrest tumor growth. more...

Unlabelled: Three-dimensional (3D) PET acquisition has the potential to reduce image noise but the advantage of 3D PET for studies outside the brain has not been well established. To compare the performance of 2-dimensional (2D) and 3D acquisition for whole-body (18)F-FDG applications, a series of patient studies were performed using a lutetium oxyorthosilicate (LSO)-based tomograph., Methods: Comparative 2D and 3D images were acquired for 27 oncology patients using an LSO-based tomograph. Data acquisition (350-650 keV, 6 ns) started 99 +/- 12 min (mean +/- SD) after injection of 624 +/- 76 MBq (18)F-FDG. Bias caused by tracer redistribution and decay was eliminated by acquiring dynamic data over a single-bed position using a protocol that alternated between septa-in and septa-out modes (2D, 3D, 2D, 3D, 2D, 3D). Frames were combined to form 8 statistically independent sinograms: four 2D replicates (105 s) and four 3D replicates (90 s). The different frame durations in 2D and 3D compensated for the different number of overlapping bed positions required for an 85-cm whole-body study. Images were reconstructed with either 2D or fully 3D ordered-subsets expectation maximization (2 iterations and 8 subsets; 2D 6-mm gaussian, 3D 5- and 6-mm gaussian). Image target-to-background ratio was assessed by dividing the lesion maximum by the mean within a neighboring background region. Image noise was assessed by applying background regions of interest to the replicate images and calculating the within-patient coefficient of variation., Results: The difference in target-to-background ratio between the 2D and 3D images, when they were filtered with 6-mm and 5-mm gaussian filters, respectively, was not highly statistically significant (P = 0.16). The mean ratio of 3D to 2D image values was 0.94 with 95% limits of agreement of 0.63-1.41. The within-patient coefficients of variation for the 2D and 3D images were 13% +/- 15% and 9% +/- 10%, respectively (P = 0.0005)., Conclusion: Under conditions of matched target to-to-background ratios, the 3D mode was found to produce images with significantly less variability than the 2D mode. These data provide support for the use of 3D acquisition with LSO detectors to reduce scan times in whole-body (18)F-FDG applications. more...

Several nanoscale carriers (nanoparticles, liposomes, water-soluble polymers, micelles and dendrimers) have been developed for targeted delivery of cancer diagnostic and therapeutic agents. These carriers can selectively target cancer sites and carry large payloads, thereby improving cancer detection and therapy effectiveness. Further, the combination of newer nuclear imaging techniques providing high sensitivity and spatial resolution such as dual modality imaging with positron emission tomography/computed tomography (PET/CT) and use of nanoscale devices to carry diagnostic and therapeutic radionuclides with high target specificity can enable more accurate detection, staging and therapy planning of cancer. The successful clinical applications of radiolabeled monoclonal antibodies for cancer detection and therapy bode well for the future of nanoscale carrier systems in clinical oncology. Several radiolabeled multifunctional nanocarriers have been effective in detecting and treating cancer in animal models. Nonetheless, further preclinical, clinical and long-term toxicity studies will be required to translate this technology to the care of patients with cancer. The objective of this review is to present a brief but comprehensive overview of the various nuclear imaging techniques and the use of nanocarriers to deliver radionuclides for the diagnosis and therapy of cancer. more...

Calciphylaxis is a highly morbid syndrome of vascular calcification and skin necrosis, the pathophysiology of which remains largely elusive. We report a patient with end-stage renal disease and multiple painful skin lesions who underwent a bone scan for extremity pain. Increased tracer accumulation was seen in the subcutaneous tissues of the trunk and lower extremities. In this case, the bone scan aided in the diagnosis and treatment of calciphylaxis for a patient who experienced a relatively short hospital stay. more...

