Assessment of Bone Lesions with F-18-FDG PET Compared with Tc-99m Bone Scintigraphy Leads to Clinically Relevant Differences in Metastatic Breast Cancer Management

It is unknown whether assessment of potential bone lesions in metastatic breast cancer (MBC) by F-18-FDG PET instead of Tc-99m bone scintigraphy (BS) supports clinically relevant changes in MBC management. Therefore, we retrospectively compared management recommendations based on bone lesion assessment by (18)FFDG PET plus contrast-enhanced CT (ceCT) or BS plus ceCT, for patients with newly diagnosed MBC. Methods: Baseline ceCT, BS, and F-18-FDG PET for all patients included in the IMPACT-MBC study (NCT01957332) at the University Medical Center Groningen were reviewed for bone lesions. If bone lesions were found by any imaging modality, virtual MBC management recommendations were made by a multidisciplinary expert panel, based on either F-18-FDG PET plus ceCT or BS plus ceCT. The panel had access to standard clinicopathologic information and baseline imaging findings outside the skeleton. Clinically relevant management differences between the 2 recommendations were defined either as different treatment intent (curative, noncurative, or unable to determine) or as different systemic or local treatment. If no bone lesions were found by any imaging modality, the patients were included in the analyses without expert review. Results: In total, 3,473 unequivocal bone lesions were identified in 10(2) evaluated patients (39% by ceCT, 26% by BS, and 87% by F-18-FDG PET). Additional bone lesions on F-18-FDG PET plus ceCT compared with BS plus ceCT led to change in MBC management recommendations in 16% of patients (95% CI, 10%-24%). BS also changed management compared with F-18-FDG PET in 1 patient (1%; 95% CI, 0%-5%). In 26% (95% CI, 19%-36%) of patients, an additional F-18-FDG PET exam was requested, because BS provided insufficient information. Conclusion: In this exploratory analysis of newly diagnosed MBC patients, F-18-FDG PET versus BS to assess bone lesions resulted in clinically relevant management differences in 16% of patients. BS delivered insufficient information in over one fourth of patients, resulting in an additional request for F-18-FDG PET. On the basis of these data, F-18-FDG PET should be considered a primary imaging modality for assessment of bone lesions in newly diagnosed MBC

Comparison of risk prediction scores for venous thromboembolism in cancer patients:A prospective cohort study

In ambulatory patients with solid cancer, routine thromboprophylaxis to prevent venous thromboembolism is not recommended. Several risk prediction scores to identify cancer patients at high risk of venous thromboembolism have been proposed, but their clinical usefulness remains a matter of debate. We evaluated and directly compared the performance of the Khorana, Vienna, PROTECHT, and CONKO scores in a multinational, prospective cohort study. Patients with advanced cancer were eligible if they were due to undergo chemotherapy or had started chemotherapy in the previous three months. The primary outcome was objectively confirmed symptomatic or incidental deep vein thrombosis or pulmonary embolism during a 6-month followup period. A total of 876 patients were enrolled, of whom 260 (30%) had not yet received chemotherapy. Fifty-three patients (6.1%) developed venous thromboembolism. The c-statistics of the scores ranged from 0.50 to 0.57. At the conventional positivity threshold of 3 points, the scores classified 13-34% of patients as high-risk; the 6-month incidence of venous thromboembolism in these patients ranged from 6.5% (95% CI: 2.8-12) for the Khorana score to 9.6% (95% CI: 6.6-13) for the PROTECHT score. High-risk patients had a significantly increased risk of venous thromboembolism when using the Vienna (subhazard ratio 1.7; 95% CI: 1.0-3.1) or PROTECHT (subhazard ratio 2.1; 95% CI: 1.23.6) scores. In conclusion, the prediction scores performed poorly in predicting venous thromboembolism in cancer patients. The Vienna CATS and PROTECHT scores appear to discriminate better between low-and high-risk patients, but further improvements are needed before they can be considered for introduction into clinical practice

Comparative biodistribution analysis across four different Zr-monoclonal antibody tracers-The first step towards an imaging warehouse

Rationale: Knowledge on monoclonal antibody biodistribution in healthy tissues in humans can support clinical drug development. Molecular imaging with positron emission tomography (PET) can yield information in this setting. However, recent imaging studies have analyzed the behavior of single antibodies only, neglecting comparison across different antibodies. Methods: We compared the distribution of four 89Zr-labeled antibodies in healthy tissue in a retrospective analysis based on the recently published harmonization protocol for 89Zr-tracers and our delineation protocol. Results: The biodistribution patterns of 89Zr-lumretuzumab, 89Zr-MMOT0530A, 89Zr-bevacizumab and 89Zr-trastuzumab on day 4 after tracer injection were largely similar. The highest tracer concentration was seen in healthy liver, spleen, kidney and intestines. About one-third of the injected tracer dose was found in the circulation, up to 15% in the liver and only 4% in the spleen and kidney. Lower tracer concentration was seen in bone marrow, lung, compact bone, muscle, fat and the brain. Despite low tracer accumulation per gram of tissue, large-volume tissues, especially fat, can influence overall distribution: On average, 5-7% of the injected tracer dose accumulated in fat, with a peak of 19% in a patient with morbid obesity. Conclusion: The similar biodistribution of the four antibodies is probably based on their similar molecular structure, binding characteristics and similar metabolic pathways. These data provide a basis for a prospectively growing, online accessible warehouse of molecular imaging data, which enables researchers to increase and exchange knowledge on whole body drug distribution and potentially supports drug development decisions

