Archive for the ‘Medical Device Therapies for Altzheimer’s Disease’ Category

Medical Device Technology for Alzheimer’s Diseases

Reporter: Danielle Smolyar


Alzheimer’s disease is said to be caused by a large number of proteins that are overproduced around a brain cell. Alzheimer’s is an irreversible disease that overtime decreases a person’s memory and the ability to perform tasks. With this disease, it is hard to function day to day life because it is hard to take on simple daily tasks or activities. It is a powerful and advanced disease that has not yet been found a cure. There have been many trials and scientists and researchers are still trying to figure out and find a cure for this disease because so many people, unfortunately, suffer from it.

This acute disease has no cure yet.  In an article titled, World Alzheimer’s Month: Exploring the latest research and devices for early detection, According to the Alzheimer’s Association,

“an estimated 5.3 million Americans are currently living with Alzheimer’s disease. By 2025, that number is expected to increase to more than seven million. Doctors diagnose dementia in around 10 million people every year, and 60–70% of these new diagnoses detect Alzheimer’s disease.”

The reality of the disease is tragic and the fact that the numbers keep growing calls for more urgency to find a cure and help innocent people fight off this disease. With society’s new technological and medical advancements, researchers have been working on finding a cure or developing a medical device to help people with Alzheimer’s. The article also states, ”Dr. Thom Wilcockson, from the UK’s Loughborough University, found that

eye-tracking technology could help identify mild cognitive impairment (MCI) in patients who might go on to develop Alzheimer’s disease in the future.”

With this technology and how advanced our society is, technology could eventually find a cure. With this device, it can help and make a considerable change in the number of people who develop Alzheimer’s. This new tool could help people prepare for the sickness or prevent future conditions from getting worse. Ultimately, if we have this technology, it can teach the world and educate the world on this condition and how we can take strides into preventing it from happening.

Dr. Thom Wilcosckon stated that looking for MCI can be a benchmark or sign for doctors to look for early development of Alzheimer’s:

Dr. Wilcockson and the research team worked with 42 patients with a diagnosis of aMCI, 47 with a diagnosis of naMCI, 68 people with dementia caused due to Alzheimer’s disease, and 92 healthy controls as part of their study. During the study, the participants were instructed to complete antisaccade tasks that are simple computer test where participants are told to look away from a distractor stimulus. The researchers found that they were able to differentiate between the two forms of MCI by looking at the eye-tracking results.

This modern technique of being able to pinpoint a specific aspect that would differentiate patients and their sicknesses from one another can cause a massive shift in the Alzheimer’s world. One step at a time, doctors, scientists, and researches are learning more about Alzheimers and are inching closer to hopefully finding a cure in the near future.


World Alzheimer’s Month: Exploring latest research and devices for early detection

World Alzheimer’s Month: Exploring latest research and devices for early detection






Alzheimer’s Disease: Novel Therapeutical Approaches — Articles of Note @PharmaceuticalIntelligence.com




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Developer of Alzheimer’s drug Exelon at Hebrew University’s School of Pharmacy: Israel Prize in Medicine awarded to Prof. Marta Weinstock-Rosin

TyrNovo’s Novel and Unique Compound, named NT219, selectively Inhibits the process of Aging and Neurodegenerative Diseases, without affecting Lifespan

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Introduction to Nanotechnology and Alzheimer disease


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Alzheimer’s Disease: Novel Therapeutical Approaches — Articles of Note @PharmaceuticalIntelligence.com



The Rogue Immune Cells That Wreck the Brain


by Adam Piore   April 4, 2016            


Microglia are part of a larger class of cells—known collectively as glia—that carry out an array of functions in the brain, guiding its development and serving as its immune system by gobbling up diseased or damaged cells and carting away debris. Along with her frequent collaborator and mentor, Stanford biologist Ben Barres, and a growing cadre of other scientists, Stevens, 45, is showing that these long-overlooked cells are more than mere support workers for the neurons they surround. Her work has raised a provocative suggestion: that brain disorders could somehow be triggered by our own bodily defenses gone bad.

In one groundbreaking paper, in January, Stevens and researchers at the Broad Institute of MIT and Harvard showed that aberrant microglia might play a role in schizophrenia—causing or at least contributing to the massive cell loss that can leave people with devastating cognitive defects. Crucially, the researchers pointed to a chemical pathway that might be targeted to slow or stop the disease. Last week, Stevens and other researchers published a similar finding for Alzheimer’s.

This might be just the beginning. Stevens is also exploring the connection between these tiny structures and other neurological diseases—work that earned her a $625,000 MacArthur Foundation “genius” grant last September.

All of this raises intriguing questions. Is it possible that many common brain disorders, despite their wide-ranging symptoms, are caused or at least worsened by the same culprit, a component of the immune system? If so, could many of these disorders be treated in a similar way—by stopping these rogue cells?


Science  31 Mar 2016;        http://dx.doi.org:/10.1126/science.aad8373      Complement and microglia mediate early synapse loss in Alzheimer mouse models.
Soyon Hong1, Victoria F. Beja-Glasser1,*, Bianca M. Nfonoyim1,*,…., Ben A. Barres6, Cynthia A. Lemere,2, Dennis J. Selkoe2,7, Beth Stevens1,8,

Synapse loss in Alzheimer’s disease (AD) correlates with cognitive decline. Involvement of microglia and complement in AD has been attributed to neuroinflammation, prominent late in disease. Here we show in mouse models that complement and microglia mediate synaptic loss early in AD. C1q, the initiating protein of the classical complement cascade, is increased and associated with synapses before overt plaque deposition. Inhibition of C1q, C3 or the microglial complement receptor CR3, reduces the number of phagocytic microglia as well as the extent of early synapse loss. C1q is necessary for the toxic effects of soluble β-amyloid (Aβ) oligomers on synapses and hippocampal long-term potentiation (LTP). Finally, microglia in adult brains engulf synaptic material in a CR3-dependent process when exposed to soluble Aβ oligomers. Together, these findings suggest that the complement-dependent pathway and microglia that prune excess synapses in development are inappropriately activated and mediate synapse loss in AD.

Genome-wide association studies (GWAS) implicate microglia and complement-related pathways in AD (1). Previous research has demonstrated both beneficial and detrimental roles of complement and microglia in plaque-related neuropathology (23); however, their roles in synapse loss, a major pathological correlate of cognitive decline in AD (4), remain to be identified. Emerging research implicates microglia and immune-related mechanisms in brain wiring in the healthy brain (1). During development, C1q and C3 localize to synapses and mediate synapse elimination by phagocytic microglia (57). We hypothesized that this normal developmental synaptic pruning pathway is activated early in the AD brain and mediates synapse loss.

Scientists have known about glia for some time. In the 1800s, the pathologist Rudolf Virchow noted the presence of small round cells packing the spaces between neurons and named them “nervenkitt” or “neuroglia,” which can be translated as nerve putty or glue. One variety of these cells, known as astrocytes, was defined in 1893. And then in the 1920s, the Spanish scientist Pio del Río Hortega developed novel ways of staining cells taken from the brain. This led him to identify and name two more types of glial cells, including microglia, which are far smaller than the others and are characterized by their spidery shape and multiple branches. It is only when the brain is damaged in adulthood, he suggested, that microglia spring to life—rushing to the injury, where it was thought they helped clean up the area by eating damaged and dead cells. Astrocytes often appeared on the scene as well; it was thought that they created scar tissue.

This emergency convergence of microglia and astrocytes was dubbed “gliosis,” and by the time Ben Barres entered medical school in the late 1970s, it was well established as a hallmark of neurodegenerative diseases, infection, and a wide array of other medical conditions. But no one seemed to understand why it occurred. That intrigued Barres, then a neurologist in training, who saw it every time he looked under a microscope at neural tissue in distress. “It was just really fascinating,” he says. “The great mystery was: what is the point of this gliosis? Is it good? Is it bad? Is it driving the disease process, or is it trying to repair the injured brain?”

Barres began looking for the answer. He learned how to grow glial cells in a dish and apply a new recording technique to them. He could measure their electrical qualities, which determine the biochemical signaling that all brain cells use to communicate and coördinate activity.

Barres’s group had begun to identify the specific compounds astrocytes secreted that seemed to cause neurons to grow synapses. And eventually, they noticed that these compounds also stimulated production of a protein called C1q.

Conventional wisdom held that C1q was activated only in sick cells—the protein marked them to be eaten up by immune cells—and only outside the brain. But Barres had found it in the brain. And it was in healthy neurons that were arguably at their most robust stage: in early development. What was the C1q protein doing there?


A stained astrocyte.

