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Safety and efficacy of cancer-targeting treatments can be improved by conditional activation enabled by the distinct milieu of the tumour microenvironment. Proteases are intricately involved in tumourigenesis and commonly dysregulated with elevated expression and activity. Design of prodrug molecules with protease -dependent activation has the potential to increase tumour-selective targeting while decreasing exposure to healthy tissues, thus improving the safety profile for patients. Higher selectivity could also allow for adminis-tration of higher doses or use of more aggressive treatment options, leading to higher therapeutic efficacy. We have previously developed an affibody-based prodrug with conditional targeting of EGFR conferred by an anti-idiotypic affibody masking domain (ZB05). We could show that binding to endogenous EGFR on cancer cells in vitro was restored following proteolytic removal of ZB05. In this study we evaluate a novel affibody-based pro -drug design, which incorporates a protease substrate sequence recognized by cancer-associated proteases and demonstrate the potential of this approach for selective tumour-targeting and shielded uptake in healthy tissues in vivo using tumour-bearing mice. This may widen the therapeutic index of cytotoxic EGFR-targeted thera-peutics by decreasing side effects, improving selectivity of drug delivery, and enabling the use of more potent cytotoxic drugs., QC 20230523

Safety and efficacy of cancer-targeting treatments can be improved by conditional activation enabled by the distinct milieu of the tumour microenvironment. Proteases are intricately involved in tumourigenesis and commonly dysregulated with elevated expression and activity. Design of prodrug molecules with protease -dependent activation has the potential to increase tumour-selective targeting while decreasing exposure to healthy tissues, thus improving the safety profile for patients. Higher selectivity could also allow for adminis-tration of higher doses or use of more aggressive treatment options, leading to higher therapeutic efficacy. We have previously developed an affibody-based prodrug with conditional targeting of EGFR conferred by an anti-idiotypic affibody masking domain (ZB05). We could show that binding to endogenous EGFR on cancer cells in vitro was restored following proteolytic removal of ZB05. In this study we evaluate a novel affibody-based pro -drug design, which incorporates a protease substrate sequence recognized by cancer-associated proteases and demonstrate the potential of this approach for selective tumour-targeting and shielded uptake in healthy tissues in vivo using tumour-bearing mice. This may widen the therapeutic index of cytotoxic EGFR-targeted thera-peutics by decreasing side effects, improving selectivity of drug delivery, and enabling the use of more potent cytotoxic drugs.

Metastatic bone disease (MBD) is the most common form of metastases, most frequently deriving from prostate cancer. MBD is screened with bone scintigraphy (BS), which have high sensitivity but low specificity for the diagnosis of MBD, often requiring further investigations. Deep learning (DL) - a machine learning technique designed to mimic human neuronal interactions- has shown promise in the field of medical imaging analysis for different purposes, including segmentation and classification of lesions. In this study, we aim to develop a DL algorithm that can classify areas of increased uptake on bone scintigraphy scans. We collected 2365 BS from three European medical centres. The model was trained and validated on 1203 and 164 BS scans respectively. Furthermore we evaluated its performance on an external testing set composed of 998 BS scans. We further aimed to enhance the explainability of our developed algorithm, using activation maps. We compared the performance of our algorithm to that of 6 nuclear medicine physicians. The developed DL based algorithm is able to detect MBD on BSs, with high specificity and sensitivity (0.80 and 0.82 respectively on the external test set), in a shorter time compared to the nuclear medicine physicians (2.5 min for AI and 30 min for nuclear medicine physicians to classify 134 BSs). Further prospective validation is required before the algorithm can be used in the clinic.

BACKGROUND: Many predictors of morbidity caused by metabolic disease are associated with body shape. 3D optical (3DO) scanning captures body shape and has been shown to accurately and precisely predict body composition variables associated with mortality risk. 3DO is safer, less expensive, and more accessible than criterion body composition assessment methods such as dual-energy X-ray absorptiometry (DXA). However, 3DO scanning has not been standardized across manufacturers for pose, mesh resolution, and post processing methods. PURPOSE: We introduce a scanner-agnostic algorithm that automatically fits a topologically consistent human mesh to 3DO scanned point clouds and predicts clinically important body metrics using a standardized body shape model. Our models transform raw scans captured by any 3DO scanner into fixed topology meshes with anatomical consistency, standardizing the outputs of 3DO scans across manufacturers and allowing for the use of common prediction models across scanning devices. METHODS: A fixed-topology body mesh template was automatically registered to 848 training scans from three different 3DO systems. Participants were between 18 and 89 years old with body mass index ranging from 14 to 52 kg/m2 . Scans were registered by first performing a coarse nearest neighbor alignment between the template and the input scan with an anatomically constrained principal component analysis (PCA) domain deformation using a device and gender specific bootstrap basis trained on 70 seed scans each. The template mesh was then optimized to fit the target with a smooth per-vertex surface-to-surface deformation. A combined unified PCA model was created from the superset of all automatically fit training scans including all three devices. Body composition predictions to DXA measurements were learned from the training mesh PCA coefficients using linear regression. Using this final unified model, we tested the accuracy of our body composition models on a withheld

PURPOSE OF REVIEW: Chicago Classification has standardized clinical approach to primary esophageal motility disorders. With new clinical data and advancing treatments, Chicago Classification has undergone multiple revisions to reflect updated findings and enhance diagnostic accuracy. This review will describe the recently published Chicago Classification version 4.0 (CCv4.0), which aimed to enhance diagnostic characterization and limit overdiagnosis of inconclusive esophageal motility diagnoses. RECENT FINDINGS: Key revisions outlined in CCv4.0 include (1) a modified standardized HRM study protocol performed in supine and upright positions, (2) recommended ancillary testing and manometric provocation for inconclusive manometric diagnoses (3) the required presence of obstructive symptoms for conclusive diagnoses of esophagogastric junction outflow obstruction, distal esophageal spasm and hypercontractile esophagus, and (4) requirement of confirmatory testing for esophagogastric junction outflow obstruction. These key modifications aim to improve diagnostic accuracy and consistency of clinically relevant esophageal motility disorders, and subsequently clinical outcomes.

Since its approval in 2018 by the US Food and Drug Administration, peptide receptor radionuclide therapy (PRRT) has become a mainstay in the treatment of neuroendocrine tumors. Lutetium-177-DOTATATE, the only approved agent, is indicated for the treatment of gastroenteropancreatic-neuroendocrine tumors. Although patient selection appears straightforward with somatostatin receptor-positron emission tomography, there is considerable complexity when deciding which patients to treat and when to start PRRT. Herein, we review the many factors that affect patient selection, focusing on the optimal patients to treat. Although significant effort has been expended to determine which patients benefit the most from PRRT, a validated predictive biomarker remains elusive. Although PRRT has been used for more than 2 decades in Europe and standards of care exist for safe treatment, there remain numerous questions regarding when PRRT should be used relative to other treatments. It is important to remember that multidisciplinary discussions are essential. Currently, there are a number of ongoing studies looking to assess the efficacy of PRRT compared with other treatment options and to optimize treatment through combination therapy, different dosing strategies, or use of different radionuclides and radioligands.

Purpose Lymphoscintigraphy is the criterion-standard method for diagnosing lymphedema, and there is no universally standardized imaging modality. In our center, we use a new approach: rest/stress intradermal lymphoscintigraphy. Methods We tested 231 consecutive patients with suspected lymphedema. All patients were studied after a complex physical therapy program to reduce edema. Two doses of Tc-99m-nanocolloid were injected intradermally. Two static planar scans were taken at rest following tracer injection. Next, patients performed an isotonic muscular exercise for 2 minutes followed by postexercise scans. Subsequently, a prolonged exercise was performed for 30 to 40 minutes, after which delayed scans were taken. Abnormal patterns were distinguished into minor or major findings, according to severity. Results We identified superficial lymphatic vessels and regional lymph nodes in approximately 80% of limbs. Deep vessels were visualized in 26% of limbs. Minor findings were reported in 22.7% of limbs examined, whereas major findings were reported in 53.2% of limbs. Conclusion We observed major findings including lymph stagnation, extravasation, or dermal backflow in a significantly higher percentage of limbs with secondary lymphedema than in primary. We also observed the deep lymphatic pathways in a significantly higher percentage of limbs with primary lymphedema. Intradermal radiotracer injection, combined with isotonic muscular exercise, may offer a better and faster imaging of lymphatic pathways, evaluating the effects of muscular exercise on lymphatic drainage. Based on the in-depth information of the lymphatic pathways provided by rest/stress intradermal lymphoscintigraphy, microsurgeons can obtain important functional information to perform supermicrosurgical lymphatic-venous anastomosis or vascularized lymph node transfer.