Short-term beneficial effects of methylene blue on kidney damage in septic shock patients

Contains fulltext : 71022.pdf (publisher's version ) (Closed access)OBJECTIVE: We previously demonstrated that upregulation of renal inducible nitric oxide synthase (iNOS) is associated with proximal tubule injury during systemic inflammation in humans. In this study we investigated the short-term effect of methylene blue (MB), an inhibitor of the NO pathway, on kidney damage and function in septic shock patients. DESIGN AND SETTING: A prospective clinical study conducted in an intensive care unit. PATIENTS: Nine patients (four men, five women, mean age 71 +/- 3 years) with confirmed or suspected bacterial infection and with refractory septic shock defined as a mean arterial pressure or = 0.2 microg/kg per minute. INTERVENTIONS: A 4 h continuous intravenous infusion of 1 mg/kg MB per hour. MEASUREMENTS AND RESULTS: The urinary excretion of NO metabolites decreased with median 90% (range 75-95%) from baseline to 6 h after MB administration. The first 24 h creatinine clearance improved by 51% (18-173%) after MB treatment but was still strongly impaired. During the first 6 h after the start of MB treatment both the urinary excretion of cytosolic glutathione S-transferase A1-1 and P1-1, markers for proximal and distal tubule damage, respectively, decreased by 45% (10-70%) and 70% (40-85) vs. baseline. After termination of the MB infusion the NO metabolites and markers of tubular injury returned to pretreatment levels. CONCLUSIONS: In septic patients with refractory shock short-term infusion of MB is associated with a decrease in NO production and an attenuation of the urinary excretion of renal tubular injury markers

A proposal for a coordinated effort for the determination of brainwide neuroanatomical connectivity in model organisms at a mesoscopic scale

In this era of complete genomes, our knowledge of neuroanatomical circuitry remains surprisingly sparse. Such knowledge is however critical both for basic and clinical research into brain function. Here we advocate for a concerted effort to fill this gap, through systematic, experimental mapping of neural circuits at a mesoscopic scale of resolution suitable for comprehensive, brain-wide coverage, using injections of tracers or viral vectors. We detail the scientific and medical rationale and briefly review existing knowledge and experimental techniques. We define a set of desiderata, including brain-wide coverage; validated and extensible experimental techniques suitable for standardization and automation; centralized, open access data repository; compatibility with existing resources, and tractability with current informatics technology. We discuss a hypothetical but tractable plan for mouse, additional efforts for the macaque, and technique development for human. We estimate that the mouse connectivity project could be completed within five years with a comparatively modest budget.Comment: 41 page

RAS and BRAF mutations in cell-free DNA are predictive for outcome of cetuximab monotherapy in patients with tissue-tested RAS wild-type advanced colorectal cancer

In metastatic colorectal cancer, RAS and BRAF mutations cause resistance to anti-EGFR therapies, such as cetuximab. Heterogeneity in RAS and BRAF mutations might explain nonresponse in a subset of patients receiving cetuximab. Analyzing mutations in plasma-derived circulating tumor DNA (ctDNA) could provide a more comprehensive overview of the mutational landscape as compared to analyses of primary and/or metastatic tumor tissue. Therefore

Aptamer-based multiplexed proteomic technology for biomarker discovery

Interrogation of the human proteome in a highly multiplexed and efficient manner remains a coveted and challenging goal in biology. We present a new aptamer-based proteomic technology for biomarker discovery capable of simultaneously measuring thousands of proteins from small sample volumes (15 [mu]L of serum or plasma). Our current assay allows us to measure ~800 proteins with very low limits of detection (1 pM average), 7 logs of overall dynamic range, and 5% average coefficient of variation. This technology is enabled by a new generation of aptamers that contain chemically modified nucleotides, which greatly expand the physicochemical diversity of the large randomized nucleic acid libraries from which the aptamers are selected. Proteins in complex matrices such as plasma are measured with a process that transforms a signature of protein concentrations into a corresponding DNA aptamer concentration signature, which is then quantified with a DNA microarray. In essence, our assay takes advantage of the dual nature of aptamers as both folded binding entities with defined shapes and unique sequences recognizable by specific hybridization probes. To demonstrate the utility of our proteomics biomarker discovery technology, we applied it to a clinical study of chronic kidney disease (CKD). We identified two well known CKD biomarkers as well as an additional 58 potential CKD biomarkers. These results demonstrate the potential utility of our technology to discover unique protein signatures characteristic of various disease states. More generally, we describe a versatile and powerful tool that allows large-scale comparison of proteome profiles among discrete populations. This unbiased and highly multiplexed search engine will enable the discovery of novel biomarkers in a manner that is unencumbered by our incomplete knowledge of biology, thereby helping to advance the next generation of evidence-based medicine