The answer lies in the fact that marking cells for elimination is not something that happens only in diseased brains; it is also essential for development. As brains develop, their neurons form far more synaptic connections than they will eventually need. Only the ones that are used are allowed to remain. This pruning allows for the most efficient flow of neural transmissions in the brain, removing noise that might muddy the signal.

Kalaria, RN. Microglia and Alzheimer’s disease. Current Opinion in Hematology: January 1999 – Volume 6 – Issue 1 – p 15

Microglia play a major role in the cellular response associated with the pathological lesions of Alzheimer’s disease. As brain-resident macrophages, microglia elaborate and operate under several guises that seem reminiscent of circulating and tissue monocytes of the leucocyte repertoire. Although microglia bear the capacity to synthesize amyloid β, current evidence is most consistent with their phagocytic role. This largely involves the removal of cerebral amyloid and possibly the transformation of amyloid β into fibrils. The phagocytic functions also encompass the generation of cytokines, reactive oxygen and nitrogen species, and various proteolytic enzymes, events that may exacerbate neuronal damage rather than incite outgrowth or repair mechanisms. Microglia do not appear to function as true antigen-presenting cells. However, there is circumstantial evidence that suggests functional heterogeneity within microglia. Pharmacological agents that suppress microglial activation or reduce microglial-mediated oxidative damage may prove useful strategies to slow the progression of Alzheimer’s disease.

Streit WJ. Microglia and Alzheimer’s disease pathogenesis. J Neurosci Res 1 July 2004; 77(1):1–8

The most visible and, until very recently, the only hypothesis regarding the involvement of microglial cells in Alzheimer’s disease (AD) pathogenesis is centered around the notion that activated microglia are neurotoxin-producing immune effector cells actively involved in causing the neurodegeneration that is the cause for AD dementia. The concept of detrimental neuroinflammation has gained a strong foothold in the AD arena and is being expanded to other neurodegenerative diseases. This review takes a comprehensive and critical look at the overall evidence supporting the neuroinflammation hypothesis and points out some weaknesses. The current work also reviews evidence for an alternative theory, the microglial dysfunction hypothesis, which, although eliminating some of the shortcomings, does not necessarily negate the amyloid/neuroinflammation theory. The microglial dysfunction theory offers a different perspective on the identity of activated microglia and their role in AD pathogenesis taking into account the most recent insights gained from studying basic microglial biology.


  1. Keren Asraf, Nofar Torika, Ella Roasso, Sigal Fleisher-Berkovich, Differential effect of intranasally administrated kinin B1 and B2 receptor antagonists in Alzheimer’s disease mice, Biological Chemistry, 2016, 397, 4CrossRef
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Kira Irving MosherabTony Wyss-Corayac. Microglial dysfunction in brain aging and Alzheimer’s disease.

Review – Part of the Special Issue: Alzheimer’s Disease – Amyloid, Tau and Beyond. Biochemical Pharmacology 15 Apr 2014; 88(4):594–604   doi:10.1016/j.bcp.2014.01.008




A Olmos-Alonso, STT Schetters, S Sri, K Askew, …, VH Perry, D Gomez-Nicola.
Pharmacological targeting of CSF1R inhibits microglial proliferation and prevents the progression of Alzheimer’s-like pathology. Brain 8 Jan 2016.  http://dx.doi.org/10.1093/brain/awv379

The proliferation and activation of microglial cells is a hallmark of several neurodegenerative conditions. This mechanism is regulated by the activation of the colony-stimulating factor 1 receptor (CSF1R), thus providing a target that may prevent the progression of conditions such as Alzheimer’s disease. However, the study of microglial proliferation in Alzheimer’s disease and validation of the efficacy of CSF1R-inhibiting strategies have not yet been reported. In this study we found increased proliferation of microglial cells in human Alzheimer’s disease, in line with an increased upregulation of the CSF1R-dependent pro-mitogenic cascade, correlating with disease severity. Using a transgenic model of Alzheimer’s-like pathology (APPswe, PSEN1dE9; APP/PS1 mice) we define a CSF1R-dependent progressive increase in microglial proliferation, in the proximity of amyloid-β plaques. Prolonged inhibition of CSF1R in APP/PS1 mice by an orally available tyrosine kinase inhibitor (GW2580) resulted in the blockade of microglial proliferation and the shifting of the microglial inflammatory profile to an anti-inflammatory phenotype. Pharmacological targeting of CSF1R in APP/PS1 mice resulted in an improved performance in memory and behavioural tasks and a prevention of synaptic degeneration, although these changes were not correlated with a change in the number of amyloid-β plaques. Our results provide the first proof of the efficacy of CSF1R inhibition in models of Alzheimer’s disease, and validate the application of a therapeutic strategy aimed at modifying CSF1R activation as a promising approach to tackle microglial activation and the progression of Alzheimer’s disease.

The neuropathology of Alzheimer’s disease shows a robust innate immune response characterized by the presence of activated microglia, with increased or de novo expression of diverse macrophage antigens (Akiyama et al., 2000; Edison et al., 2008), and production of inflammatory cytokines (Dickson et al., 1993; Fernandez-Botran et al., 2011). Evidence indicates that non-steroidal anti-inflammatory drugs (NSAIDs) protect from the onset or progression of Alzheimer’s disease (Hoozemans et al., 2011), suggestive of the idea that inflammation is a causal component of the disease rather than simply a consequence of the neurodegeneration. In fact, inflammation (Holmes et al., 2009), together with tangle pathology (Nelson et al., 2012) or neurodegeneration-related biomarkers (Wirth et al., 2013) correlate better with cognitive decline than amyloid-b accumulation, but the underlying mechanisms of the sequence of events that contribute to the clinical symptoms are poorly understood. The contribution of inflammation to disease pathogenesis is supported by recent genome-wide association studies, highlighting immune-related genes such as CR1 (Jun et al., 2010), TREM2 (Guerreiro et al., 2013; Jonsson et al., 2013) or HLA-DRB5–HLA-DRB1 in association with Alzheimer’s disease (European Alzheimer’s Disease et al., 2013). Additionally, a growing body of evidence suggests that systemic inflammation may interact with the innate immune response in the brain to act as a ‘driver’ of disease progression and exacerbate symptoms (Holmes et al., 2009, 2011). Microglial cells are the master regulators of the neuroin- flammatory response associated with brain disease (GomezNicola and Perry, 2014a, b). Activated microglia have been demonstrated in transgenic models of Alzheimer’s disease (LaFerla and Oddo, 2005; Jucker, 2010) and have been recently shown to dominate the gene expression landscape of patients with Alzheimer’s disease (Zhang et al., 2013). Recently, microglial activation through the transcription factor PU.1 has been reported to be capital for the progression of Alzheimer’s disease, highlighting the role of microglia in the disease-initiating steps (Gjoneska et al., 2015). Results from our group, using a murine model of chronic neurodegeneration (prion disease), show large numbers of microglia with an activated phenotype (Perry et al., 2010) and a cytokine profile similar to that of Alzheimer’s disease (Cunningham et al., 2003). The expansion of the microglial population during neurodegeneration is almost exclusively dependent upon proliferation of resident cells (GomezNicola et al., 2013, 2014a; Li et al., 2013). An increased microglial proliferative activity has also been described in a mouse model of Alzheimer’s disease (Kamphuis et al., 2012) and in post-mortem samples from patients with Alzheimer’s disease (Gomez-Nicola et al., 2013, 2014b). This proliferative activity is regulated by the activation of the colony stimulating factor 1 receptor (CSF1R; GomezNicola et al., 2013). Pharmacological strategies inhibiting the kinase activity of CSF1R provide beneficial effects on the progression of chronic neurodegeneration, highlighting the detrimental contribution of microglial proliferation (Gomez-Nicola et al., 2013). The presence of a microglial proliferative response with neurodegeneration is also supported by microarray analysis correlating clinical scores of incipient Alzheimer’s disease with the expression of Cebpa and Spi1 (PU.1), key transcription factors controlling microglial lineage commitment and proliferation (Blalock et al., 2004). Consistent with these data, Csf1r is upregulated in mouse models of amyloidosis (Murphy et al., 2000), as well as in human post-mortem samples from patients with Alzheimer’s disease (Akiyama et al., 1994). Although these ideas would lead to the evaluation of the efficacy of CSF1R inhibitors in Alzheimer’s disease, we have little evidence regarding the level of microglial proliferation in Alzheimer’s disease or the effects of CSF1R targeting in animal models of Alzheimer’s disease-like pathology. In this study, we set out to define the microglial proliferative response in both human Alzheimer’s disease and a mouse model of Alzheimer’s disease-like pathology, as well as the activation of the CSF1R pathway. We provide evidence for a consistent and robust activation of a microglial proliferative response, associated with the activation of CSF1R. We provide proof-of-target engagement and efficacy of an orally available CSF1R inhibitor (GW2580), which inhibits microglial proliferation and partially prevents the pathological progression of Alzheimer’s disease-like pathology, supporting the evaluation of CSF1R-targeting approaches as a therapy for Alzheimer’s disease.