Proteins are remarkable molecules with diverse and specialized functions playing essential roles in most biological processes. One such function is protecting us from diseases by the action of antibodies in our immune system that can recognize and mediate the destruction of invading pathogens by binding to foreign epitopes found on non-self proteins. The concept of utilizing specific protein-protein interactions to achieve a therapeutic effect has for several decades been a cornerstone for the development of cancer-directed treatments. While antibodies have formed a basis for the development of such drugs, other protein alternatives may be engineered to complement current antibody-based treatments, and may even prove to possess superior features. This thesis focuses on the engineering of affibody molecules, a small alternative scaffold protein, for design and development of novel cancer-targeting therapeutic and diagnostic drugs. There are many different strategies that have been investigated for inhibiting cancer progression and tumour growth with perhaps one of the most straightforward involving disruption of dysregulated growth-promoting signalling pathways. Members of the human epidermal growth factor receptor (HER) family is prominently expressed in various cancer types and have been shown to be intricately involved in tumorigenesis. One of the members (HER3) often becomes upregulated in cancer and have been shown to mediate acquired resistance to targeted therapies by the mechanism of ligand-induced activation. We have designed five novel affibody-based HER3-targeting molecules able to prevent ligand-binding and consequently activation of HER3. We investigated the targeting properties and biodistribution profiles of these molecules in vivo and subsequently evaluated the anti-tumour efficacy for the most promising variants in direct comparison to a HER3-targeting antibody with a similar inhibitory mechanism. We observed a large influence of design on both th, Proteiner är anmärkningsvärda molekyler med varierande och specialiserade funktioner som spelar ytterst viktiga roller i de flesta biologiska processer. En av dessa funktioner är att skydda oss från sjukdomar genom verkan av antikroppar i vårt immunsystem som kan känna igen och förmedla förstörelsen av invaderande patogener genom att binda till främmande epitoper som finns på icke-självproteiner. Konceptet att använda specifika protein-protein interaktioner för att uppnå en terapeutisk effekt har under flera decennier varit en hörnsten för utvecklingen av cancerriktade behandlingar. Även om antikroppar har utgjort en grund för utvecklingen av sådana läkemedel, kan andra proteinalternativ konstrueras för att komplettera nuvarande antikroppsbaserade behandlingar och kan till och med visa sig ha överlägsna egenskaper. Denna avhandling fokuserar på konstruktionen av målsökande affibody-molekyler, ett litet alternativt protein, för design och utveckling av nya terapeutiska läkemedel och diagnostiska verktyg för cancer. Det finns många olika strategier som har undersökts för att hämma cancerprogression och tumörtillväxt varav ett relativt enkelt tillvägagångsätt involverar störningar av dysreglerade tillväxtfrämjande signalvägar. Medlemmar av den humana epidermala tillväxtfaktorreceptorfamiljen (HER) uttrycks högt i olika cancertyper och har visat sig vara starkt involverade i tumörbildning. En av medlemmarna (HER3) blir ofta uppreglerad i cancer och har visat sig förmedla förvärvad resistens mot riktade terapier genom en mekanism av ligand-inducerad aktivering. Vi har designat fem nya affibody-baserade HER3-bindande molekyler som kan förhindra ligandbindning och följaktligen aktivering av HER3. Vi undersökte bindningsegenskaperna och biodistributionsprofilerna för dessa molekyler in vivo och utvärderade därefter antitumöreffektiviteten för de mest lovande varianterna i direkt jämförelse med en HER3-riktad antikropp med en liknande hämmande mekanism. Vi observerade ett, QC 2022-03-08

No abstract available

Proteins are remarkable molecules with diverse and specialized functions playing essential roles in most biological processes. One such function is protecting us from diseases by the action of antibodies in our immune system that can recognize and mediate the destruction of invading pathogens by binding to foreign epitopes found on non-self proteins. The concept of utilizing specific protein-protein interactions to achieve a therapeutic effect has for several decades been a cornerstone for the development of cancer-directed treatments. While antibodies have formed a basis for the development of such drugs, other protein alternatives may be engineered to complement current antibody-based treatments, and may even prove to possess superior features. This thesis focuses on the engineering of affibody molecules, a small alternative scaffold protein, for design and development of novel cancer-targeting therapeutic and diagnostic drugs. There are many different strategies that have been investigated for inhibiting cancer progression and tumour growth with perhaps one of the most straightforward involving disruption of dysregulated growth-promoting signalling pathways. Members of the human epidermal growth factor receptor (HER) family is prominently expressed in various cancer types and have been shown to be intricately involved in tumorigenesis. One of the members (HER3) often becomes upregulated in cancer and have been shown to mediate acquired resistance to targeted therapies by the mechanism of ligand-induced activation. We have designed five novel affibody-based HER3-targeting molecules able to prevent ligand-binding and consequently activation of HER3. We investigated the targeting properties and biodistribution profiles of these molecules in vivo and subsequently evaluated the anti-tumour efficacy for the most promising variants in direct comparison to a HER3-targeting antibody with a similar inhibitory mechanism. We observed a large influence of design on both th, Proteiner är anmärkningsvärda molekyler med varierande och specialiserade funktioner som spelar ytterst viktiga roller i de flesta biologiska processer. En av dessa funktioner är att skydda oss från sjukdomar genom verkan av antikroppar i vårt immunsystem som kan känna igen och förmedla förstörelsen av invaderande patogener genom att binda till främmande epitoper som finns på icke-självproteiner. Konceptet att använda specifika protein-protein interaktioner för att uppnå en terapeutisk effekt har under flera decennier varit en hörnsten för utvecklingen av cancerriktade behandlingar. Även om antikroppar har utgjort en grund för utvecklingen av sådana läkemedel, kan andra proteinalternativ konstrueras för att komplettera nuvarande antikroppsbaserade behandlingar och kan till och med visa sig ha överlägsna egenskaper. Denna avhandling fokuserar på konstruktionen av målsökande affibody-molekyler, ett litet alternativt protein, för design och utveckling av nya terapeutiska läkemedel och diagnostiska verktyg för cancer. Det finns många olika strategier som har undersökts för att hämma cancerprogression och tumörtillväxt varav ett relativt enkelt tillvägagångsätt involverar störningar av dysreglerade tillväxtfrämjande signalvägar. Medlemmar av den humana epidermala tillväxtfaktorreceptorfamiljen (HER) uttrycks högt i olika cancertyper och har visat sig vara starkt involverade i tumörbildning. En av medlemmarna (HER3) blir ofta uppreglerad i cancer och har visat sig förmedla förvärvad resistens mot riktade terapier genom en mekanism av ligand-inducerad aktivering. Vi har designat fem nya affibody-baserade HER3-bindande molekyler som kan förhindra ligandbindning och följaktligen aktivering av HER3. Vi undersökte bindningsegenskaperna och biodistributionsprofilerna för dessa molekyler in vivo och utvärderade därefter antitumöreffektiviteten för de mest lovande varianterna i direkt jämförelse med en HER3-riktad antikropp med en liknande hämmande mekanism. Vi observerade ett, QC 2022-03-08

Proteins are remarkable molecules with diverse and specialized functions playing essential roles in most biological processes. One such function is protecting us from diseases by the action of antibodies in our immune system that can recognize and mediate the destruction of invading pathogens by binding to foreign epitopes found on non-self proteins. The concept of utilizing specific protein-protein interactions to achieve a therapeutic effect has for several decades been a cornerstone for the development of cancer-directed treatments. While antibodies have formed a basis for the development of such drugs, other protein alternatives may be engineered to complement current antibody-based treatments, and may even prove to possess superior features. This thesis focuses on the engineering of affibody molecules, a small alternative scaffold protein, for design and development of novel cancer-targeting therapeutic and diagnostic drugs. There are many different strategies that have been investigated for inhibiting cancer progression and tumour growth with perhaps one of the most straightforward involving disruption of dysregulated growth-promoting signalling pathways. Members of the human epidermal growth factor receptor (HER) family is prominently expressed in various cancer types and have been shown to be intricately involved in tumorigenesis. One of the members (HER3) often becomes upregulated in cancer and have been shown to mediate acquired resistance to targeted therapies by the mechanism of ligand-induced activation. We have designed five novel affibody-based HER3-targeting molecules able to prevent ligand-binding and consequently activation of HER3. We investigated the targeting properties and biodistribution profiles of these molecules in vivo and subsequently evaluated the anti-tumour efficacy for the most promising variants in direct comparison to a HER3-targeting antibody with a similar inhibitory mechanism. We observed a large influence of design on both th, Proteiner är anmärkningsvärda molekyler med varierande och specialiserade funktioner som spelar ytterst viktiga roller i de flesta biologiska processer. En av dessa funktioner är att skydda oss från sjukdomar genom verkan av antikroppar i vårt immunsystem som kan känna igen och förmedla förstörelsen av invaderande patogener genom att binda till främmande epitoper som finns på icke-självproteiner. Konceptet att använda specifika protein-protein interaktioner för att uppnå en terapeutisk effekt har under flera decennier varit en hörnsten för utvecklingen av cancerriktade behandlingar. Även om antikroppar har utgjort en grund för utvecklingen av sådana läkemedel, kan andra proteinalternativ konstrueras för att komplettera nuvarande antikroppsbaserade behandlingar och kan till och med visa sig ha överlägsna egenskaper. Denna avhandling fokuserar på konstruktionen av målsökande affibody-molekyler, ett litet alternativt protein, för design och utveckling av nya terapeutiska läkemedel och diagnostiska verktyg för cancer. Det finns många olika strategier som har undersökts för att hämma cancerprogression och tumörtillväxt varav ett relativt enkelt tillvägagångsätt involverar störningar av dysreglerade tillväxtfrämjande signalvägar. Medlemmar av den humana epidermala tillväxtfaktorreceptorfamiljen (HER) uttrycks högt i olika cancertyper och har visat sig vara starkt involverade i tumörbildning. En av medlemmarna (HER3) blir ofta uppreglerad i cancer och har visat sig förmedla förvärvad resistens mot riktade terapier genom en mekanism av ligand-inducerad aktivering. Vi har designat fem nya affibody-baserade HER3-bindande molekyler som kan förhindra ligandbindning och följaktligen aktivering av HER3. Vi undersökte bindningsegenskaperna och biodistributionsprofilerna för dessa molekyler in vivo och utvärderade därefter antitumöreffektiviteten för de mest lovande varianterna i direkt jämförelse med en HER3-riktad antikropp med en liknande hämmande mekanism. Vi observerade ett, QC 2022-03-08