Unlabelled: Endothelial cells in tumor angiogenesis are highly accessible, genetically stable and present unique molecular markers for targeted therapy. Neoplasia is also characterized by enhanced vascular permeability and disordered lymphatics so that both active and passive targeting strategies may play a role in localizing angiogenesis-targeted agents. To investigate the relative importance of these targeting strategies, the tissue biodistribution of both endothelial-specific and nonspecific peptides and their macromolecular peptide-copolymer conjugates were studied in 2 xenograft models of prostate cancer. Tumor-to-normal tissue background ratios (T/B) of these constructs were compared to evaluate the effect of molecular size on blood clearance and nonspecific vascular permeability., Methods: Water-soluble N-(2-hydroxypropyl)methacrylamide (HPMA) copolymers were synthesized with side chains terminated in a doubly cyclized Arg-Gly-Asp motif KACDCRGDCFCG (RGD4C: active peptide targeting the alpha(V)beta(3) integrin) and KACDCRGECFCG (RGE4C: nonactive peptide). The bioactivity of the polymer conjugates and free peptides was characterized in vitro by endothelial cell adhesion assay. The (99m)Tc(CO)(3)-labeled compounds were injected into SCID mice bearing DU145 or PC-3 prostate tumor xenografts for scintigraphic imaging and necropsy organ counting., Results: HPMA copolymer-RGD4C conjugates showed similar inhibition of cell adhesion as free RGD4C attached to (99m)Tc(CO)(3) chelator N-omega-bis(2-pyridylmethyl)-L-lysine (RGD4C-DPK) and were significantly higher (P < 0.05) than RGE4C, HPMA copolymer-RGE4C, and a hydrolyzed HPMA copolymer precursor. Scintigraphic images obtained at 24 h showed specific tumor localization of HPMA copolymer-RGD4C and RGD4C compared with RGE4C conjugates in both prostate tumor models. Twenty-four-hour necropsy data in the DU145 model showed significantly higher (P < 0.001) tumor localization for HPMA copolymer-RGD4C (4.60 +/- 1.80%ID/g [percentage injected dose per gram tissue]) and RGD4C-DPK (3.37 +/- 0.32%ID/g) compared with HPMA copolymer-RGE4C (1.24 +/- 0.15%ID/g) and RGE4C-DPK (0.32 +/- 0.04%ID/g). Similar results were observed in the PC-3 model. Moreover, higher T/B for the polymer conjugates indicated reduced extravasation of the targeted polymeric conjugates in normal tissues., Conclusion: Specific molecular targeting of the alpha(v)beta(3) integrin and nonspecific vascular permeability are both significant in the relative tumor localization of polymeric conjugates of RGD4C. Extravascular leak in nonspecific organs appears to be a major factor in reducing the T/B for the peptide molecules. more...

Sites of neovascular angiogenesis are important chemotherapy targets. In this study, the synthesis, characterization, in-vivo imaging and biodistribution of a technetium-99m labeled, water-soluble, N-(2-hydroxypropyl) methacrylamide (HPMA) copolymer carrying doubly cyclized Arg-Gly-Asp motifs (HPMA copolymer-RGD4C conjugate) are reported. In vitro endothelial cell adhesion assays indicated that HPMA copolymer-RGD4C conjugates inhibited alphaVbeta3-mediated endothelial cell adhesion while HPMA copolymer Arg-Gly-Glu control conjugates (HPMA copolymer-RGE4C conjugate) and hydrolyzed HPMA copolymer precursor (HPMA copolymer) showed no activity. The scintigraphic images of prostate tumor bearing SCID mice obtained 24 h post-i.v. injection indicated greater tumor localization of HPMA copolymer-RGD4C conjugate than the control, HPMA copolymer-RGE4C conjugate. The 24-h necropsy radioactivity data showed that HPMA copolymer-RGD4C conjugate had significantly higher (p<0.001) tumor localization compared to HPMA copolymer-RGE4C conjugate and HPMA copolymer. Also, HPMA copolymer-RGD4C conjugates had sustained tumor retention over 72 h and reasonably efficient clearance from the background organs. These results suggest that specific tumor angiogenesis targeting is possible with HPMA copolymer-RGD4C conjugates. This construct provides a foundation that should support targeted delivery of radionuclides and drugs to solid tumors for diagnostic and therapeutic applications. more...