Post-mortem samples of Alzheimer’s disease For immunohistochemical analysis, human brain autopsy tissue samples (temporal cortex, paraffin-embedded, formalin- fixed, 96% formic acid-treated, 6-mm sections) from the National CJD Surveillance Unit Brain Bank (Edinburgh, UK) were obtained from cases of Alzheimer’s disease (five females and five males, age 58–76) or age-matched controls (four females and five males, age 58–79), in whom consent for use of autopsy tissues for research had been obtained. All cases ful- filled the criteria for the pathological diagnosis of Alzheimer’s disease. Ethical permission for research on autopsy materials stored in the National CJD Surveillance Unit was obtained from Lothian Region Ethics Committee

Figure 1 Characterization of the microglial proliferative response in Alzheimer’s disease. (A–C) Immunohistochemical analysis and quantification of the number of total microglial cells (Iba1+ ; A) or proliferating microglial cells (Iba1+Ki67 + ; B) in the grey (GM) and white matter (WM) of the temporal cortex of Alzheimer’s disease cases (AD) and age-matched non-demented controls (NDC). (C) Representative pictures of the localization of a marker of proliferation (Ki67, dark blue) in microglial cells (Iba1+ , brown) in the grey matter of the temporal cortex of non-demented controls or Alzheimer’s disease cases. (D) RT-PCR analysis of the mRNA expression of CSF1R, CSF1, IL34, SPI1 (PU.1), CEBPA, RUNX1 and PCNA in the temporal cortex of Alzheimer’s disease cases and age-matched non-demented controls. Expression of mRNA represented as mean SEM and indicated as relative expression to the normalization factor (geometric mean of four housekeeping genes; GAPDH, HPRT, 18S and GUSB) using the 2-CT method. Statistical differences: *P 50.05, **P 50.01, ***P 50.001. Data were analysed with a two-way ANOVA and a post hoc Tukey test (A and B) or with a two-tailed Fisher t-test (D). Scale bar in C = 50 mm.

Increased microglial proliferation and CSF1R activity are closely associated with the progression of Alzheimer’s disease-like pathology 

Pharmacological targeting of CSF1R activation with an orally-available inhibitor blocks microglial proliferation in APP/PS1 mice

CSF1R inhibition prevents the progression of Alzheimer’s disease-like pathology

The innate immune component has a clear influence over the onset and progression of Alzheimer’s disease. The analysis of therapeutic approaches aimed at controlling neuroinflammation in Alzheimer’s disease is moving forward at the preclinical and clinical level, with several clinical trials aimed at modulating inflammatory components of the disease. We have previously demonstrated that the proliferation of microglial cells is a core component of the neuroinflammatory response in a model of prion disease, another chronic neurodegenerative disease, and is controlled by the activation of CSF1R (Gomez-Nicola et al., 2013). This aligns with recent reports pinpointing the causative effect of the activation of the microglial proliferative response on the neurodegenerative events of human and mouse Alzheimer’s disease, highlighting the activity of the master regulator PU.1 (Gjoneska et al., 2015). Our results provide a proof of efficacy of CSF1R inhibition for the blockade of microglial proliferation in a model of Alzheimer’s disease-like pathology. Treatment with the orally available CSF1R kinase-inhibitor (GW2580) proves to be an effective disease-modifying approach, partially improving memory and behavioural performance, and preventing synaptic degeneration. These results support the previously reported link of the inflammatory response generated by microglia in models of Alzheimer’s disease with the observed synaptic and behavioural deficits, regardless of amyloid deposition (Jones and Lynch, 2014).

Our findings support the relevance of CSF1R signalling and microglial proliferation in chronic neurodegeneration and validate the evaluation of CSF1R inhibitors in clinical trials for Alzheimer’s disease. Our findings show that the inhibition of microglial proliferation in a model of Alzheimer’s disease-like pathology does not modify the burden of amyloid-b plaques, suggesting an uncoupling of the amyloidogenic process from the pathological progression of the disease.



Role of infectious agent in Alzheimer’s Disease?

Alzheimer’s disease, snake venome, amyloid and transthyretin

Alzheimer’s Disease – tau art thou, or amyloid

Breakthrough Prize for Alzheimer’s Disease 2016

Tau and IGF1 in Alzheimer’s Disease

Amyloid and Alzheimer’s Disease

Important Lead in Alzheimer’s Disease Model


BACE1 Inhibition role played in the underlying Pathology of Alzheimer’s Disease

Late Onset of Alzheimer’s Disease and One-carbon Metabolism



New Alzheimer’s Protein – AICD




Introduction to Nanotechnology and Alzheimer disease



Brain Biobank

Removing Alzheimer plaques

Tracking protein expression

Schizophrenia genomics

Breakup of amyloid plaques

Mindful Discoveries

Beyond tau and amyloid

Serum Folate and Homocysteine, Mood Disorders, and Aging

Long Term Memory and Prions

Retromer in neurological disorders

Neurovascular pathways to neurodegeneration

Studying Alzheimer’s biomarkers in Down syndrome

Amyloid-Targeting Immunotherapy Targeting Neuropathologies with GSK33 Inhibitor

Brain Science

Sleep quality, amyloid and cognitive decline

microglia and brain maintenance

Notable Papers in Neurosciences

New Molecules to reduce Alzheimer’s and Dementia risk in Diabetic patients

The Alzheimer Scene around the Web




  • Alzheimer’s disease
  • microglia
  • gliosis
  • neurodegeneration
  • inflammation


Read Full Post »

Removing Alzheimer plaques

Larry H. Bernstein, MD, FCAP, Curator



Transdermal implant releases antibodies to trigger immune system to clear Alzheimer’s plaques            March 21, 2016



An implant that can prevent Alzheimer’s disease. A new capsule can be implanted under the skin to release antibodies that “tag” amyloid beta, signalling the patient’s immune system to clear it before it forms Alzheimer’s plaques. (credit: École polytechnique fédérale de Lausanne



To be most effective, this treatment has to be given as early as possible, before the first signs of cognitive decline. Currently, this requires repeated vaccine injections, which can cause side effects. The new implant can deliver a steady, safe flow of antibodies.

Protection from immune-system rejection

Cell encapsulation device for long-term subcutaneous therapeutic antibody delivery. (B) Macroscopic view of the encapsulation device, composed of a transparent frame supporting polymer permeable membranes and reinforced with an outer polyester mesh. (C) Dense neovascularization develops around a device containing antibody-secreting C2C12 myoblasts, 8 months after implantation in the mouse subcutaneous tissue. (D and E) Representative photomicrographs showing encapsulated antibody-secreting C2C12 myoblasts surviving at high density within the flat sheet device 39 weeks after implantation. (E) Higher magnification: note that the cells produce a collagen-rich matrix stained in blue with Masson’s trichrome protocol. Asterisk: polypropylene porous membrane. Scale bars = 750 mm (B and C),100 mm (D), 50 mm (E). (credit: Aurelien Lathuiliere et al./BRAIN)

The lab of Patrick Aebischer at EPFL designed the “macroencapsulation device” (capsule) with two permeable membranes sealed together with a polypropylene frame, containing a hydrogel that facilitates cell growth. All the materials used are biocompatible and the device is reproducible for large-scale manufacturing.

The cells of choice are taken from muscle tissue, and the permeable membranes let them interact with the surrounding tissue to get all the nutrients and molecules they need. The cells have to be compatible with the patient to avoid triggering the immune system against them, like a transplant can. To do that, the capsule’s membranes shield the cells from being identified and attacked by the immune system. This protection also means that cells from a single donor can be used on multiple patients.

The researchers tested the device mice in a genetic line commonly used to simulate Alzheimer’s disease over a course of 39 weeks, showing dramatic reduction of amyloid beta plaque load in the brain. The treatment also reduced the phosphorylation of the protein tau, another sign of Alzheimer’s observed in these mice.

“The proof-of-concept work demonstrates clearly that encapsulated cell implants can be used successfully and safely to deliver antibodies to treat Alzheimer’s disease and other neurodegenerative disorders that feature defective proteins,” according to the researchers.

The work is published in the journal BRAIN. It involved a collaboration between EPFL’s Neurodegenerative Studies Laboratory (Brain Mind Institute), the Swiss Light Source (Paul Scherrer Institute), and F. Hoffmann-La Roche. It was funded by the Swiss Commission for Technology and Innovation and F. Hoffmann-La Roche Ltd.