Decalcification of Breast Cancer Bone Metastases with EDTA Does Not Affect ER, PR, and HER2 Results

In metastatic breast cancer (MBC), expression of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor-2 (HER2) guides treatment selection. In case of bone-only metastatic disease, ER, PR, and HER2 status assessment may be hampered by decalcification. We aimed to determine the optimal decalcification method, and to study discordance of receptor expression between paired primary breast tumors and optimally decalcified bone metastases. First, decalcification was simulated using acetic acid, hydrochloric/formic acid, and EDTA on 12 primary breast carcinomas. ER, PR, and HER2 immunohistochemistry (IHC) and HER2 in situ hybridization (ISH) were assessed, before and after the 3 decalcification methods. EDTA was considered t

"I am pregnant and my husband has diabetes. Is there a risk for my child?" A qualitative study of questions asked by email about the role of genetic susceptibility to diabetes

<p>Abstract</p> <p>Background</p> <p>Diabetes Mellitus is a global health problem. Scientific knowledge on the genetics of diabetes is expanding and is more and more utilised in clinical practice and primary prevention strategies. Health consumers have become increasingly interested in genetic information. In the Netherlands, the <it>National Genetic Research and Information Center </it>provides online information about the genetics of diabetes and thereby offers website visitors the opportunity to ask a question per email. The current study aims at exploring people's need of (additional) information about the role of inheritance in diabetes. Results may help to tailor existing clinical and public (online) genetic information to the needs of an increasing population at risk for diabetes.</p> <p>Methods</p> <p>A data base with emailed questions about diabetes and inheritance (n = 172) is used in a secondary content analysis. Questions are posted in 2005-2009 via a website providing information about more than 600 inheritable disorders, including all diabetes subtypes. Queries submitted were classified by contents as well as persons' demographic profiles.</p> <p>Results</p> <p>Questions were received by diabetes patients (49%), relatives (30%), and partners (21%). Questioners were relatively young (54.8% ≤ 30 years) and predominantly female (83%). Most queries related to type 1 diabetes and concerned topics related to (future) pregnancy and family planning. Questioners mainly asked for risk estimation, but also clarifying information (about genetics of diabetes in general) and advice (mostly related to family planning) was requested. Preventive advice to reduce own diabetes risk was hardly sought.</p> <p>Conclusions</p> <p>Genetic information on diabetes provided by professionals or public health initiatives should address patients, as well as relatives and partners. In particular women are receptive to genetic information; they worry about the diabetes related health of (future) offspring. It seems important that information on the contribution of genetics to type 1 diabetes is more readily available. Considering the high prevalence of type 2 diabetes with strong evidence for a genetic predisposition, more effort seems needed to promote awareness around familial clustering and primary prevention.</p

Lesion detection by [89Zr]Zr-DFO-girentuximab and [18F]FDG-PET/CT in patients with newly diagnosed metastatic renal cell carcinoma

Purpose: The main objective of this preliminary analysis of the IMaging PAtients for Cancer drug selecTion (IMPACT)-renal cell cancer (RCC) study is to evaluate the lesion detection of baseline contrast-enhanced CT, [89Zr]Zr-DFO-girentuximab-PET/CT and [18F]FDG-PET/CT in detecting ccRCC lesions in patients with a good or intermediate prognosis metastatic clear cell renal cell carcinoma (mccRCC) according to the International Metastatic Database Consortium (IMDC) risk model. Methods: Between February 2015 and March 2018, 42 newly diagnosed mccRCC patients with good or intermediate prognosis, eligible for watchful waiting, were included. Patients underwent CT, [89Zr]Zr-DFO-girentuximab-PET/CT and [18F]FDG-PET/CT at baseline. Scans were independently reviewed and lesions of ≥10 mm and lymph nodes of ≥15 mm at CT were analyzed. For lesions with [89Zr]Zr-DFO-girentuximab or [18F]FDG-uptake visually exceeding background uptake, maximum standardized uptake values (SUVmax) were measured. Results: A total of 449 lesions were detected by ≥1 modality (median per patient: 7; ICR 4.25–12.75) of which 42% were in lung, 22% in lymph nodes and 10% in bone. Combined [89Zr]Zr-DFO-girentuximab-PET/CT and CT detected more lesions than CT alone: 91% (95%CI: 87–94) versus 56% (95%CI: 50–62, p = 0.001), respectively, and more than CT and [18F]FDG-PET/CT combined (84% (95%CI:79–88, p < 0.005). Both PET/CTs detected more bone and soft tissue lesions compared to CT alone. Conclusions: The addition of [89Zr]Zr-DFO-girentuximab-PET/CT and [18F]FDG-PET/CT to CT increases lesion detection compared to CT alone in newly diagnosed good and intermediate prognosis mccRCC patients eligible for watchful waiting