Background: Fanolesomab (NeutroSpec) is a murine monoclonal Tc labelled anti-CD15 IgM antibody that localizes collections of human polymorphonuclear neutrophils (PMNs) at sites of infection., Objectives: The objectives of this study were to evaluate the safety of repeated injections of fanolesomab and the extent of induction of human anti-mouse antibody (HAMA) response., Methods: Thirty healthy adults (15 men and 15 women) were enrolled in the study. Subjects were injected on two separate occasions, separated by 21 days, with 125 microg of fanolesomab that had been labelled with decayed Tc. HAMA assays were performed on blood samples drawn prior to each injection, and at 7 and 28 days following the second injection. Safety was determined by monitoring for adverse events, and for changes in vital signs, physical examination and clinical laboratory measurements., Results: Five subjects exhibited induction of HAMA (16.7%; 95% CI, 6.3-34.2%). Two were considered marginal responses (increase from 5 to 31, and 5 to 20 and 24 ng x ml), and three were considered moderate (7 to 228, 7 to 140 and 270, and 7 to 35 and 450 ng x ml). There were no strong responses (greater than 1000 ng x ml). Seven subjects experienced adverse events, most of which were coincidental to administration of fanolesomab. There were no serious or severe adverse events., Conclusions: Repeated fanolesomab injections at clinically useful doses does not appear to induce a strong HAMA response nor does it present a risk for serious adverse events. more...

Purpose: To synthesize novel technetium-99m (99mTc)-labeled N-(2-hydroxypropyl) methacrylamide (HPMA) copolymers and characterize the effect of charge and molecular weight on their biodistribution in SCID mice., Methods: Electronegative and neutral 7-kDa, 21-kDa, and 70-kDa HPMA copolymers containing a 99mTc chelating comonomer, bearing N-omega-bis(2-pyridylmethyl)-L-lysine (DPK), were synthesized by free-radical precipitation copolymerization. The copolymers were labeled via 99mTc tricarbonyl chelation to DPK-bearing comonomer. They were characterized by side-chain content, molecular weight, molecular weight distribution, radiochemical purity, and labeling stability. Scintigraphic images were obtained during the first 90 min and at 24 h postintravenous injection in SCID mice. At 24 h, organ radioactivity was determined from necropsy tissue counting., Results: 99mTc-labeled HPMA copolymers showed greater than 90% stability over a 24-h challenge with cysteine and histidine. Scintigraphic images and the necropsy data showed that the negatively charged copolymers were eliminated from the body significantly faster than the neutral copolymers in a size-dependent manner., Conclusions: To facilitate clinical scintigraphic imaging, stable chelation of 99mTc may be achieved by incorporation of a DPK-bearing comonomer into the HPMA backbone. Electronegative and neutral 99mTc-labeled HPMA copolymers of 7, 21, and 70 kDa show significant variation in organ biodistribution in SCID mice. 99mTc-labeled HPMA copolymers could be used as diagnostic agents and to study pharmacokinetics of delivery systems based on these copolymers. more...

The dissemination of positron emission tomography (PET) technology has enabled a functional approach to the evaluation of lung cancer that complements the anatomic assessment provided by chest radiography, computed tomography (CT) scanning, and magnetic resonance imaging. PET has excellent sensitivity and good specificity for the determination of malignancy in the solitary pulmonary nodule, but these data must be weighed against the evidence of instances of false-positive results because of inflammatory lesions and false-negative results in small- or low-metabolism neoplasms. Therefore, PET may not be advisable when these scenarios apply. Furthermore, in a patient with a very high pretest likelihood of lung cancer (eg, a new or enlarging spiculated nodule in a long-time smoker), the value of PET is less certain because a negative result may be discounted. PET has altered the approach to the staging of lung cancer. It adds value to the evaluation of the mediastinum and extrathoracic structures compared to conventional methods by upstaging or downstaging a substantial proportion of patients. If the staging assessment is negative on PET, the use of mediastinoscopy may be obviated in selected cases. Histologic confirmation of positive PET findings should be obtained before excluding patients from curative resection. PET provides incremental information to CT in the evaluation of persistent and recurrent disease, and response measured on PET appears more accurate as a predictor of ultimate survival. The more recent development of PET-CT permits fusion of anatomic and functional information. Early investigations suggest that this strategy provides superior results compared to either technique alone. more...