Proteins are remarkable molecules with diverse and specialized functions playing essential roles in most biological processes. One such function is protecting us from diseases by the action of antibodies in our immune system that can recognize and mediate the destruction of invading pathogens by binding to foreign epitopes found on non-self proteins. The concept of utilizing specific protein-protein interactions to achieve a therapeutic effect has for several decades been a cornerstone for the development of cancer-directed treatments. While antibodies have formed a basis for the development of such drugs, other protein alternatives may be engineered to complement current antibody-based treatments, and may even prove to possess superior features. This thesis focuses on the engineering of affibody molecules, a small alternative scaffold protein, for design and development of novel cancer-targeting therapeutic and diagnostic drugs. There are many different strategies that have been investigated for inhibiting cancer progression and tumour growth with perhaps one of the most straightforward involving disruption of dysregulated growth-promoting signalling pathways. Members of the human epidermal growth factor receptor (HER) family is prominently expressed in various cancer types and have been shown to be intricately involved in tumorigenesis. One of the members (HER3) often becomes upregulated in cancer and have been shown to mediate acquired resistance to targeted therapies by the mechanism of ligand-induced activation. We have designed five novel affibody-based HER3-targeting molecules able to prevent ligand-binding and consequently activation of HER3. We investigated the targeting properties and biodistribution profiles of these molecules in vivo and subsequently evaluated the anti-tumour efficacy for the most promising variants in direct comparison to a HER3-targeting antibody with a similar inhibitory mechanism. We observed a large influence of design on both th, Proteiner är anmärkningsvärda molekyler med varierande och specialiserade funktioner som spelar ytterst viktiga roller i de flesta biologiska processer. En av dessa funktioner är att skydda oss från sjukdomar genom verkan av antikroppar i vårt immunsystem som kan känna igen och förmedla förstörelsen av invaderande patogener genom att binda till främmande epitoper som finns på icke-självproteiner. Konceptet att använda specifika protein-protein interaktioner för att uppnå en terapeutisk effekt har under flera decennier varit en hörnsten för utvecklingen av cancerriktade behandlingar. Även om antikroppar har utgjort en grund för utvecklingen av sådana läkemedel, kan andra proteinalternativ konstrueras för att komplettera nuvarande antikroppsbaserade behandlingar och kan till och med visa sig ha överlägsna egenskaper. Denna avhandling fokuserar på konstruktionen av målsökande affibody-molekyler, ett litet alternativt protein, för design och utveckling av nya terapeutiska läkemedel och diagnostiska verktyg för cancer. Det finns många olika strategier som har undersökts för att hämma cancerprogression och tumörtillväxt varav ett relativt enkelt tillvägagångsätt involverar störningar av dysreglerade tillväxtfrämjande signalvägar. Medlemmar av den humana epidermala tillväxtfaktorreceptorfamiljen (HER) uttrycks högt i olika cancertyper och har visat sig vara starkt involverade i tumörbildning. En av medlemmarna (HER3) blir ofta uppreglerad i cancer och har visat sig förmedla förvärvad resistens mot riktade terapier genom en mekanism av ligand-inducerad aktivering. Vi har designat fem nya affibody-baserade HER3-bindande molekyler som kan förhindra ligandbindning och följaktligen aktivering av HER3. Vi undersökte bindningsegenskaperna och biodistributionsprofilerna för dessa molekyler in vivo och utvärderade därefter antitumöreffektiviteten för de mest lovande varianterna i direkt jämförelse med en HER3-riktad antikropp med en liknande hämmande mekanism. Vi observerade ett, QC 2022-03-08

Proteins are remarkable molecules with diverse and specialized functions playing essential roles in most biological processes. One such function is protecting us from diseases by the action of antibodies in our immune system that can recognize and mediate the destruction of invading pathogens by binding to foreign epitopes found on non-self proteins. The concept of utilizing specific protein-protein interactions to achieve a therapeutic effect has for several decades been a cornerstone for the development of cancer-directed treatments. While antibodies have formed a basis for the development of such drugs, other protein alternatives may be engineered to complement current antibody-based treatments, and may even prove to possess superior features. This thesis focuses on the engineering of affibody molecules, a small alternative scaffold protein, for design and development of novel cancer-targeting therapeutic and diagnostic drugs. There are many different strategies that have been investigated for inhibiting cancer progression and tumour growth with perhaps one of the most straightforward involving disruption of dysregulated growth-promoting signalling pathways. Members of the human epidermal growth factor receptor (HER) family is prominently expressed in various cancer types and have been shown to be intricately involved in tumorigenesis. One of the members (HER3) often becomes upregulated in cancer and have been shown to mediate acquired resistance to targeted therapies by the mechanism of ligand-induced activation. We have designed five novel affibody-based HER3-targeting molecules able to prevent ligand-binding and consequently activation of HER3. We investigated the targeting properties and biodistribution profiles of these molecules in vivo and subsequently evaluated the anti-tumour efficacy for the most promising variants in direct comparison to a HER3-targeting antibody with a similar inhibitory mechanism. We observed a large influence of design on both th, Proteiner är anmärkningsvärda molekyler med varierande och specialiserade funktioner som spelar ytterst viktiga roller i de flesta biologiska processer. En av dessa funktioner är att skydda oss från sjukdomar genom verkan av antikroppar i vårt immunsystem som kan känna igen och förmedla förstörelsen av invaderande patogener genom att binda till främmande epitoper som finns på icke-självproteiner. Konceptet att använda specifika protein-protein interaktioner för att uppnå en terapeutisk effekt har under flera decennier varit en hörnsten för utvecklingen av cancerriktade behandlingar. Även om antikroppar har utgjort en grund för utvecklingen av sådana läkemedel, kan andra proteinalternativ konstrueras för att komplettera nuvarande antikroppsbaserade behandlingar och kan till och med visa sig ha överlägsna egenskaper. Denna avhandling fokuserar på konstruktionen av målsökande affibody-molekyler, ett litet alternativt protein, för design och utveckling av nya terapeutiska läkemedel och diagnostiska verktyg för cancer. Det finns många olika strategier som har undersökts för att hämma cancerprogression och tumörtillväxt varav ett relativt enkelt tillvägagångsätt involverar störningar av dysreglerade tillväxtfrämjande signalvägar. Medlemmar av den humana epidermala tillväxtfaktorreceptorfamiljen (HER) uttrycks högt i olika cancertyper och har visat sig vara starkt involverade i tumörbildning. En av medlemmarna (HER3) blir ofta uppreglerad i cancer och har visat sig förmedla förvärvad resistens mot riktade terapier genom en mekanism av ligand-inducerad aktivering. Vi har designat fem nya affibody-baserade HER3-bindande molekyler som kan förhindra ligandbindning och följaktligen aktivering av HER3. Vi undersökte bindningsegenskaperna och biodistributionsprofilerna för dessa molekyler in vivo och utvärderade därefter antitumöreffektiviteten för de mest lovande varianterna i direkt jämförelse med en HER3-riktad antikropp med en liknande hämmande mekanism. Vi observerade ett, QC 2022-03-08

Cardiac resynchronization therapy (CRT) is a disease-modifying therapy in patients with chronic heart failure (CHF). Current guidelines ascribe CRT eligibility on three parameters only: left ventricular ejection fraction (LVEF), QRS duration, and New York Heart Association (NYHA) functional class. However, one-third of CHF patients does not benefit from CRT. This study evaluated whether 123I-meta-iodobenzylguanidine (123I-mIBG) assessed cardiac sympathetic activity could optimize CRT patient selection. A total of 78 stable CHF subjects (age 66.8 ± 9.6 years, 73% male, LVEF 25.2 ± 6.7%, QRS duration 153 ± 23 ms, NYHA 2.2 ± 0.7) referred for CRT implantation were enrolled. Subjects underwent 123I-mIBG scintigraphy prior to implantation. Early and late heart-to-mediastinum (H/M) ratio and 123I-mIBG washout were calculated. CRT response was defined as either an increase of LVEF to >35%, any improvement in LVEF of >10%, QRS shortening to <150 ms, or improvement in NYHA class of >1 class. In 33 patients LVEF increased to >35%, QRS decreased <150 ms in 36 patients, and NYHA class decreased in 33 patients. Late H/M ratio and hypertension were independent predictors of LVEF improvement to >35% (P = 0.0014 and P = 0.0149, respectively). In addition, early H/M ratio, LVEF, and absence of diabetes mellitus (DM) were independent predictors for LVEF improvement by >10%. No independent predictors were found for QRS shortening to <150 ms or improvement in NYHA class. Early and late H/M ratio were independent predictors of CRT response when improvement of LVEF was used as measure of response. Therefore, cardiac 123I-mIBG scintigraphy may be used as a tool to optimize selection of subjects that might benefit from CRT.

Targeting of human epidermal growth factor type 2 (HER2) using monoclonal antibodies, antibody-drug conjugates and tyrosine kinase inhibitors extends survival of patients with HER2-expressing metastatic breast cancer. High expression of HER2 is a predictive biomarker for such specific treatment. Accurate determination of HER2 expression level is necessary for stratification of patients to targeted therapy. Non-invasive in vivo radionuclide molecular imaging of HER2 has a potential of repetitive measurements, addressing issues of heterogeneous expression and conversion of HER2 status during disease progression or in response to therapy. Imaging probes based of several classes of targeting proteins are currently in preclinical and early clinical development. Both preclinical and clinical data suggest that the most promising are imaging agents based on small proteins, such as single domain antibodies or engineered scaffold proteins. These agents permit a very specific high-contrast imaging at the day of injection.

Mutations in SQSTM1 are strongly associated with Paget's disease of bone (PDB), but little is known about the clinical characteristics of those with early disease. Radionuclide bone scans, biochemical markers of bone turnover, and clinical characteristics were analyzed in SQSTM1 mutation carriers who took part in the Zoledronic acid in the Prevention of Paget's disease (ZiPP) study. We studied 222 individuals, of whom 54.9% were female, with mean ± SE age of 50.1 ± 0.6 years. Twelve SQSTM1 mutations were observed, including p.Pro392Leu, which was present in 141 of 222 (63.5%) subjects. Bone scan examination revealed evidence of PDB in 20 subjects (9.0%), ten of whom (50%) had a single affected site. Participants with lesions were older than those without lesions but the difference was not significant (53.6 ± 9.1 versus 49.8 ± 8.9; p =.07). The mean age of participants with lesions was not significantly different from the age at which their parents were diagnosed with PDB (55 years versus 59 years, p =.17). All individuals with lesions were asymptomatic. Serum concentrations of total alkaline phosphatase (ALP) normalized to the upper limit of normal in each center were higher in those with lesions (0.75 ± 0.69 versus 0.42 ± 0.29 arbitary units; p <.0001). Similar findings were observed for other biochemical markers of bone turnover, but the sensitivity of ALP and other markers in detecting lesions was poor. Asymptomatic PDB is present in about 9% of SQSTM1 mutation carriers by the fifth decade. Further follow-up of this cohort will provide important information on the natural history of early PDB and its response to treatment.