Abstract of A subcutaneous cellular implant for passive immunization against amyloid-β reduces brain amyloid and tau pathologies

Passive immunization against misfolded toxic proteins is a promising approach to treat neurodegenerative disorders. For effective immunotherapy against Alzheimer’s disease, recent clinical data indicate that monoclonal antibodies directed against the amyloid-β peptide should be administered before the onset of symptoms associated with irreversible brain damage. It is therefore critical to develop technologies for continuous antibody delivery applicable to disease prevention. Here, we addressed this question using a bioactive cellular implant to deliver recombinant anti-amyloid-β antibodies in the subcutaneous tissue. An encapsulating device permeable to macromolecules supports the long-term survival of myogenic cells over more than 10 months in immunocompetent allogeneic recipients. The encapsulated cells are genetically engineered to secrete high levels of anti-amyloid-β antibodies. Peripheral implantation leads to continuous antibody delivery to reach plasma levels that exceed 50 µg/ml. In a proof-of-concept study, we show that the recombinant antibodies produced by this system penetrate the brain and bind amyloid plaques in two mouse models of the Alzheimer’s pathology. When encapsulated cells are implanted before the onset of amyloid plaque deposition in TauPS2APP mice, chronic exposure to anti-amyloid-β antibodies dramatically reduces amyloid-β40 and amyloid-β42 levels in the brain, decreases amyloid plaque burden, and most notably, prevents phospho-tau pathology in the hippocampus. These results support the use of encapsulated cell implants for passive immunotherapy against the misfolded proteins, which accumulate in Alzheimer’s disease and other neurodegenerative disorders.




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Passive immunization using monoclonal antibodies has recently emerged for the treatment of neurological diseases. In particular, monoclonal antibodies can be administered to target the misfolded proteins that progressively aggregate and propagate in the CNS and contribute to the histopathological signature of neurodegenerative diseases. Alzheimer’s disease is the most prevalent proteinopathy, characterized by the deposition of amyloid plaques and neurofibrillary tangles. According to the ‘amyloid cascade hypothesis’, which is supported by strong genetic evidence (Goate and Hardy, 2012), the primary pathogenic event in Alzheimer’s disease is the accumulation and aggregation of amyloid-β into insoluble extracellular plaques in addition to cerebral amyloid angiopathy (Hardy and Selkoe, 2002). High levels of amyloid-β may cause a cascade of deleterious events, including neurofibrillary tangle formation, neuronal dysfunction and death. Anti-amyloid-β antibodies have been developed to interfere with the amyloid-β cascade. Promising data obtained in preclinical studies have validated immunotherapy against Alzheimer’s disease, prompting a series of clinical trials (Bard et al., 2000;Bacskai et al., 2002; Oddo et al., 2004; Wilcock et al., 2004a; Bohrmann et al., 2012). Phase III trials using monoclonal antibodies directed against soluble amyloid-β (bapineuzumab and solanezumab) in patients with mild-to-moderate Alzheimer’s disease showed some effects on biomarkers that are indicative of target engagement. These trials, however, missed the primary endpoints, and it is therefore believed that anti-amyloid-β immunotherapy should be administered at the early presymptomatic stage (secondary prevention) to better potentiate therapeutic effects (Doody et al., 2014; Salloway et al., 2014). For the treatment of Alzheimer’s disease, it is likely that long-term treatment using a high dose of monoclonal antibody will be required. However, bolus administration of anti-amyloid-β antibodies may aggravate dose-dependent adverse effects such as amyloid-related imaging abnormalities (ARIA) (Sperling et al., 2012). In addition, the cost of recombinant antibody production and medical burden associated with repeated subcutaneous or intravenous bolus injections may represent significant constraints, especially in the case of preventive immunotherapy initiated years before the onset of clinical symptoms in patients predisposed to develop Alzheimer’s disease.

Therefore, alternative methods need to be developed for the continuous, long-term administration of antibodies. Here, we used an implant based on a high-capacity encapsulated cell technology (ECT) (Lathuiliere et al., 2014b). The ECT device contains myogenic cells genetically engineered for antibody production. Macromolecules can be exchanged between the implanted cells and the host tissue through a permeable polymer membrane. As the membrane shields the implanted cells from immune rejection in allogeneic conditions, it is possible to use a single donor cell source for multiple recipients. We demonstrate that anti-amyloid immunotherapy using an ECT device implanted in the subcutaneous tissue can achieve therapeutic effects inside the brain. Chronic exposure to anti-amyloid-β monoclonal antibodies produced in vivo using the ECT technology leads to a significant reduction of the amyloid brain pathology in two mouse models of Alzheimer’s disease.


Microglial phagocytosis study

The measurement of antibody-mediated amyloid-β phagocytosis was performed as proposed previously (Webster et al., 2001). In this study, we used either purified preparations of full mAb-11 IgG2a antibody, or a purified Fab antibody fragment. A suspension of 530 µM fluorescent fibrillar amyloid-β42 was prepared in 10 mM HEPES (pH 7.4) by stirring overnight at room temperature. The resulting suspension contained 30 µM fluorescein-conjugated amyloid-β42 and 500 µM unconjugated amyloid-β42 (Bachem). IgG-fibrillar amyloid-β42 immune complexes were obtained by preincubating fluorescent fibrillar amyloid-β42 at a concentration of 50 µM in phosphate-buffered saline (PBS) with various concentrations of purified mAb-11 IgG2a or Fab antibody fragment for 30 min at 37 °C. The immune complexes were washed twice by centrifugation for 5 min at 14 000g and resuspended in the initial volume to obtain a fluorescent fibrillar amyloid-β42 solution (total amyloid-β42 concentration: 530 µM). The day before the experiment, 8 × 104 C8-B4 cells were plated in 24-well plates. The medium was replaced with serum-free DMEM before the addition of the peptides. The cells were incubated for 30 min with fibrillar amyloid-β42 or IgG-fibrillar amyloid-β42 added to the culture medium. Next, the cells were washed twice with Hank’s Balanced Salt Solution (HBSS) and subsequently detached by trypsinization, which also eliminates surface-bound fibrillar amyloid-β42. The cells were fixed for 10 min in 4% paraformaldehyde and finally resuspended in PBS. The cell fluorescence was determined with a flow cytometer (Accuri C6; BD Biosciences), and the data were analysed using the FlowJo software (TreeStar Inc.). To determine the effect of the anti-amyloid-β antibodies on amyloid-β phagocytosis, the concentration of fluorescent fibrillar amyloid-β42 was set at 1.5 µM, which is in the linear region of the dose-response curve depicting fibrillar amyloid-β42 phagocytosis in C8-B4 cells (Fig. 2C). All experiments were performed in duplicate.


The implantation of genetically engineered cells within a retrievable subcutaneous device leads to the continuous production of monoclonal antibodies in vivo. This technology achieves steady therapeutic monoclonal antibody levels in the plasma, offering an effective alternative to bolus injections for passive immunization against chronic diseases. Peripheral delivery of anti-amyloid-β monoclonal antibody by ECT leads to a significant reduction of amyloid burden in two mouse models of Alzheimer’s disease. The effect of the ECT treatment is more pronounced when passive immunization is preventively administered in TauPS2APP mice, most notably decreasing the phospho-tau pathology.

With the recent development of biomarkers to monitor Alzheimer’s pathology, it is recognized that a steady increase in cerebral amyloid over the course of decades precedes the appearance of the first cognitive symptoms (reviewed in Sperling et al., 2011). The current consensus therefore suggests applying anti-amyloid-β immunotherapy during this long asymptomatic phase to avoid the downstream consequences of amyloid deposition and to leverage neuroprotective effects. Several preventive clinical trials have been recently initiated for Alzheimer’s disease. The Alzheimer’s Prevention Initiative (API) and the Dominantly Inherited Alzheimer Network (DIAN) will test antibody candidates in presymptomatic dominant mutation carriers, while the Anti-Amyloid treatment in the Asymptomatic Alzheimer’s disease (A4) trial enrols asymptomatic subjects after risk stratification. If individuals with a high risk of developing Alzheimer’s disease can be identified using current biomarker candidates, these patients are the most likely to benefit from chronic long-term anti-amyloid-β immunotherapy. However, such a treatment may pose a challenge to healthcare systems, as the production capacity of the antibody and its related cost would become a challenging issue (Skoldunger et al., 2012). Therefore, the development of alternative technologies to chronically administer anti-amyloid-β antibody is an important aspect for therapeutic interventions at preclinical disease stages.