Administration of yttrium-90 microspheres via the hepatic artery is an attractive approach to selectively deliver therapeutic doses of radiation to liver malignancies. This procedure allows delivering radiation absorbed doses in excess of 100 Gy to the tumors without significant liver toxicity. The microsphere therapy involves different specialties including medical oncology, radiation oncology, nuclear medicine, interventional radiology, medical physics, and radiation safety. We have treated 80 patients with nonresectable hepatic tumors with yttrium-90 microspheres during the past two years on an institutional study protocol. The nominal radiation absorbed dose to the tumor in this study was 150 Gy. Required activity was calculated based on the nominal radiation absorbed dose and patient's liver volume obtained from the CT scan, assuming a uniform distribution of the microspheres within the liver. Microspheres were administered via a catheter placed into the hepatic artery. The actual radiation absorbed doses to tumors and normal liver tissue were calculated retrospectively based on the patient's 99mTc-MAA study and CT scans. As expected, the activity uptake within the liver was found to be highly nonuniform and multifold tumor to nontumor uptake was observed. A partition model was used to calculate the radiation absorbed dose within each region. For a typical patient the calculated radiation absorbed doses to the tumor and liver were 402 and 118 Gy, respectively. The radiation safety procedure involves confinement of the source and proper disposal of the contaminated materials. The average exposure rates at 1 m from the patients and on contact just anterior to the liver were 6 and 135 uSv/h, respectively. The special physics and dosimetry protocol developed for this procedure is presented. more...

Lower-limb deep venous thrombosis (DVT) affects between 1% to 2% of hospitalized patients. These thrombi disrupt the vascular integrity of the lower limbs and are the source of emboli that kill approximately 200,000 patients each year in the United States. The causes of thrombosis include vessel wall damage, stasis or low flow, and hypercoagulability. These factors favor clot formation by disrupting the balance of the opposing coagulative and fibrinolytic systems. The symptoms and signs of venous thrombosis are caused by obstruction to venous outflow, vascular inflammation, or pulmonary embolization. About 70% of patients referred for clinically suspected venous thrombosis, however, do not have the diagnosis confirmed by objective testing. Among the 30% who have venous thrombosis, about 85% have proximal vein thrombosis, and the remainder have thrombosis confined to the calf. Physicians cannot rely on signs and symptoms to make the diagnosis of DVT and must depend on imaging studies to guide treatment. Patients with proximal vein thrombosis who are inadequately treated have a 47% frequency of recurrent venous thromboembolism over 3 months. In contrast, clinically detectable recurrence occurs in less than 2% of patients with proximal vein thrombosis if an adequate anticoagulant response is achieved. Of the diagnostic procedures for DVT, venography is the only invasive test of proven value, and ultrasonographic (US) studies are the most commonly used noninvasive modaity. Other procedures are occasionally used to diagnose DVT, including impedance plethysmography, computed tomography, and magnetic resonance imaging. US examinations are noninvasive, they are rapidly obtained, and they can be performed serially. In symptomatic patients, venous US is sensitive and specific for proximal DVT; however, US is insensitive to calf vein thrombosis and to asymptomatic DVT occurring after surgery. Patients with symptoms of recurrent DVT also can present a difficult diagnostic problem. Only about 20% to 30% of these individuals actually have the disease; the rest have symptoms arising from chronic venous insufficiency or from any of the causes of lower extremity pain. After an acute episode, up to 50% of patients have compression ultrasound abnormalities for 6 months that are indistinguishable from the original findings of DVT. Hence, there are a significant number of patients and clinical circumstances in which the diagnosis of DVT is difficult. 99mTc-radiolabeled peptides that target the molecular biology of thrombosis should aid in the management of the disease, particularly in asymptomatic patients at high risk, in patients with recurrent symptoms, in patients with active DVT in the calf and/or pelvis, and in patients with intermediate- or low-probability lung scans. more...