SCOPUS: le.j, info:eu-repo/semantics/published

Mutations in SQSTM1 are strongly associated with Paget's disease of bone (PDB), but little is known about the clinical characteristics of those with early disease. Radionuclide bone scans, biochemical markers of bone turnover, and clinical characteristics were analyzed in SQSTM1 mutation carriers who took part in the Zoledronic acid in the Prevention of Paget's disease (ZiPP) study. We studied 222 individuals, of whom 54.9% were female, with mean ± SE age of 50.1 ± 0.6 years. Twelve SQSTM1 mutations were observed, including p.Pro392Leu, which was present in 141 of 222 (63.5%) subjects. Bone scan examination revealed evidence of PDB in 20 subjects (9.0%), ten of whom (50%) had a single affected site. Participants with lesions were older than those without lesions but the difference was not significant (53.6 ± 9.1 versus 49.8 ± 8.9; p = .07). The mean age of participants with lesions was not significantly different from the age at which their parents were diagnosed with PDB (55 years versus 59 years, p = .17). All individuals with lesions were asymptomatic. Serum concentrations of total alkaline phosphatase (ALP) normalized to the upper limit of normal in each center were higher in those with lesions (0.75 ± 0.69 versus 0.42 ± 0.29 arbitary units; p < .0001). Similar findings were observed for other biochemical markers of bone turnover, but the sensitivity of ALP and other markers in detecting lesions was poor. Asymptomatic PDB is present in about 9% of SQSTM1 mutation carriers by the fifth decade. Further follow-up of this cohort will provide important information on the natural history of early PDB and its response to treatment. © 2020 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research.

The 18F-AV-1451 PET tracer binds to tau, an Alzheimer's disease biomarker. The standardized uptake value ratio (SUVR) 80-100 min window is widely used to quantify tau binding, although 18F-AV-1451 continues increasing relative to a reference region in regions with tau deposition. Left uncorrected, acquisition time inaccuracies can lead to errors from -4% to 6% in 20-min SUVR measurements in subjects with Alzheimer's disease. In 40 subjects with scans from 75-115 min following 18F-AV-1451 injection, we created 20-min reconstructions (4×5 min) of start-times ranging from 75-85 min, as proxies of offset scans and calculated the mean in regions of interest (ROIs). We developed a segmented least squares (SLS) method to obtain error-minimizing weighting coefficients for 18F-AV-1451 ROIs that best predict SUVR 80-100 from weighted means of SUVRs from offset start-times. We compared residual errors of our SLS method to those in: 1) uncorrected offset 20-min-SUVRs; 2) the mean of five-min frames within the 80-100 window; and 3) a least-squares interpolation method. We evaluated errors induced by start-time offset on SUVRs for each method. TheSLS, which corrected using least-squares coefficients of 5-min components, consistently reduced errors across all offset starttimes. Effect size analysis for simulated clinical longitudinal 18F-AV-1451 drug trials showed that uncorrected 20-min offset SUVRs would require up to 20% more participants to detect treatment effects compared with using SLS. Correction of SUVR scan-time errors by SLS minimizes errors compared with other correction methods and may be extended to other scanners and tracers.

Eligibility for somatostatin receptor (SSTR) radionuclide therapy uses the qualitative Krenning score based on 111In-pentetreotide planar scintigraphy as was performed in the NETTER-1 trial. The purpose of this study was to determine the effect of using SSTR PET-based Krenning score in comparison to 111In-pentetreotide. Methods: This was a post hoc head-to-head comparison of 68Ga-DOTATATE-based and 111In-pentetreotide-based Krenning scores in 150 patients included in a prospective phase 2 study (NCT01967537). Patients were imaged using 68Ga-DOTATATE PET/CT, 111In-pentetreotide planar scintigraphy, and SPECT/CT within 1 wk. SSTR ligand uptake was graded using the Krenning score independently by 3 readers. Results: The detection rate of SSTR-expressing disease (Krenning scores 2-4) was 23%, 38%, and 72% with planar imaging, SPECT, and SSTR PET, respectively. The Krenning score was higher with SSTR PET (2.71 ± 1.74) than with planar imaging (0.75 ± 1.37; P < 0.001) or SPECT (1.23 ± 1.57; P < 0.001). In patients with a Krenning score of at least 3 on SSTR PET, the detection rate of planar imaging and SPECT was lower for lesions smaller than 2 cm than lesions 2 cm or larger: 15% and 24% versus 78% and 89%, respectively (P < 0.001). For lesions larger than 5 cm, Krenning scores between SSTR PET and 111In-pentetreotide were nearly equivalent. Lesion size did not have an impact on SSTR PET Krenning scores. Interreader agreement was higher for SSTR PET than for planar imaging or SPECT (0.79 vs. 0.67 and 0.50, respectively). Conclusion: SSTR PET results in higher Krenning scores than 111In-pentetreotide, particularly when lesions measured 2 cm or less. Small lesion size resulted in low Krenning scores using 111In-pentetreotide, but lesion size did not affect SSTR PET-based Krenning scores. The results of the NETTER-1 trial cannot be directly applied to patients with small lesions. Further study of peptide receptor radionuclide therapy in patients with small lesions n

INTRODUCTION: Paget's disease of bone (PDB) is characterised by increased and disorganised bone remodelling affecting one or more skeletal sites. Complications include bone pain, deformity, deafness and pathological fractures. Mutations in sequestosome-1 (SQSTM1) are strongly associated with the development of PDB. Bisphosphonate therapy can improve bone pain in PDB, but there is no evidence that treatment alters the natural history of PDB or prevents complications. The Zoledronate in the Prevention of Paget's disease trial (ZiPP) will determine if prophylactic therapy with the bisphosphonate zoledronic acid (ZA) can delay or prevent the development of PDB in people who carry SQSTM1 mutations. METHODS AND ANALYSIS: People with a family history of PDB aged >30 years who test positive for SQSTM1 mutations are eligible to take part. At the baseline visit, participants will be screened for the presence of bone lesions by radionuclide bone scan. Biochemical markers of bone turnover will be measured and questionnaires completed to assess pain, health-related quality of life (HRQoL), anxiety and depression. Participants will be randomised to receive a single intravenous infusion of 5 mg ZA or placebo and followed up annually for between 4 and 8 years at which point baseline assessments will be repeated. The primary endpoint will be new bone lesions assessed by radionuclide bone scan. Secondary endpoints will include changes in biochemical markers of bone turnover, pain, HRQoL, anxiety, depression and PDB-related skeletal events. ETHICS AND DISSEMINATION: The study was approved by the Fife and Forth Valley Research Ethics Committee on 22 December 2008 (08/S0501/84). Following completion of the trial, a manuscript will be submitted to a peer-reviewed journal. The results of this trial will inform clinical practice by determining if early intervention with ZA in presymptomatic individuals with SQSTM1 mutations can prevent or slow the development of bone lesions with an advers

The literature review examines the historical aspects and key issues of the clinical application of new radiopharmaceuticals (RF) for positron emission tomography (PET). The gold standard for measuring effective renal plasma flow is p-[18F] fluorohippurate ([18F] PFH) due to its structure close to p-aminoimpurate one. [18F] FDS is a new potential tracer for the diagnosis of acute renal failure. PET tracers Re (CO) 3 ([18F] FEDA) and [18F] PFH are effective as surrogate markers for the selection of patients for endoradiotherapy with a potential nephrotoxic profile, in patients with hematopoietic malignant tumours and prostate cancer. PET imaging of the kidneys and urinary system can be of additional importance in difficult clinical situations and provide effective support in making diagnostic decisions, in particular in paediatric patients. Further scientific diagnostic research should focus on the synthesis of new radiopharmaceuticals that will have ideal properties for renal functional imaging, low binding to plasma proteins, high metabolic stability and low hepatobiliary clearance., В статье рассмотрены исторические аспекты и ключевые вопросы клинического применения новых радиофармпрепаратов (РФП) для позитронно-эмиссионной томографии (ПЭТ). Золотым стандартом для измерения эффективного ренального плазмотока является p-[18F] фторгиппурат ([18F] PFH) благодаря структуре, схожей с р-аминоимпуратом. [18F] FDS — новый потенциальный трейсер для диагностики острой почечной недостаточности. ПЭТ-трейсеры Re (CO) 3 ([18F] FEDA) и [18F] PFH являются эффективными суррогатными маркерами с целью отбора пациентов для эндорадиотерапии с потенциальным нефротоксическим профилем, у больных с гемопоэтическими злокачественными опухолями, раком предстательной железы. ПЭТ-визуализация почек и мочевыделительной системы может иметь дополнительное значение в сложных клинических ситуациях и обеспечивать эффективную поддержку в принятии диагностических решений, в частности у педиатрических пациентов. Дальнейший научный диагностический поиск должен быть направлен на синтезирование новых РФП, которые будут иметь идеальные свойства для почечной функциональной визуализации, низкое связывание с белками плазмы, высокую метаболическую стабильность и низкий гепатобилиарный клиренс., У статті розглянуто історичні аспекти та ключові питання клінічного застосування нових радіофармпрепаратів (РФП) для позитронно-емісійної томографії (ПЕТ). Золотим стандартом для вимірювання ефективного ренального плазмотоку є p-[18F] фторгіпурат ([18F] PFH) завдяки структурі, що подібна до р-аміноімпурату. [18F] FDS — новий потенціальний трейсер для діагностики гострої ниркової недостатності. ПЕТ-трейсери Re (CO) 3 ([18F] FEDA) і [18F] PFH є ефективними сурогатними маркерами з метою відбору пацієнтів для ендорадіотерапії з потенційним нефротоксичним профілем, у хворих на гемопоетичні злоякісні пухлини, рак передміхурової залози. ПЕТ-візуалізація нирок і сечовидільної системи може мати додаткове значення у складних клінічних ситуаціях і забезпечувати ефективну підтримку у прийнятті діагностичних рішень, зокрема у педіатричних пацієнтів. Подальший науковий діагностичний пошук повинен бути спрямований на синтезування нових РФП, які матимуть ідеальні властивості для ренальної функціональної візуалізації, низьке зв’язування з білками плазми, високу метаболічну стабільність та низький гепатобіліарний кліренс.