Here, we show that the ECT technology for the peripheral delivery of anti-amyloid-β monoclonal antibodies can significantly reduce cerebral amyloid pathology in two mouse models of Alzheimer’s disease. The subcutaneous tissue is a site of implantation easily accessible and therefore well adapted to preventive treatment. It is, however, challenging to reach therapeutic efficacy, as only a small fraction of the produced anti-amyloid-β monoclonal antibodies are expected to cross the blood–brain barrier, although they can next persist in the brain for several months (Wang et al., 2011; Bohrmann et al., 2012). Our results are consistent with previous reports, which have shown that the systemic administration of anti-amyloid-β antibodies can decrease brain amyloid burden in preclinical Alzheimer’s disease models (Bard et al., 2000, 2003; DeMattos et al., 2001; Wilcock et al., 2004a, b; Buttini et al., 2005; Adolfsson et al., 2012).

Remarkably, striking differences exist among therapeutic anti-amyloid-β antibodies in their ability to clear already existing plaques. Soluble amyloid-β species can saturate the small fraction of pan-amyloid-β antibodies entering the CNS and inhibit further target engagement (Demattos et al., 2012). Therefore, antibodies recognizing soluble amyloid-β may fail to bind and clear insoluble amyloid deposits (Das et al., 2001; Racke et al., 2005; Levites et al., 2006; Bohrmann et al., 2012). Furthermore, antibody-amyloid-β complexes are drained towards blood vessels, promoting cerebral amyloid angiopathy (CAA) and subsequent microhaemorrhages. The mAb-11 antibody used in the present study is similar to gantenerumab, which is highly specific for amyloid plaques and reduces amyloid burden in patients with Alzheimer’s disease (Bohrmann et al., 2012; Demattos et al., 2012; Ostrowitzki et al., 2012). We find that the murine IgG2a mAb-11 antibody efficiently enhances the phagocytosis of amyloid-β fibrils by microglial cells. In addition, ECT administration of the mAb-11 F(ab’)2 fragment lacking the Fc region fails to recruit microglial cells, and leads only to a trend towards clearance of the amyloid plaques. Therefore, our results suggest a pivotal role for microglial cells in the clearance of amyloid plaques following mAb-11 delivery by ECT. Importantly, we do not find any evidence that this treatment may cause microhaemorrhages in the mouse models used in this study. It remains entirely possible that direct binding to amyloid plaques of a F(ab’)2 fragment lacking effector functionality can contribute to therapeutic efficacy, as suggested by previous studies using antibody fragments (Bacskai et al., 2002;Tamura et al., 2005; Wang et al., 2010; Cattepoel et al., 2011). However, compared to IgG2a, the lower plasma levels achieved with F(ab’)2 are likely to limit the efficacy of peripheral ECT-mediated immunization. The exact role of the effector domain and its interaction with immune cells expressing Fc receptors, could be determined by comparing the therapeutic effects of a control antibody carrying a mutated Fc portion, similar to a previous study which addressed this question using deglycosylated anti-amyloid-β antibodies (Wilcock et al., 2006a; Fuller et al., 2014).

Remarkably, continuous administration of mAb-11 initiated before plaque deposition had a dramatic effect on the amyloid pathology in TauPS2APP mice, underlining the efficacy of preventive anti-amyloid-β treatments. In this mouse model, where tau hyperphosphorylation is enhanced by amyloid-β (Grueninger et al., 2010), the treatment decreases the number of AT8- and phospho-S422-positive neurons in the hippocampus. Furthermore, the number of MC1-positive hippocampal neurons is significantly reduced, which also indicates an effect of anti-amyloid-β immunotherapy on the accumulation of misfolded tau. These results highlight the effect of amyloid-β clearance on other manifestations of the Alzheimer’s pathology. In line with these findings, previous studies have shown evidence for a decrease in tau hyperphosphorylation following immunization against amyloid-β, both in animal models and in patients with Alzheimer’s disease (Oddo et al., 2004; Wilcock et al., 2009;Boche et al., 2010; Serrano-Pozo et al., 2010; Salloway et al., 2014).

Similar to the subcutaneous injection of recombinant proteins (Schellekens, 2005), ECT implants can elicit significant immune responses against the secreted recombinant antibody. An anti-drug antibody response was detected in half of the mice treated with the mAb-11-releasing devices, in the absence of any anti-CD4 treatment. The glycosylation profile of the mAb-11 synthesized in C2C12 myoblasts is comparable to standard material produced by myeloma or HEK293 cells (Lathuiliere et al., 2014a). Although we cannot exclude that local release by ECT leads to antibody aggregation and denaturation, it is unlikely that this mode of administration further contributes to compound immunogenicity. Because the Fab regions of the chimeric recombinant mAb-11 IgG2a contain human CDRs, it remains to be determined whether the ECT-mediated delivery of antibodies fully matched with the host species would trigger an anti-drug antibody response.

Further developments will be needed to scale up this delivery system to humans. The possibility of using a single allogeneic cell source for all intended recipients is a crucial advantage of the ECT technology to standardize monoclonal antibody delivery. However, the development of renewable cell sources of human origin will be essential to ECT application in the clinic. Although the ARPE-19 cell line has been successfully adapted to ECT and used in clinical trials (Dunn et al., 1996; Zhang et al., 2011), the development of human myogenic cells (Negroni et al., 2009) is an attractive alternative that is worth exploring. Based on the PK analysis of recombinant mAb-11 antibody subcutaneously injected in mice (Supplementary material), we estimate that the flat sheet devices chronically release mAb-11 at a rate of 6.8 and 11.8 µg/h, to reach a plasma level of 50 µg/ml in the implanted animals. In humans, injected IgG1 has a longer half-life (21–25 days), with a volume of distribution of ∼100 ml/kg and an estimated clearance of 0.2 ml/h/kg. These values indicate that the predicted antibody exposure in humans, based on the rate of mAb-11 secretion achieved by ECT in mice, would be only 10 to 20-fold lower than the typical regimens based on monthly bolus injection of 1 mg/kg anti-amyloid-β monoclonal antibody. Hence, it is realistic to consider ECT for therapeutic monoclonal antibody delivery in humans, as the flat sheet device could be scaled up to contain higher amounts of cells. Furthermore, recent progress to engineer antibodies for increased penetration into the brain will enable lowering dosing of biotherapeutics to achieve therapeutic efficacy (Bien-Ly et al., 2014; Niewoehner et al., 2014). For some applications, intrathecal implantation could be preferred to chronically deliver monoclonal antibodies directly inside the CNS (Aebischer et al., 1996; Marroquin Belaunzaran et al., 2011).

Overall, ECT provides a novel approach for the local and systemic delivery of recombinant monoclonal antibodies in the CNS. It will expand the possible therapeutic options for immunotherapy against neurodegenerative disorders associated with the accumulation of misfolded proteins, including Alzheimer’s and Parkinson’s diseases, dementia with Lewy bodies, frontotemporal lobar dementia and amyotrophic lateral sclerosis (Gros-Louis et al., 2010; Bae et al., 2012; Rosenmann, 2013).

encapsulated cell technology
monoclonal antibody

The most powerful part of the article is the methodology of the transdermal patch of genetically engineered cells which appear to give a constant stream of antibody therapy. This would be better for the authors to have highlighted because the protein delivery system is great work. However it is a shame that the Alzheimer’s field is still relying on these mouse models which are appearing to lead the filed down a path which leads to failed clinical trials. Lilly has just dropped their Alzheimer’s program and unless the filed shifts to a different hypothesis of disease etilology I feel the whole field will be stuck where it is.



View Abstract

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Reporter and Curator: Dr. Sudipta Saha, Ph.D.


  • condoms,
  • withdrawal / pulling out,
  • outercourse, and
  • vasectomy.




















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Curator and Interviewer: Stephen J. Williams, Ph.D.



In today’s post, I had the opportunity to talk with both Dr. William Kinney, Chief Scientific Officer and Thoma Kikis, Founder/CMO of KannaLife Sciences based in the Pennsylvania Biotech Center of Bucks County.   KannaLifeSciences, although highlighted in national media reports and Headline news (HLN TV)for their work on cannabis-derived compounds, is a phyto-medical company focused on the discipline surrounding pharmacognosy, the branch of pharmacology dealing with natural drugs and their constituents.

Below is the interview with Dr. Kinney and Mr. Kikis of KannaLife Sciences and Leaders in Pharmaceutical Business Intelligence (LPBI)


PA Biotech Questions answered by Dr. William Kinney, Chief Scientific Officer of KannaLife Sciences



LPBI: Your parent company   is based in New York. Why did you choose the Bucks County Pennsylvania Biotechnology Center?