Unlabelled: Scintigraphic detection of occult disease is limited by background activity in the blood and in the extravascular space that reduces target-specific contrast. To lower nonspecific background activity, we have studied the in vivo biodistribution kinetics of a clot-targeting molecule (MH1 Fab') attached to (99m)Tc-dextran. We tested the hypothesis that the complex will have better background clearance than the directly radiolabeled clot-targeting molecule., Methods: Fab' fragments of MH1 Fab' antifibrin antibody were coupled to (99m)Tc-sulfhydryl dextran through disulfide exchange, and clot binding bioreactivity was tested in vitro and in vivo in a rabbit jugular vein thrombus model. To assess the background clearance kinetics and extravascular leakage, we studied (99m)Tc-dextran, (99m)Tc-MH1 Fab', and the (99m)Tc-dextran-labeled MH1 Fab' complexes in rats., Results: (99m)Tc-radiolabeled dextran derivatives were radiochemically stable and retained clot-binding bioreactivity in vivo. In the rat model, blood and tissue clearance of the (99m)Tc-dextran MH1 Fab' constructs was substantially improved relative to directly radiolabeled MH1 Fab'. At 1 h, total and extravascular tracer localizations in lung and muscle were significantly lower for 99mTc-dextranradiolabeled MH1 Fab' than for (99m)Tc-MH1 Fab' (P < 0.05)., Conclusion: The study observations suggest that radiolabeling through a (99m)Tc-dextran moiety may improve the detection of pulmonary emboli and other clinically important fixed intravascular targets by lowering nonspecific background activity. more...

Lymphoscintigraphy is an established means to determine the lymphatic drainage patterns from malignant tissues and edematous extremities. Unfortunately, there are no commercially available dedicated radiopharmaceuticals labeled for use in lymphoscintigraphy studies. The authors report a simple way to extemporaneously compound pharmaceutical-grade Tc-99m dextran 70 to meet this need. Pharmaceutical-quality Tc-99m dextran 70 injection is prepared by a simple rapid method from drug intermediates that are marketed as parenteral drug products. The radiolabeling process yields a product of high radiochemical purity, with good in vitro and in vivo stability. The authors illustrate the use of this product in a patient with melanoma to show the lymphatic drainage pattern before surgery. The method described permits rapid compounding of Tc-99m dextran 70 injection from drug components that are intended for parenteral administration. Tc-99m dextran 70 provides the option of performing lymphoscintigraphy in any clinical nuclear medicine setting. more...

Because adenocarcinoma of the breast expresses receptors for alpha-fetoprotein (AFP), we studied Tc-99m AFP as a radiopharmaceutical to detect breast cancer. The biodistribution of Tc-99m radiolabeled natural human AFP (full length) and recombinant domain III (DIII) of human AFP was compared to Tc-99m sestamibi and Tl-201 in a murine model of human breast cancer. Estrogen receptor positive (MCF7, T-47D) and estrogen receptor negative (MDA-MB-231, BT-20) human breast cancer xenografts were grown subcutaneously in the lateral thorax region of immunosuppressed mice (ICR SCID). Quantitative comparisons of percent-injected dose per gram of tissue (%ID/gram) and tumor to thigh ratio (T/Th) were performed at 0-60 minutes and at 24 hours following injection. For most tumors, T/Th for AFP and DIII was significantly greater than T/Th for Tc-99m sestamibi and Tl-201. In all breast cancers (BT-20, MCF7, MDA-MB-231, T-47D), Tc-99m AFP T/Th increased from 60 minutes to 24 hours, suggesting good tumor retention of this radiopharmaceutical. DIII and AFP had significantly higher %ID/gram than either Tl-201 or Tc-99m sestamibi when considered across all tumor types at both 60 minutes and 24 hours. The data suggests that localization of Tc-99m AFP in human breast cancer xenografts is initially rapid, increases with time, and is superior to Tc-99m sestamibi and Tl-201. Given its high uptake by breast cancer cells, its low non-tumor localization and its rapid renal excretion, these Tc-99m AFP preparations may be useful agents to detect human breast carcinoma. more...