Radionuclide molecular imaging is a promising tool that becomes increasingly important as targeted cancer therapies are developed. To ensure an effective treatment, a molecular stratification of the cancer is a necessity. To accomplish this, visualization of cancer associated molecular abnormalities in vivo by molecular imaging is the method of choice. ADAPTs, a novel type of small protein scaffold, have been utilized to select and develop high affinity binders to different proteinaceous targets. One of these binders, ADAPT6 selectively interacts with human epidermal growth factor 2 (HER2) with low nanomolar affinity and can therefore be used for its in vivo visualization. Molecular design and optimization of labeled anti-HER2 ADAPT has been explored in several earlier studies, showing that small changes in the scaffold affect the biodistribution of the domain. In this study, we evaluate how the biodistribution properties of ADAPT6 is affected by the commonly used maleimido derivatives of the macrocyclic chelators NOTA, NODAGA, DOTA and DOTAGA with the aim to select the best variants for SPECT and PET imaging. The different conjugates were labeled with 111In for SPECT and 68Ga for PET. The acquired data show that the combination of a radionuclide and a chelator for its conjugation has a strong influence on the uptake of ADAPT6 in normal tissues and thereby gives a significant variation in tumor-toorgan ratios. Hence, it was concluded that the best variant for SPECT imaging is 111In-(HE)3DANS-ADAPT6-GSSC-DOTA while the best variant for PET imaging is 68Ga-(HE)3DANS-ADAPT6-GSSC-NODAGA., De 2 första författarna delar förstaförfattarskapet.

Radionuclide molecular imaging is a promising tool that becomes increasingly important as targeted cancer therapies are developed. To ensure an effective treatment, a molecular stratification of the cancer is a necessity. To accomplish this, visualization of cancer associated molecular abnormalities in vivo by molecular imaging is the method of choice. ADAPTs, a novel type of small protein scaffold, have been utilized to select and develop high affinity binders to different proteinaceous targets. One of these binders, ADAPT6 selectively interacts with human epidermal growth factor 2 (HER2) with low nanomolar affinity and can therefore be used for its in vivo visualization. Molecular design and optimization of labeled anti-HER2 ADAPT has been explored in several earlier studies, showing that small changes in the scaffold affect the biodistribution of the domain. In this study, we evaluate how the biodistribution properties of ADAPT6 is affected by the commonly used maleimido derivatives of the macrocyclic chelators NOTA, NODAGA, DOTA and DOTAGA with the aim to select the best variants for SPECT and PET imaging. The different conjugates were labeled with 111In for SPECT and 68Ga for PET. The acquired data show that the combination of a radionuclide and a chelator for its conjugation has a strong influence on the uptake of ADAPT6 in normal tissues and thereby gives a significant variation in tumor-toorgan ratios. Hence, it was concluded that the best variant for SPECT imaging is 111In-(HE)3DANS-ADAPT6-GSSC-DOTA while the best variant for PET imaging is 68Ga-(HE)3DANS-ADAPT6-GSSC-NODAGA., De 2 första författarna delar förstaförfattarskapet.

Radionuclide molecular imaging is a promising tool that becomes increasingly important as targeted cancer therapies are developed. To ensure an effective treatment, a molecular stratification of the cancer is a necessity. To accomplish this, visualization of cancer associated molecular abnormalities in vivo by molecular imaging is the method of choice. ADAPTs, a novel type of small protein scaffold, have been utilized to select and develop high affinity binders to different proteinaceous targets. One of these binders, ADAPT6 selectively interacts with human epidermal growth factor 2 (HER2) with low nanomolar affinity and can therefore be used for its in vivo visualization. Molecular design and optimization of labeled anti-HER2 ADAPT has been explored in several earlier studies, showing that small changes in the scaffold affect the biodistribution of the domain. In this study, we evaluate how the biodistribution properties of ADAPT6 is affected by the commonly used maleimido derivatives of the macrocyclic chelators NOTA, NODAGA, DOTA and DOTAGA with the aim to select the best variants for SPECT and PET imaging. The different conjugates were labeled with In-111 for SPECT and Ga-68 for PET. The acquired data show that the combination of a radionuclide and a chelator for its conjugation has a strong influence on the uptake of ADAPT6 in normal tissues and thereby gives a significant variation in tumor-toorgan ratios. Hence, it was concluded that the best variant for SPECT imaging is In-111-(HE)(3)DANS-ADAPT6-GSSC-DOTA while the best variant for PET imaging is Ga-68-(HE)(3)DANS-ADAPT6-GSSC-NODAGA., QC 20200421

Radionuclide molecular imaging is a promising tool that becomes increasingly important as targeted cancer therapies are developed. To ensure an effective treatment, a molecular stratification of the cancer is a necessity. To accomplish this, visualization of cancer associated molecular abnormalities in vivo by molecular imaging is the method of choice. ADAPTs, a novel type of small protein scaffold, have been utilized to select and develop high affinity binders to different proteinaceous targets. One of these binders, ADAPT6 selectively interacts with human epidermal growth factor 2 (HER2) with low nanomolar affinity and can therefore be used for its in vivo visualization. Molecular design and optimization of labeled anti-HER2 ADAPT has been explored in several earlier studies, showing that small changes in the scaffold affect the biodistribution of the domain. In this study, we evaluate how the biodistribution properties of ADAPT6 is affected by the commonly used maleimido derivatives of the macrocyclic chelators NOTA, NODAGA, DOTA and DOTAGA with the aim to select the best variants for SPECT and PET imaging. The different conjugates were labeled with 111In for SPECT and 68Ga for PET. The acquired data show that the combination of a radionuclide and a chelator for its conjugation has a strong influence on the uptake of ADAPT6 in normal tissues and thereby gives a significant variation in tumor-toorgan ratios. Hence, it was concluded that the best variant for SPECT imaging is 111In-(HE)3DANS-ADAPT6-GSSC-DOTA while the best variant for PET imaging is 68Ga-(HE)3DANS-ADAPT6-GSSC-NODAGA., De 2 första författarna delar förstaförfattarskapet.

Radionuclide molecular imaging is a promising tool that becomes increasingly important as targeted cancer therapies are developed. To ensure an effective treatment, a molecular stratification of the cancer is a necessity. To accomplish this, visualization of cancer associated molecular abnormalities in vivo by molecular imaging is the method of choice. ADAPTs, a novel type of small protein scaffold, have been utilized to select and develop high affinity binders to different proteinaceous targets. One of these binders, ADAPT6 selectively interacts with human epidermal growth factor 2 (HER2) with low nanomolar affinity and can therefore be used for its in vivo visualization. Molecular design and optimization of labeled anti-HER2 ADAPT has been explored in several earlier studies, showing that small changes in the scaffold affect the biodistribution of the domain. In this study, we evaluate how the biodistribution properties of ADAPT6 is affected by the commonly used maleimido derivatives of the macrocyclic chelators NOTA, NODAGA, DOTA and DOTAGA with the aim to select the best variants for SPECT and PET imaging. The different conjugates were labeled with 111In for SPECT and 68Ga for PET. The acquired data show that the combination of a radionuclide and a chelator for its conjugation has a strong influence on the uptake of ADAPT6 in normal tissues and thereby gives a significant variation in tumor-toorgan ratios. Hence, it was concluded that the best variant for SPECT imaging is 111In-(HE)3DANS-ADAPT6-GSSC-DOTA while the best variant for PET imaging is 68Ga-(HE)3DANS-ADAPT6-GSSC-NODAGA., De 2 första författarna delar förstaförfattarskapet.

Radionuclide molecular imaging is a promising tool that becomes increasingly important as targeted cancer therapies are developed. To ensure an effective treatment, a molecular stratification of the cancer is a necessity. To accomplish this, visualization of cancer associated molecular abnormalities in vivo by molecular imaging is the method of choice. ADAPTs, a novel type of small protein scaffold, have been utilized to select and develop high affinity binders to different proteinaceous targets. One of these binders, ADAPT6 selectively interacts with human epidermal growth factor 2 (HER2) with low nanomolar affinity and can therefore be used for its in vivo visualization. Molecular design and optimization of labeled anti-HER2 ADAPT has been explored in several earlier studies, showing that small changes in the scaffold affect the biodistribution of the domain. In this study, we evaluate how the biodistribution properties of ADAPT6 is affected by the commonly used maleimido derivatives of the macrocyclic chelators NOTA, NODAGA, DOTA and DOTAGA with the aim to select the best variants for SPECT and PET imaging. The different conjugates were labeled with 111In for SPECT and 68Ga for PET. The acquired data show that the combination of a radionuclide and a chelator for its conjugation has a strong influence on the uptake of ADAPT6 in normal tissues and thereby gives a significant variation in tumor-toorgan ratios. Hence, it was concluded that the best variant for SPECT imaging is 111In-(HE)3DANS-ADAPT6-GSSC-DOTA while the best variant for PET imaging is 68Ga-(HE)3DANS-ADAPT6-GSSC-NODAGA., De 2 första författarna delar förstaförfattarskapet.

Radionuclide imaging is a well-established and important diagnostic tool. The collected data contain physiological information as opposed to other traditional anatomical imaging techniques like X-ray computed tomography. The Anger Camera remains the primary device for nuclear medical imaging since its invention in 1957 [1]. However, despite the achieved advance in the imaging quality through the years, there are still performance limitations, resulting from the limited detection efficiency, reduced spatial resolution of highly energetic gamma rays, fixed dependency of the spatial resolution and detection efficiency from the used collimator and others. In order to overcome these limitations, the concept of “Single Plane Compton Imaging” (SPCI) has been proposed [2]. This concept, based on the idea of a “Directional Gamma Radiation Detector” [3] - [4] is now being explored experimentally. We will present first experimental results obtained with a GAGG scintillator pixel array read out by a digital silicon photomultiplier array. The detector is operated in our laboratory and exposed to gamma radiation emitted from radioactive sources. Information about the source positions is derived from the energy spectra of coincident events in adjacent scintillator pixels.