Dr. Kinney: The Bucks County Pennsylvania Biotechnology Center has several aspects that were attractive to us.  They have a rich talent pool of pharmaceutically trained medicinal chemists, an NIH trained CNS pharmacologist,  a scientific focus on liver disease, and a premier natural product collection.


LBPI: The Blumberg Institute and Natural Products Discovery Institute has acquired a massive phytochemical library. How does this resource benefit the present and future plans for KannaLife?


Dr. Kinney: KannaLife is actively mining this collection for new sources of neuroprotective agents and is in the process of characterizing the active components of a specific biologically active plant extract.  Jason Clement of the NPDI has taken a lead on these scientific studies and is on our Advisory Board. 


LPBI: Was the state of Pennsylvania and local industry groups support KannaLife’s move into the Doylestown incubator?


Dr. Kinney: The move was not State influenced by state or industry groups. 


LPBI: Has the partnership with Ben Franklin Partners and the Center provided you with investment opportunities?


Dr. Kinney: Ben Franklin Partners has not yet been consulted as a source of capital.


LPBI: The discipline of pharmacognosy, although over a century old, has relied on individual investigators and mainly academic laboratories to make initial discoveries on medicinal uses of natural products. Although there have been many great successes (taxol, many antibiotics, glycosides, etc.) many big pharmaceutical companies have abandoned this strategy considering it a slow, innefective process. Given the access you have to the chemical library there at Buck County Technology Center, the potential you had identified with cannabanoids in diseases related to oxidative stress, how can KannaLife enhance the efficiency of finding therapeutic and potential preventive uses for natural products?


Dr. Kinney: KannaLife has the opportunity to improve upon natural molecules that have shown medically uses, but have limitations related to safety and bioavailability. By applying industry standard medicinal chemistry optimization and assay methods, progress is being made in improving upon nature.  In addition KannaLife has access to one of the most commercially successful natural products scientists and collections in the industry.


LPBI: How does the clinical & regulatory experience in the Philadelphia area help a company like Kannalife?


Dr. Kinney: Within the region, KannaLife has access to professionals in all areas of drug development either by hiring displaced professionals or partnering with regional contract research organizations.


LPBI  You are focusing on an interesting mechanism of action (oxidative stress) and find your direction appealing (find compounds to reverse this, determine relevant disease states {like HCE} then screen these compounds in those disease models {in hippocampal slices}).  As oxidative stress is related to many diseases are you trying to develop your natural products as preventative strategies, even though those type of clinical trials usually require massive numbers of trial participants or are you looking to partner with a larger company to do this?


Dr. Kinney: Our strategy is to initially pursue Hepatic Encephalophy (HE) as the lead orphan disease indication and then partner with other organizations to broaden into other areas that would benefit from a neuroprotective agent.  It is expected the HE will be responsive to an acute treatment regimen.   We are pursuing both natural products and new chemical entities for this development path.



General Questions answered by Thoma Kikis, Founder/CMO of KannaLife Sciences


LPBI: How did KannaLife get the patent from the National Institutes of Health?


My name is Thoma Kikis I’m the co-founder of KannaLife Sciences. In 2010, my partner Dean Petkanas and I founded KannaLife and we set course applying for the exclusive license of the ‘507 patent held by the US Government Health and Human Services and National Institutes of Health (NIH). We spent close to 2 years working on acquiring an exclusive license from NIH to commercially develop Patent 6,630,507 “Cannabinoids as Antioxidants and Neuroprotectants.” In 2012, we were granted exclusivity from NIH to develop a treatment for a disease called Hepatic Encephalopathy (HE), a brain liver disease that stems from cirrhosis.


Cannabinoids are the chemicals that compose the Cannabis plant. There are over 85 known isolated Cannabinoids in Cannabis. The cannabis plant is a repository for chemicals, there are over 400 chemicals in the entire plant. We are currently working on non-psychoactive cannabinoids, cannabidiol being at the forefront.


As we started our work on HE and saw promising results in the area of neuroprotection we sought out another license from the NIH on the same patent to treat CTE (Chronic Traumatic Encephalopathy), in August of 2014 we were granted the additional license. CTE is a concussion related traumatic brain disease with long term effects mostly suffered by contact sports players including football, hockey, soccer, lacrosse, boxing and active military soldiers.


To date we are the only license holders of the US Government held patent on cannabinoids.



LPBI: How long has this project been going on?


We have been working on the overall project since 2010. We first started work on early research for CTE in early-2013.



LPBI: Tell me about the project. What are the goals?


Our focus has always been on treating diseases that effect the Brain. Currently we are looking for solutions in therapeutic agents designed to reduce oxidative stress, and act as immuno-modulators and neuroprotectants.


KannaLife has an overall commitment to discover and understand new phytochemicals. This diversification of scientific and commercial interests strongly indicates a balanced and thoughtful approach to our goals of providing standardized, safer and more effective medicines in a socially responsible way.


Currently our research has focused on the non-psychoactive cannabidiol (CBD). Exploring the appropriate uses and limitations and improving its safety and Metered Dosing. CBD has a limited therapeutic window and poor bioavailability upon oral dosing, making delivery of a consistent therapeutic dose challenging. We are also developing new CBD-like molecules to overcome these limitations and evaluating new phytochemicals from non-regulated plants.


KannaLife’s research is led by experienced pharmaceutically trained professionals; Our Scientific team out of the Pennsylvania Biotechnology Center is led by Dr. William Kinney and Dr. Douglas Brenneman both with decades of experience in pharmaceutical R&D.



LPBI: How do cannabinoids help neurological damage? -What sort of neurological damage do they help?


Cannabinoids and specifically cannabidiol work to relieve oxidative stress, and act as immuno-modulators and neuroprotectants.


So far our pre-clinical results show that cannabidiol is a good candidate as a neuroprotectant as the patent attests to. Our current studies have been to protect neuronal cells from toxicity. For HE we have been looking specifically at ammonia and ethanol toxicity.



– How did it go from treating general neurological damage to treating CTE? Is there any proof yet that cannabinoids can help prevent CTE? What proof?


We started examining toxicity first with ammonia and ethanol in HE and then posed the question; If CBD is a neuroprotectant against toxicity then we need to examine what it can do for other toxins. We looked at CTE and the toxin that causes it, tau. We just acquired the license in August from the NIH for CTE and are beginning our pre-clinical work in the area of CTE now with Dr. Ron Tuma and Dr. Sara Jane Ward at Temple University in Philadelphia.



LPBI: How long until a treatment could be ready? What’s the timeline?


We will have research findings in the coming year. We plan on filing an IND (Investigational New Drug application) with the FDA for CBD and our molecules in 2015 for HE and file for CTE once our studies are done.



LPBI: What other groups are you working with regarding CTE?


We are getting good support from former NFL players who want solutions to the problem of concussions and CTE. This is a very frightening topic for many players, especially with the controversy and lawsuits surrounding it. I have personally spoken to several former NFL players, some who have CTE and many are frightened at what the future holds.


We enrolled a former player, Marvin Washington. Marvin was an 11 year NFL vet with NY Jets, SF 49ers and won a SuperBowl on the 1998 Denver Broncos. He has been leading the charge on KannaLife’s behalf to raise awareness to the potential solution for CTE.


We tried approaching the NFL in 2013 but they didn’t want to meet. I can understand that they don’t want to take a position. But ultimately, they’re going to have to make a decision and look into different research to treat concussions. They have already given the NIH $30 Million for research into football related injuries and we hold a license with the NIH, so we wanted to have a discussion. But currently cannabinoids are part of their substance abuse policy connected to marijuana. Our message to the NFL is that they need to lead the science, not follow it.


Can you imagine the NFL’s stance on marijuana treating concussions and CTE? These are topics they don’t want to touch but will have to at some point.


LPBI: Thank you both Dr. Kinney and Mr. Kikis.


Please look for future posts in this series on the Philly Biotech Scene on this site

Also, if you would like your Philadelphia biotech startup to be highlighted in this series please contact me or

http://pharmaceuticalintelligence.com at:

sjwilliamspa@comcast.net or @StephenJWillia2  or @pharma_BI.

Our site is read by ~ thousand international readers DAILY and thousands of Twitter followers including venture capital.


Other posts on this site in this VIBRANT PHILLY BIOTECH SCENE SERIES OR referring to PHILADELPHIA BIOTECH include:


RAbD Biotech Presents at 1st Pitch Life Sciences-Philadelphia




LytPhage Presents at 1st Pitch Life Sciences-Philadelphia

Hastke Inc. Presents at 1st Pitch Life Sciences-Philadelphia


Pfizer Cambridge Collaborative Innovation Events: ‘The Role of Innovation Districts in Metropolitan Areas to Drive the Global an | Basecamp Business

Mapping the Universe of Pharmaceutical Business Intelligence: The Model developed by LPBI and the Model of Best Practices LLC



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(includes interviews with CyberDoctor’s CEO Akhila Satish and various oncologists)


Writer/Curator: Stephen J. Williams, Ph.D.