A patient with shortness of breath had a high probability lung scan for pulmonary embolism, but no obvious embolic source. Whole-body scintigraphy using Tc-99m labeled Fab' antifibrin monoclonal antibody showed large central pulmonary emboli as well as tracer uptake in the right atrium and aortic arch. No lower extremity clot was detected. This case shows significant differences in the appearance of pulmonary embolism as assessed by direct clot and ventilation-perfusion scintigraphy. It shows the importance of the heart as the origin of pulmonary emboli and the utility of direct thrombus visualization. more...

Objective: To define the nature, incidence and consequence of a possible interaction between etidronate (for the treatment of hypercalcemia) and methylene diphosphonate labelled with technetium-99m (99mTc-MDP) (for bone scanning)., Materials and Methods: The authors reviewed hospital pharmacy records for a period of 2 years and identified 18 patients who had received etidronate. Of this group, 6 patients (4 men and 2 women, ranging in age from 56 to 76 years) had undergone bone scanning with 99mTc-MDP while receiving etidronate. Five of the patients had hypercalcemia associated with metastatic disease, and the sixth had hyperparathyroidism., Results: All bone scans demonstrated poor uptake of tracer by bone accompanied by high soft-tissue background. There was loss of bone definition below the mid-thigh, and in 5 of the 6 patients there was indistinguishable rib uptake. In 1 of the patients, there was absence of uptake in 2 previously defined metastatic lesions., Conclusion: Recent oral or intravenous administration of etidronate is a contraindication to bone scintigraphy, as it markedly decreases sensitivity for bone disease. Bone scintigraphy should be timed so that it is performed before etidronate treatment or, if that is not possible, more than 2 to 4 weeks after the therapy has been completed. more...

Unlabelled: New diagnostic modalities are often judged relative to accepted standard procedures. These comparisons are influenced by the accuracy of the standard test and the prevalence of disease in the study population. We evaluated the importance of these factors in the assessment of antifibrin scintigraphy when used to detect deep venous thrombosis., Methods: Scintigraphy is compared to contrast venography in two populations of patients with different disease prevalence. We calculate the sensitivity and specificity by limb site (calf, knee, thigh) and the overall diagnosis for each modality. The sensitivity and specificity results obtained using venography as a gold standard are compared to those obtained using a maximum likelihood statistical procedure that does not require comparison to a standard test., Results: A significant variation in the apparent sensitivity, specificity and accuracy is found for antifibrin scintigraphy as related to limb site, disease prevalence and use of a gold standard. The value of antifibrin scintigraphy sensitivity (84.7%) and specificity (75.8%) predicted by the maximum likelihood analysis are substantially higher than those obtained from the estimates based on the use of venography as a gold standard for both high and low disease prevalence populations. The sensitivities and specificities of antifibrin scintigraphy (84.7% and 75.8%, respectively) and venography (71.7% and 80.7%, respectively) are comparable for the combined study group of 268 patients., Conclusion: To obtain unbiased evaluations of a new diagnostic modality, it is essential to take into account the errors of the standard reference test and disease prevalence in the study population. The results of our analysis suggest that it may not be appropriate to use contrast venography as a gold standard in the assessment of new diagnostic imaging procedures for DVT. more...