Anger cameras are still the primary technology for radionuclide imaging in nuclear medicine [1]. Despite the achieved advances in improving the image quality over the past 60 years since its invention [2], there are physical limits to the camera performance (limited detection efficiency, decreasing spatial resolution of high energetic gamma rays, fixed dependency of the spatial resolution and detection efficiency from the used collimator). In order to overcome these limitations, the concept of the “Single Plane Compton Camera” (SPCC, see also Ref. [3]) was developed. The SPCC is based on the idea of the “Directional Gamma Radiation Detector” published in Ref. [4] and [5]. A setup for the investigation of the SPCC concept was developed recently at the Helmholtz-Zentrum Dresden - Rossendorf. Based on a GAGG:Ce (Gadolinium Aluminum Gallium Garnet, Gd3Al2Ga3O12) scintillator array and read out by digital silicon photomultipliers the setup is intend to deliver spatial information of activity distributions. The authors will present first experimental results acquired with the new setup and will compare them to predictions obtained from particle transport calculations performed with GEANT 4 [6]. [1] S. R. Cherry, J. A. Sorenson and M. E. Phelps, Physics in Nuclear Medicine, 4th ed., Elsevier, 2013. [2] H. Anger, "A new instrument for mapping gamma ray emitters," Biology and Medicine Quaterly Report, 1957. [3] G. Pausch et al., Paper N60-1 presented at the 2016 IEEE NSS/MIC in Strasbourg, France, Conference Record [4] G. Kraft et al., U.S. patent no. 8030617 B2, granted in Oct. 2011 [5] A. Gueorguiev et al. U.S. patent no. 8299441 B2, granted in Oct. 2012 [6] A. Allison, "Geant 4 - a simulation toolkit", Nucl. Instr. and Meth. A. 506, (2003) 250-303

Anger cameras are still the primary technology for radionuclide imaging in nuclear medicine [1]. Despite the achieved advances in improving the image quality over the past 60 years since its invention [2], there are physical limits to the camera performance (limited detection efficiency, decreasing spatial resolution of high energetic gamma rays, fixed dependency of the spatial resolution and detection efficiency from the used collimator). In order to overcome these limitations, the concept of the “Single Plane Compton Camera” (SPCC, see also Ref. [3]) was developed. The SPCC is based on the idea of the “Directional Gamma Radiation Detector” published in Ref. [4] and [5]. A setup for the investigation of the SPCC concept was developed recently at the Helmholtz-Zentrum Dresden - Rossendorf. Based on a GAGG:Ce (Gadolinium Aluminum Gallium Garnet, Gd3Al2Ga3O12) scintillator array and read out by digital silicon photomultipliers the setup is intend to deliver spatial information of activity distributions. The authors will present first experimental results acquired with the new setup and will compare them to predictions obtained from particle transport calculations performed with GEANT 4 [6]. [1] S. R. Cherry, J. A. Sorenson and M. E. Phelps, Physics in Nuclear Medicine, 4th ed., Elsevier, 2013. [2] H. Anger, "A new instrument for mapping gamma ray emitters," Biology and Medicine Quaterly Report, 1957. [3] G. Pausch et al., Paper N60-1 presented at the 2016 IEEE NSS/MIC in Strasbourg, France, Conference Record [4] G. Kraft et al., U.S. patent no. 8030617 B2, granted in Oct. 2011 [5] A. Gueorguiev et al. U.S. patent no. 8299441 B2, granted in Oct. 2012 [6] A. Allison, "Geant 4 - a simulation toolkit", Nucl. Instr. and Meth. A. 506, (2003) 250-303

Radionuclide imaging is a well-established and important diagnostic tool. The collected data contain physiological information as opposed to other traditional anatomical imaging techniques like X-ray computed tomography. The Anger Camera remains the primary device for nuclear medical imaging since its invention in 1957 [1]. However, despite the achieved advance in the imaging quality through the years, there are still performance limitations, resulting from the limited detection efficiency, reduced spatial resolution of highly energetic gamma rays, fixed dependency of the spatial resolution and detection efficiency from the used collimator and others. In order to overcome these limitations, the concept of “Single Plane Compton Imaging” (SPCI) has been proposed [2]. This concept, based on the idea of a “Directional Gamma Radiation Detector” [3] - [4] is now being explored experimentally. We will present first experimental results obtained with a GAGG scintillator pixel array read out by a digital silicon photomultiplier array. The detector is operated in our laboratory and exposed to gamma radiation emitted from radioactive sources. Information about the source positions is derived from the energy spectra of coincident events in adjacent scintillator pixels.

No prior studies have compared Tc-99m tilmanocept (TcTM) one-day and two-day injection protocols for sentinel lymph node (SLN) biopsy in breast cancer (BC). We retrospectively identified patients with clinically node-negative BC undergoing SLN biopsy at our institution. Patients received a single, intradermal peritumoral injection of TcTM on day of surgery or day prior to surgery in addition to an intraoperative injection of isosulfan blue dye. Univariable and multivariable Poisson regression count models were constructed to assess the effects of injection timing, radiologist, patient and surgeon characteristics on the number of removed SLNs. A total of 617 patients underwent SLN biopsy with TcTM and blue dye. Sixty-seven (10.9%) patients were injected with the two-day protocol. Patients in the one-day protocol had a mean of 3.0 (standard deviation (SD) 1.9) SLNs removed compared with 2.7 (SD 1.4) SLNs in the two-day protocol, P-value = .13. On multivariable analysis, patient age and operating surgeon significantly affected the number of removed SLNs; however, the injection timing and the nuclear radiologist did not influence the number of removed SLNs. The performance of Tc-99m tilmanocept did not differ significantly between one-day and two-day injection protocols. These results are similar to other radiotracers used for SLN biopsy in BC.

BACKGROUND:The objective of this study was to examine the use of preoperative cardiac stress testing (PCST) in the Southern California Vascular Outcomes Improvement Collaborative (So Cal VOICe). METHODS:A retrospective review was performed on data in all modules of the So Cal VOICe from September 2012 through May 2016. PCST was defined as stress echocardiogram or nuclear stress test. A new postoperative myocardial infarction (MI) was defined as troponin elevation and/or electrocardiogram/imaging changes with or without ischemic symptoms. Only elective cases in patients with asymptomatic cardiac status were included in the study. RESULTS:During the study period, 3,063 procedures meeting the inclusion criteria were performed in 7 registries: carotid endarterectomy (CEA), carotid artery stent, thoracic endovascular aneurysm repair, infrainguinal bypass (Infra), endovascular aneurysm repair (EVAR), suprainguinal bypass (Supra), and open abdominal aortic aneurysm repair (OAAA). PCST varied across registries from 17% in PVI to 62% in OAAA. PCST in CEA varied across 9 institutions from 10% to 79%. PCST in EVAR varied across 7 institutions from 14% to 83%. PCST in Infra varied across 4 institutions from 10% to 57%. Of the 12 patients across all registries who had a new MI, 6 had PCST, one of which was abnormal. CONCLUSIONS:The incidence of PCST varies widely across registries and institutions in the So Cal VOICe. Despite the wide variation, the incidence of new postoperative MI is exceptionally low. Further studies should evaluate the cost-effectiveness of the PCST practices and future quality improvement efforts should focus on standardization of indications for PCST.

Single-event ion imaging enables the direct reconstruction of the relative stopping power (RSP) information required for ion-beam therapy. Helium ions were recently hypothesized to be the optimal species for such technique. The purpose of this work is to investigate the effect of secondary fragments on the image quality of helium CT (HeCT) and to assess the performance of a prototype proton CT (pCT) scanner when operated with helium beams in Monte Carlo simulations and experiment. Experiments were conducted installing the U.S. pCT consortium prototype scanner at the Heidelberg Ion-Beam Therapy Center (HIT). Simulations were performed with the scanner using the TOPAS toolkit. HeCT images were reconstructed for a cylindrical water phantom, the CTP404 (sensitometry), and the CTP528 (line-pair) [Formula: see text] ® modules. To identify and remove individual events caused by fragmentation, the multistage energy detector of the scanner was adapted to function as a [Formula: see text] telescope. The use of the developed filter eliminated the otherwise arising ring artifacts in the HeCT reconstructed images. For the HeCT reconstructed images of a water phantom, the maximum RSP error was improved by almost a factor 8 with respect to unfiltered images in the simulation and a factor 10 in the experiment. Similarly, for the CTP404 module, the mean RSP accuracy improved by a factor 6 in both the simulation and the experiment when the filter was applied (mean relative error 0.40% in simulation, 0.45% in experiment). In the evaluation of the spatial resolution through the CTP528 module, the main effect of the filter was noise reduction. For both simulated and experimental images the spatial resolution was ∼4 lp cm-1. In conclusion, the novel filter developed for secondary fragments proved to be effective in improving the visual quality and RSP accuracy of the reconstructed images. With the filter, the pCT scanner is capable of accurate HeCT imaging.

Single-event ion imaging enables the direct reconstruction of the relative stopping power (RSP) information required for ion-beam therapy. Helium ions were recently hypothesized to be the optimal species for such technique. The purpose of this work is to investigate the effect of secondary fragments on the image quality of helium CT (HeCT) and to assess the performance of a prototype proton CT (pCT) scanner when operated with helium beams in Monte Carlo simulations and experiment. Experiments were conducted installing the U.S. pCT consortium prototype scanner at the Heidelberg Ion-Beam Therapy Center (HIT). Simulations were performed with the scanner using the TOPAS toolkit. HeCT images were reconstructed for a cylindrical water phantom, the CTP404 (sensitometry), and the CTP528 (line-pair) [Formula: see text] ® modules. To identify and remove individual events caused by fragmentation, the multistage energy detector of the scanner was adapted to function as a [Formula: see text] telescope. The use of the developed filter eliminated the otherwise arising ring artifacts in the HeCT reconstructed images. For the HeCT reconstructed images of a water phantom, the maximum RSP error was improved by almost a factor 8 with respect to unfiltered images in the simulation and a factor 10 in the experiment. Similarly, for the CTP404 module, the mean RSP accuracy improved by a factor 6 in both the simulation and the experiment when the filter was applied (mean relative error 0.40% in simulation, 0.45% in experiment). In the evaluation of the spatial resolution through the CTP528 module, the main effect of the filter was noise reduction. For both simulated and experimental images the spatial resolution was ∼4 lp cm-1. In conclusion, the novel filter developed for secondary fragments proved to be effective in improving the visual quality and RSP accuracy of the reconstructed images. With the filter, the pCT scanner is capable of accurate HeCT imaging.

INTRODUCTION: Radiolabelled autologous white blood cells (WBC) scintigraphy is being standardized all over the world to ensure high quality, specificity and reproducibility. Similarly, in many European countries radiolabelled anti-granulocyte antibodies (anti-G-mAb) are used instead of WBC with high diagnostic accuracy. The EANM Inflammation & Infection Committee is deeply involved in this process of standardization as a primary goal of the group. AIM: The main aim of this guideline is to support and promote good clinical practice despite the complex environment of a national health care system with its ethical, economic and legal aspects that must also be taken into consideration. METHOD: After the standardization of the WBC labelling procedure (already published), a group of experts from the EANM Infection & Inflammation Committee developed and validated these guidelines based on published evidences. RESULTS: Here we describe image acquisition protocols, image display procedures and image analyses as well as image interpretation criteria for the use of radiolabelled WBC and monoclonal antigranulocyte antibodies. Clinical application for WBC and anti-G-mAb scintigraphy is also described. CONCLUSIONS: These guidelines should be applied by all nuclear medicine centers in favor of a highly reproducible standardized practice.