UPDATE 5/15/2019












  • 17-27% for hematologic malignancies
  • 53-98% for breast cancer
  • 97% for ovarian cancer



Tackling The Oral Chemotherapy-Patient Adherence Problem


Documented factors leading to non-adherence to oral oncology medications include

  1. Patient feels better so stop taking the drug
  2. Patient feels worse so stops taking the drug
  3. Confusing and complicated dosing regimen
  4. Inability to afford medications
  5. Poor provider-patient relationships
  6. Adverse effects of medication
  8. Inadequate education/instruction of discharge




  • Inaccuracy of self-reporting
  • Lack of applicability of external measurements such as pill counts


  • Therapy support (dosing reminders)
  • Education
  • Side effect management


may be a cost-efficient methodology to improve medical adherence.










From the Roswell Park Cancer Institute blog post Making Mobile Health Work








The McKesson Foundation’s Mobilizing for Health initiative



CancerNet announces mobile application (from cancer.net)














Akhila Satish Picture



Ms. Akhila Satish, CEO CyberDoctor













Results from the study



As mentioned in the article:












LBPI: Thank you Akhila!





Mobile Health Applications on Rise in Developing World: Worldwide Opportunity





  • strengths
  • weaknesses
  • opportunities
  • threats


  • accessibility
  • acceptance and low-cost
  • adaptation to local culture
  • government involvement

while threats to such projects could include

  • lack of funding
  • unreliable infrastructure
  • unclear healthcare system responsibilities



Dr. Louis Bretes, an oncologist from Portugal, when asked



Informatics era but..
The main question is that chronic patients are special ones.
Cancer patients have to deal with prognosis, even in therapies
with curative intent such as aromatase inhibitors are potent

“The main app is his/her doctor”


UPDATE 5/15/2019





























There were 5 steps in the development process 






How Social Media, Mobile Are Playing a Bigger Part in Healthcare





Post Acute Care – Driver of Variation in Healthcare Costs

Kaiser data network aims to improve cancer, heart disease outcomes


Additional references




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Author and Curator: Larry H Bernstein, MD, FCAP


Curator: Aviva Lev-Ari, PhD, RN






Summary Table for TM - Part 1

Summary Table for TM – Part 1




There are some developments that deserve additional development:




Electron Transport and Bioenergetics

Deferred for metabolomics topic

Synthetic Biology

Introduction to Synthetic Biology and Metabolic Engineering


http://www.ibiology.org Lecturers generously donate their time to prepare these lectures. The project is funded by NSF and NIGMS, and is supported by the ASCB and HHMI.










II. Regulatory Effects of Mammalian microRNAs


Current Basic and Pathological Approaches to
Additional information is available at the end of the chapter
1. Introduction

Schematic representation of Calcium Cycling in Contractile and Proliferating VSMCs

Schematic representation of Calcium Cycling in Contractile and Proliferating VSMCs



Contraction of VSMCs occurs during oscillatory Ca transient.


Time for New DNA Synthesis and Sequencing Cost Curves

By Rob Carlson














28 Nov 2013 | PR Web




Life at the Speed of Light


NHMU Lecture featuring – J. Craig Venter, Ph.D.













Where Will the Century of Biology Lead Us?

By Randall Mayes



Biology + Engineering = Synthetic Biology











Synthesizing Synthetic Biology: PLOS Collections




Silencing Cancers with Synthetic siRNAs


Genomics Now—and Beyond the Bubble


BY MICHAEL BROOKS    17 APR, 2014     http://www.newstatesman.com/









Stepping into DIYbio and Synthetic Biology at ScienceHack









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Writer & reporter: Dror Nir, PhD




I hope for your agreement on the matter.

Quantitative Imaging in Cancer Evolution and Ecology





© RSNA, 2013





















Quantitative Imaging and Radiomics






Figure 3: Chart shows the five processes in radiomics.








Spatially Explicit Analysis of Tumor Heterogeneity















Emerging Strategies for Tumor Habitat Characterization

















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    4. et al


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    1. Yachida S,
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Recent comprehensive review on the role of ultrasound in breast cancer management

Writer, reporter and curator: Dror Nir, PhD

Breast Cancer Imaging

Word Cloud Created by Noam Steiner Tomer 8/10/2020

The paper below by R Hooley is a beautifully written review on how ultrasound could (and should) be practiced to better support breast cancer screening, staging, and treatment. The authors went as well into the effort of describing the benefits from combining ultrasonography with the other frequently used imaging modalities; i.e. mammography, tomosynthesis and MRI. Post treatment use of ultrasound is not discussed although this is a major task for this modality.

I would like to recommend giving attention to two very small (but for me very important) paragraphs: “Speed of Sound Imaging” and “Lesion Annotation”


Breast Ultrasonography: State of the Art

Regina J. Hooley, MDLeslie M. Scoutt, MD and Liane E. Philpotts, MD

Department of Diagnostic Radiology, Yale University School of Medicine, 333 Cedar St, PO Box 208042, New Haven, CT 06520-8042.

Address correspondence to R.J.H. (e-mail: regina.hooley@yale.edu).

Ultrasonography (US) has become an indispensable tool in breast imaging. Breast US was first introduced in the 1950s by using radar techniques adapted from the U.S. Navy (1). Over the next several decades, US in breast imaging was primarily used to distinguish cystic from solid masses. This was clinically important, as a simple breast cyst is a benign finding that does not require further work-up. However, most solid breast lesions remained indeterminate and required biopsy, as US was not adequately specific in differentiating benign from malignant solid breast masses. However, recent advances in US technology have allowed improved characterization of solid masses.

In 1995, Stavros et al (2) published a landmark study demonstrating that solid breast lesions could be confidently characterized as benign or malignant by using high-resolution grays-cale US imaging. Benign US features include few (two or three) gentle lobulations, ellipsoid shape, and a thin capsule, as well as a homogeneously echogenic echotexture. Malignant US features include spiculation, taller-than-wide orientation, angular margins, microcalcifications, and posterior acoustic shadowing. With these sonographic features, a negative predictive value of 99.5% and a sensitivity of 98.4% for the diagnosis of malignancy were achieved. These results have subsequently been validated by others (3,4) and remain the cornerstone of US characterization of breast lesions today. These features are essential in the comprehensive US assessment of breast lesions, described by the Breast Imaging and Reporting Data System (BI-RADS) (5).

US is both an adjunct and a complement to mammography. Advances in US technology include harmonic imaging, compound imaging, power Doppler, faster frame rates, higher resolution transducers, and, more recently, elastography and three-dimensional (3D) US. Currently accepted clinical indications include evaluation of palpable abnormalities and characterization of masses detected at mammography and magnetic resonance (MR) imaging. US may also be used as an adjuvant breast cancer screening modality in women with dense breast tissue and a negative mammogram. These applications of breast US have broadened the spectrum of sonographic features currently assessed, even allowing detection of noninvasive disease, a huge advance beyond the early simplistic cyst-versus-solid assessment. In addition, US is currently the primary imaging modality recommended to guide interventional breast procedures.

The most subtle US features of breast cancers are likely to be best detected by physicians who routinely synthesize findings from multiple imaging modalities and clinical information, as well as perform targeted US to correlate with lesions detected at mammography or MR imaging. Having a strong understanding of the technical applications of US and image optimization, in addition to strong interpretive and interventional US skills, is essential for today’s breast imager.


Optimal Imaging Technique

US is operator dependent, and meticulous attention to scanning technique as well as knowledge of the various technical options available are imperative for an optimized and accurate breast US examination. US is an interactive, dynamic modality. Although breast US scanning may be performed by a sonographer or mammography technologist, the radiologist also benefits greatly from hands-on scanning (Fig 1). Berg et al (6) demonstrated that US interpretive performance was improved if the radiologist had direct experience performing breast US scanning, including rescanning after the technologist. Real-time scanning also provides the opportunity for thorough evaluation of lesions and permits detailed lesion analysis compared with analyzing static images on a workstation. Subtle irregular or indistinct margins, artifacts, and architectural distortions may be difficult to capture on static images. Real-time scanning also allows the operator to assess lesion mobility, location, and relationship to adjacent structures and allows direct assessment of palpable lesions and other clinical findings. Moreover, careful review of any prior imaging studies is imperative to ensure accurate lesion correlation.