Radionuclide imaging of epidermal growth factor receptor (EGFR) expression in tumors may stratify patients for EGFR-targeting therapies and predict response or resistance to certain treatments. Affibody molecules, which are nonimmunoglobulin scaffold proteins, have a high potential as probes for molecular imaging. In this study, maleimido derivative of desferrioxamine B (DFO) chelator was site-specifically coupled to the C-terminal cysteine of the anti-EGFR affibody molecule ZEGFR:2377, and the DFO-ZEGFR:2377 conjugate was labeled with the generator-produced positron-emitting radionuclide Ga-68. Stability, specificity of binding to EGFR-expressing cells, and processing of [Ga-68]Ga-DFO-ZEGFR:2377 by cancer cells after binding were evaluated in vitro. In vivo studies were performed in nude mice bearing human EGFR-expressing A431 epidermoid cancer xenografts. The biodistribution of [Ga-68]Ga-DFO-ZEGFR:2377 was directly compared with the biodistribution of [Zr-89]Zr-DFO-ZEGFR:2377. DFO-ZEGFR:2377 was efficiently (isolated yield of 73 +/- 3%) and stably labeled with Ga-68. Binding of [Ga-68]Ga-DFO-ZEGFR:2377 to EGFR-expressing cells in vitro was receptor-specific and proportional to the EGFR expression level. In vivo saturation experiment demonstrated EGFR-specific accumulation of [Ga-68]Ga-DFO-ZEGFR:2377 in A431 xenografts. Compared to [Zr-89]Zr-DFO-ZEGFR:2377, [Ga-68]Ga-DFO-ZEGFR:2377 demonstrated significantly (p < 0.05) higher uptake in tumors and lower uptake in spleen and bones. This resulted in significantly higher tumor-to-organ ratios for [Ga-68]Ga-DFO-ZEGFR:2377. In conclusion, [Ga-68]Ga-DFO-ZEGFR:2377 is a promising probe for imaging of EGFR expression.

Radionuclide molecular imaging is a promising tool for visualization of cancer associated molecular abnormalities in vivo and stratification of patients for specific therapies. ADAPT is a new type of small engineered proteins based on the scaffold of an albumin binding domain of protein G. ADAPTs have been utilized to select and develop high affinity binders to different proteinaceous targets. ADAPT6 binds to human epidermal growth factor 2 (HER2) with low nanomolar affinity and can be used for its in vivo visualization. Molecular design of 111In-labeled anti-HER2 ADAPT has been optimized in several earlier studies. In this study, we made a direct comparison of two of the most promising variants, having either a DEAVDANS or a (HE)3DANS sequence at the N-terminus, conjugated with a maleimido derivative of DOTA to a GSSC amino acids sequence at the C-terminus. The variants (designated DOTA-C59-DEAVDANS-ADAPT6-GSSC and DOTA-C61-(HE)3DANS-ADAPT6-GSSC) were stably labeled with 111In for SPECT and 68Ga for PET. Biodistribution of labeled ADAPT variants was evaluated in nude mice bearing human tumor xenografts with different levels of HER2 expression. Both variants enabled clear discrimination between tumors with high and low levels of HER2 expression. 111In-labeled ADAPT6 derivatives provided higher tumor-to-organ ratios compared to 68Ga-labeled counterparts. The best performing variant was DOTA-C61-(HE)3DANS-ADAPT6-GSSC, which provided tumor-to-blood ratios of 208 ± 36 and 109 ± 17 at 3 h for 111In and 68Ga labels, respectively.

Radionuclide imaging of epidermal growth factor receptor (EGFR) expression in tumors may stratify patients for EGFR-targeting therapies and predict response or resistance to certain treatments. Affibody molecules, which are nonimmunoglobulin scaffold proteins, have a high potential as probes for molecular imaging. In this study, maleimido derivative of desferrioxamine B (DFO) chelator was site-specifically coupled to the C-terminal cysteine of the anti-EGFR affibody molecule ZEGFR:2377, and the DFO-ZEGFR:2377 conjugate was labeled with the generator-produced positron-emitting radionuclide Ga-68. Stability, specificity of binding to EGFR-expressing cells, and processing of [Ga-68]Ga-DFO-ZEGFR:2377 by cancer cells after binding were evaluated in vitro. In vivo studies were performed in nude mice bearing human EGFR-expressing A431 epidermoid cancer xenografts. The biodistribution of [Ga-68]Ga-DFO-ZEGFR:2377 was directly compared with the biodistribution of [Zr-89]Zr-DFO-ZEGFR:2377. DFO-ZEGFR:2377 was efficiently (isolated yield of 73 +/- 3%) and stably labeled with Ga-68. Binding of [Ga-68]Ga-DFO-ZEGFR:2377 to EGFR-expressing cells in vitro was receptor-specific and proportional to the EGFR expression level. In vivo saturation experiment demonstrated EGFR-specific accumulation of [Ga-68]Ga-DFO-ZEGFR:2377 in A431 xenografts. Compared to [Zr-89]Zr-DFO-ZEGFR:2377, [Ga-68]Ga-DFO-ZEGFR:2377 demonstrated significantly (p < 0.05) higher uptake in tumors and lower uptake in spleen and bones. This resulted in significantly higher tumor-to-organ ratios for [Ga-68]Ga-DFO-ZEGFR:2377. In conclusion, [Ga-68]Ga-DFO-ZEGFR:2377 is a promising probe for imaging of EGFR expression.

Radionuclide imaging of epidermal growth factor receptor (EGFR) expression in tumors may stratify patients for EGFR-targeting therapies and predict response or resistance to certain treatments. Affibody molecules, which are nonimmunoglobulin scaffold proteins, have a high potential as probes for molecular imaging. In this study, maleimido derivative of desferrioxamine B (DFO) chelator was site-specifically coupled to the C-terminal cysteine of the anti-EGFR affibody molecule ZEGFR:2377, and the DFO-ZEGFR:2377 conjugate was labeled with the generator-produced positron-emitting radionuclide Ga-68. Stability, specificity of binding to EGFR-expressing cells, and processing of [Ga-68]Ga-DFO-ZEGFR:2377 by cancer cells after binding were evaluated in vitro. In vivo studies were performed in nude mice bearing human EGFR-expressing A431 epidermoid cancer xenografts. The biodistribution of [Ga-68]Ga-DFO-ZEGFR:2377 was directly compared with the biodistribution of [Zr-89]Zr-DFO-ZEGFR:2377. DFO-ZEGFR:2377 was efficiently (isolated yield of 73 +/- 3%) and stably labeled with Ga-68. Binding of [Ga-68]Ga-DFO-ZEGFR:2377 to EGFR-expressing cells in vitro was receptor-specific and proportional to the EGFR expression level. In vivo saturation experiment demonstrated EGFR-specific accumulation of [Ga-68]Ga-DFO-ZEGFR:2377 in A431 xenografts. Compared to [Zr-89]Zr-DFO-ZEGFR:2377, [Ga-68]Ga-DFO-ZEGFR:2377 demonstrated significantly (p < 0.05) higher uptake in tumors and lower uptake in spleen and bones. This resulted in significantly higher tumor-to-organ ratios for [Ga-68]Ga-DFO-ZEGFR:2377. In conclusion, [Ga-68]Ga-DFO-ZEGFR:2377 is a promising probe for imaging of EGFR expression., QC 20181120

Radionuclide imaging of epidermal growth factor receptor (EGFR) expression in tumors may stratify patients for EGFR-targeting therapies and predict response or resistance to certain treatments. Affibody molecules, which are nonimmunoglobulin scaffold proteins, have a high potential as probes for molecular imaging. In this study, maleimido derivative of desferrioxamine B (DFO) chelator was site-specifically coupled to the C-terminal cysteine of the anti-EGFR affibody molecule ZEGFR:2377, and the DFO-ZEGFR:2377 conjugate was labeled with the generator-produced positron-emitting radionuclide Ga-68. Stability, specificity of binding to EGFR-expressing cells, and processing of [Ga-68]Ga-DFO-ZEGFR:2377 by cancer cells after binding were evaluated in vitro. In vivo studies were performed in nude mice bearing human EGFR-expressing A431 epidermoid cancer xenografts. The biodistribution of [Ga-68]Ga-DFO-ZEGFR:2377 was directly compared with the biodistribution of [Zr-89]Zr-DFO-ZEGFR:2377. DFO-ZEGFR:2377 was efficiently (isolated yield of 73 +/- 3%) and stably labeled with Ga-68. Binding of [Ga-68]Ga-DFO-ZEGFR:2377 to EGFR-expressing cells in vitro was receptor-specific and proportional to the EGFR expression level. In vivo saturation experiment demonstrated EGFR-specific accumulation of [Ga-68]Ga-DFO-ZEGFR:2377 in A431 xenografts. Compared to [Zr-89]Zr-DFO-ZEGFR:2377, [Ga-68]Ga-DFO-ZEGFR:2377 demonstrated significantly (p < 0.05) higher uptake in tumors and lower uptake in spleen and bones. This resulted in significantly higher tumor-to-organ ratios for [Ga-68]Ga-DFO-ZEGFR:2377. In conclusion, [Ga-68]Ga-DFO-ZEGFR:2377 is a promising probe for imaging of EGFR expression.

Radionuclide imaging of epidermal growth factor receptor (EGFR) expression in tumors may stratify patients for EGFR-targeting therapies and predict response or resistance to certain treatments. Affibody molecules, which are nonimmunoglobulin scaffold proteins, have a high potential as probes for molecular imaging. In this study, maleimido derivative of desferrioxamine B (DFO) chelator was site-specifically coupled to the C-terminal cysteine of the anti-EGFR affibody molecule ZEGFR:2377, and the DFO-ZEGFR:2377 conjugate was labeled with the generator-produced positron-emitting radionuclide Ga-68. Stability, specificity of binding to EGFR-expressing cells, and processing of [Ga-68]Ga-DFO-ZEGFR:2377 by cancer cells after binding were evaluated in vitro. In vivo studies were performed in nude mice bearing human EGFR-expressing A431 epidermoid cancer xenografts. The biodistribution of [Ga-68]Ga-DFO-ZEGFR:2377 was directly compared with the biodistribution of [Zr-89]Zr-DFO-ZEGFR:2377. DFO-ZEGFR:2377 was efficiently (isolated yield of 73 +/- 3%) and stably labeled with Ga-68. Binding of [Ga-68]Ga-DFO-ZEGFR:2377 to EGFR-expressing cells in vitro was receptor-specific and proportional to the EGFR expression level. In vivo saturation experiment demonstrated EGFR-specific accumulation of [Ga-68]Ga-DFO-ZEGFR:2377 in A431 xenografts. Compared to [Zr-89]Zr-DFO-ZEGFR:2377, [Ga-68]Ga-DFO-ZEGFR:2377 demonstrated significantly (p < 0.05) higher uptake in tumors and lower uptake in spleen and bones. This resulted in significantly higher tumor-to-organ ratios for [Ga-68]Ga-DFO-ZEGFR:2377. In conclusion, [Ga-68]Ga-DFO-ZEGFR:2377 is a promising probe for imaging of EGFR expression.

Radionuclide imaging of epidermal growth factor receptor (EGFR) expression in tumors may stratify patients for EGFR-targeting therapies and predict response or resistance to certain treatments. Affibody molecules, which are nonimmunoglobulin scaffold proteins, have a high potential as probes for molecular imaging. In this study, maleimido derivative of desferrioxamine B (DFO) chelator was site-specifically coupled to the C-terminal cysteine of the anti-EGFR affibody molecule ZEGFR:2377, and the DFO-ZEGFR:2377 conjugate was labeled with the generator-produced positron-emitting radionuclide Ga-68. Stability, specificity of binding to EGFR-expressing cells, and processing of [Ga-68]Ga-DFO-ZEGFR:2377 by cancer cells after binding were evaluated in vitro. In vivo studies were performed in nude mice bearing human EGFR-expressing A431 epidermoid cancer xenografts. The biodistribution of [Ga-68]Ga-DFO-ZEGFR:2377 was directly compared with the biodistribution of [Zr-89]Zr-DFO-ZEGFR:2377. DFO-ZEGFR:2377 was efficiently (isolated yield of 73 +/- 3%) and stably labeled with Ga-68. Binding of [Ga-68]Ga-DFO-ZEGFR:2377 to EGFR-expressing cells in vitro was receptor-specific and proportional to the EGFR expression level. In vivo saturation experiment demonstrated EGFR-specific accumulation of [Ga-68]Ga-DFO-ZEGFR:2377 in A431 xenografts. Compared to [Zr-89]Zr-DFO-ZEGFR:2377, [Ga-68]Ga-DFO-ZEGFR:2377 demonstrated significantly (p < 0.05) higher uptake in tumors and lower uptake in spleen and bones. This resulted in significantly higher tumor-to-organ ratios for [Ga-68]Ga-DFO-ZEGFR:2377. In conclusion, [Ga-68]Ga-DFO-ZEGFR:2377 is a promising probe for imaging of EGFR expression.

Background: Thyroid nodules are a common clinical problem, and differentiated thyroid cancer is becoming increasingly prevalent. Methods: Six scientific Italian societies entitled to cure thyroid cancer patients (the Italian Thyroid Association, the Medical Endocrinology Association, the Italian Society of Endocrinology, the Italian Association of Nuclear Medicine and Molecular Imaging, the Italian Society of Unified Endocrine Surgery and the Italian Society of Anatomic Pathology and Diagnostic Cytology) felt the need to develop a consensus report based on significant scientific advances occurred in the field. Objective: The document includes recommendations regarding initial evaluation of thyroid nodules, clinical and ultrasound criteria for fine-needle aspiration biopsy, initial management of thyroid cancer including staging and risk assessment, surgical management, radioiodine remnant ablation, and levothyroxine therapy, short-term and long-term follow-up strategies, and management of recurrent and metastatic disease. The objective of this consensus is to inform clinicians, patients, researchers, and health policy makers about the best strategies (and their limitations) relating to the diagnosis and treatment of differentiated thyroid cancer.

Single-event ion imaging enables the direct reconstruction of the relative stopping power (RSP) information required for ion-beam therapy. Helium ions were recently hypothesized to be the optimal species for such technique. The purpose of this work is to investigate the effect of secondary fragments on the image quality of helium CT (HeCT) and to assess the performance of a prototype proton CT (pCT) scanner when operated with helium beams in Monte Carlo simulations and experiment. Experiments were conducted installing the U.S. pCT consortium prototype scanner at the Heidelberg Ion-Beam Therapy Center (HIT). Simulations were performed with the scanner using the TOPAS toolkit. HeCT images were reconstructed for a cylindrical water phantom, the CTP404 (sensitometry), and the CTP528 (line-pair) [Formula: see text] ® modules. To identify and remove individual events caused by fragmentation, the multistage energy detector of the scanner was adapted to function as a [Formula: see text] telescope. The use of the developed filter eliminated the otherwise arising ring artifacts in the HeCT reconstructed images. For the HeCT reconstructed images of a water phantom, the maximum RSP error was improved by almost a factor 8 with respect to unfiltered images in the simulation and a factor 10 in the experiment. Similarly, for the CTP404 module, the mean RSP accuracy improved by a factor 6 in both the simulation and the experiment when the filter was applied (mean relative error 0.40% in simulation, 0.45% in experiment). In the evaluation of the spatial resolution through the CTP528 module, the main effect of the filter was noise reduction. For both simulated and experimental images the spatial resolution was ∼4 lp cm-1. In conclusion, the novel filter developed for secondary fragments proved to be effective in improving the visual quality and RSP accuracy of the reconstructed images. With the filter, the pCT scanner is capable of accurate HeCT imaging.

OBJECTIVE Diagnosing bone infection in the diabetic foot is challenging and often requires several diagnostic procedures, including advanced imaging. We compared the diagnostic performances of MRI, radiolabeled white blood cell (WBC) scintigraphy (either with 99mTc-hexamethylpropyleneamineoxime [HMPAO] or 111In-oxine), and [18F]fluorodeoxyglucose positron emission tomography (18F-FDG-PET)/ computed tomography. RESEARCH DESIGN AND METHODS We searchedMedline andEmbase as of August 2016 for studies of diagnostic tests on patients known or suspected to have diabetes and a foot infection. We performed a systematic review using criteria recommended by the Cochrane Review of a database that included prospective and retrospective diagnostic studies performed on patients with diabetes in whom there was a clinical suspicion of osteomyelitis of the foot. The preferred reference standard was bone biopsy and subsequent pathological (or microbiological) examination. RESULTS Our review found 6,649 articles; 3,894 in Medline and 2,755 in Embase. A total of 27 full articles and 2 posters was selected for inclusion in the analysis. The performance characteristics for the 18F-FDG-PET were: sensitivity, 89%; specificity, 92%; diagnostic odds ratio (DOR), 95; positive likelihood ratio (LR), 11; and negative LR, 0.11. For WBC scan with 111In-oxine, the values were: sensitivity, 92%; specificity, 75%; DOR, 34; positive LR, 3.6; and negative LR, 0.1. For WBC scan with 99mTc-HMPAO, the values were: sensitivity, 91%; specificity, 92%; DOR, 118; positive LR, 12; and negative LR, 0.1. Finally, forMRI, the valueswere: sensitivity, 93%; specificity, 75%; DOR, 37; positive LR, 3.66, and negative LR, 0.10. CONCLUSIONS The various modalities have similar sensitivity, but 18F-FDG-PET and 99mTc-HMPAO-labeled WBC scintigraphy offer the highest specificity. Larger prospective studies with a direct comparison among the different imaging techniques are required.

Vesicoureteral reflux (VUR) has been linked to recurrent urinary tract infections (UTIs), renal scarring, hypertension, renal insufficiency and end-stage kidney disease. Different imaging strategies have been proposed to approach children presenting with UTI to sort out patients with significant VUR while minimizing patient morbidity, radiation exposure and financial burden. None of these imaging strategies is universally accepted. The"top-down approach" (TDA) aims at restricting the number of voiding cystourethrograms (VCUGs) and its associated morbidity while identifying patients with clinically-significant reflux. In this approach, children presenting with febrile UTIs are acutely investigated with dimercapto-succinic acid (DMSA) renal scans to identify patients with renal parenchymal inflammation. Those with evidence of renal affection are offered VCUG and late DMSA scan to identify VUR and permanent renal scarring, respectively. Although TDA could identify clinically-significant VUR with high sensitivity, it is not without limitations. The approach segregates patients based on the presence of DMSA cortical lesions omitting the morbidity and the economic burden of UTI. Additionally, some of DMSA lesions are attributed to congenital dysplasia and unrelated to UTI. Ionizing radiation exposure, financial costs, limited availability of DMSA scans in the acute setting, variability in interpreting the results and low yield of actionable findings on DMSA scans are some other limitations. In this review, we tried to address the drawbacks of the TDA and reinforce the value of patient-centered approach for VUR.

IntroductionThe overall goal of the Alzheimer's Disease Neuroimaging Initiative (ADNI) is to validate biomarkers for Alzheimer's disease (AD) clinical trials. ADNI-3, which began on August 1, 2016, is a 5-year renewal of the current ADNI-2 study.MethodsADNI-3 will follow current and additional subjects with normal cognition, mild cognitive impairment, and AD using innovative technologies such as tau imaging, magnetic resonance imaging sequences for connectivity analyses, and a highly automated immunoassay platform and mass spectroscopy approach for cerebrospinal fluid biomarker analysis. A Systems Biology/pathway approach will be used to identify genetic factors for subject selection/enrichment. Amyloid positron emission tomography scanning will be standardized using the Centiloid method. The Brain Health Registry will help recruit subjects and monitor subject cognition.ResultsMultimodal analyses will provide insight into AD pathophysiology and disease progression.DiscussionADNI-3 will aim to inform AD treatment trials and facilitate development of AD disease-modifying treatments.