The US examination is generally well tolerated by the patient. Gentle but firm transducer pressure and optimal patient positioning are essential, with the patient’s arm relaxed and flexed behind the head. Medial lesions should generally be scanned in the supine position, and lateral lesions, including the axilla, should usually be scanned with the patient in the contralateral oblique position. This allows for elimination of potential artifact secondary to inadequate compression of breast tissue.


Gray-Scale Imaging

Typical US transducers used in breast imaging today have between 192 and 256 elements along the long axis. When scanning the breast, a linear 12–5-MHz transducer is commonly used. However, in small-breasted women (with breast thickness < 3 cm) or when performing targeted US to evaluate a superficial lesion, a linear 17–5-MHz transducer may be used. Such high-frequency transducers provide superb spatial and soft-tissue resolution, permitting substantially improved differentiation of subtle shades of gray, margin resolution, and lesion conspicuity in the background of normal breast tissue (Fig 2). However, the cost of such a high insonating frequency is decreased penetration due to attenuation of the ultrasound beam, making visualization of deep posterior tissue difficult (ie, greater than 3 cm in depth by using a linear 17–5-MHz transducer or greater than 5 cm in depth by using a linear 12–5-MHz transducer).



During the initial US survey of the region of interest in the breast, the depth should be set so that the pectoralis muscle is visualized along the posterior margin of the field of view. Initial gain settings should be adjusted so that fat at all levels is displayed as a midlevel gray. Simple cysts are anechoic. Compared with breast fat, most solid masses are hypoechoic, while the skin, Cooper ligaments, and fibrous tissue are echogenic. Time gain compensation, which adjusts image brightness at different depths from the skin to compensate for attenuation of the ultrasound beam as it penetrates into the breast tissue, may be set manually or, with appropriate equipment, may be adjusted automatically during real-time scanning or even during postprocessing of the image.

When searching for a lesion initially identified at mammography or MR imaging, careful correlation with lesion depth and surrounding anatomic structures is imperative. Lesion location may be affected by the patient’s position, which differs during mammography, US, and MR imaging examinations. Attention to surrounding background tissue may assist in accurate lesion correlation across multiple modalities. If a mass identified at mammography or MR imaging is surrounded entirely by fat or fibroglandular tissue, at US it should also be surrounded by hypoechoic fat or echogenic fibroglandular tissue, respectively. Similarly, careful attention to the region of clinical concern is necessary when scanning a palpable abnormality to ensure that the correct area is scanned. The examiner should place a finger on the palpable abnormality and then place the transducer directly over the region. Occasionally, the US examination may be performed in the sitting position if a breast mass can only be palpated when the patient is upright.

After a lesion is identified, or while searching for a subtle finding, the depth or field of view may be adjusted as needed. The depth should be decreased to better visualize more superficial structures or increased to better visualize deeper posterior lesions. The use of multiple focal zones also improves resolution at multiple depths simultaneously and should be used, if available. Although this reduces the frame rate, the reduction is typically negligible when scanning relatively superficial structures within the breast. If a single focal zone is selected to better evaluate a single lesion, the focal zone should be centered at the same level as the area of interest or minimally posterior to the area of interest, for optimal visualization.


Spatial Compounding, Speckle Reduction, and Harmonic Imaging

Spatial compound imaging and speckle reduction are available on most high-end US units and should be routinely utilized throughout the breast US examination. Unlike standard US imaging, in which ultrasound pulses are transmitted in a single direction perpendicular to the long axis of the transducer, spatial compounding utilizes electronic beam steering to acquire multiple images obtained from different angles within the plane of imaging (79). A single composite image is then obtained in real-time by averaging frames obtained by ultrasound beams acquired from these multiple angles (10). Artifactual echoes, including speckle and other spurious noise, as well as posterior acoustic patterns, including posterior enhancement (characteristic of simple cysts) and posterior acoustic shadowing (characteristic of some solid masses), are substantially reduced. However, returning echoes from real structures are enhanced, providing improved contrast resolution (9) so that ligaments, edge definition, and lesion margins, including spiculations, echogenic halos, posterior and lateral borders, as well as microcalcifications, are better defined. Speckle reduction is a real-time postprocessing technique that also enhances contrast resolution, improves border definition, is complementary to spatial compounding, and can be used simultaneously.

When a lesion is identified, harmonic imaging may also be applied—usually along with spatial compounding—to better characterize a cyst or a subtle solid mass. The simultaneous use of spatial compounding and harmonic imaging may decrease the frame rate, although this usually does not impair real-time evaluation. Harmonic imaging relies on filtering the multiple higher harmonic frequencies, which are multiples of the fundamental frequencies. All tissue is essentially nonlinear to sound propagation and the ultrasound pulse is distorted as it travels through breast tissue, creating harmonic frequencies (9). The returning ultrasound signal therefore contains both the original fundamental frequency and its multiples, or harmonics. Harmonic imaging allows the higher harmonic frequencies to be selected and used to create the gray-scale images (89). Lower-frequency superficial reverberation echoes are thereby reduced, allowing improved characterization of simple cysts (particularly if small) through the elimination of artifactual internal echoes often seen in fluid. Harmonic imaging also improves lateral resolution (10) and may also improve contrast between fatty tissue and subtle lesions, allowing better definition of subtle lesion margins and posterior shadowing (Fig 3).





Speed of Sound Imaging

Conventional US systems set the speed of sound in tissue at a uniform 1540 m/sec (10). However, the speed of sound in tissues of different composition is variable and this variability may compromise US image quality. Breast tissue usually contains fat, and the speed of sound in fat, of approximately 1430–1470 m/sec, is slower than the assumed standard (11). Accurate speed of sound imaging, in which the US transducer may be optimized for the presence of fat within breast tissue, has been shown to improve lateral resolution (12). Additionally, it can be used to better characterize tissue interfaces, lesion margins, and microcalcifications (13) and may also be useful to identify subtle hypoechoic lesions surrounded by fatty breast tissue. Speed of sound imaging is available on most high-end modern US units and is an optional adjustment, depending on whether predominately fatty, predominately dense, or mixed breast tissue is being scanned.


 Lesion Annotation

When a mass is identified and the US settings are optimized, the mass should be scanned with US “sweeps” through the entire lesion in multiple planes. Images of the lesion in the radial and antiradial views should be captured and annotated with “right” or “left,” clock face position, and centimeters from the nipple. Radial and anti-radial scanning planes are preferred over standard transverse and sagittal scanning planes because scanning the breast along the normal axis of the mammary ducts and lobar tissues allows improved understanding of the site of lesion origin and better visualization of ductal extension and helps narrow the differential diagnosis (14). Images should be captured with and without calipers to allow margin assessment on static images. Lesion size should be measured in three dimensions, reporting the longest horizontal diameter first, followed by the anteroposterior diameter, then the orthogonal horizontal.


 Extended-Field-of-View Imaging

Advanced US technology permits extended-field-of-view imaging beyond the footprint of the transducer. By using a freehand technique, the operator slides the transducer along the desired region to be imaged. The resultant images are stored in real-time and, by applying pattern recognition, a single large-field-of-view image is obtained (7). This can be helpful in measuring very large lesions as well as the distance between multiple structures in the breast and for assessing the relationship of multifocal disease (located in the same quadrant as the index cancer or within 4–5 cm of the index cancer, along the same duct system) and/or multicentric disease (located in a different quadrant than the index cancer, or at a distance greater than 4–5 cm, along a different duct system).


 Doppler US

Early studies investigating the use of color, power, and quantitative spectral Doppler US in the breast reported that the presence of increased vascularity, as well as changes in the pulsatility and resistive indexes, showed that these Doppler findings could be used to reliably characterize malignant lesions (15,16). However, other investigators have demonstrated substantial overlap of many of these Doppler characteristics in both benign and malignant breast lesions (17). Gokalp et al (18) also demonstrated that the addition of power Doppler US and spectral analysis to BI-RADS US features of solid breast masses did not improve specificity. While the current BI-RADS US lexicon recommends evaluation of lesion vascularity, it is not considered mandatory (5).

Power Doppler is generally more sensitive than color Doppler to low-flow volumes typical of breast lesions. Light transducer pressure is necessary to prevent occlusion of slow flow owing to compression of the vessel lumen. Currently both power and color Doppler are complementary tools to gray-scale imaging, and power Doppler may improve sensitivity in detecting malignant breast lesions (18,19). Demonstration of irregular branching central or penetrating vascularity within a solid mass raises suspicion of malignant neovascularity (20). Recently, the parallel artery and vein sign has been described as a reliable feature that has the potential to enable prediction of benignity in solid masses so that biopsy may be avoided. In a single study, a paired artery and vein was present in 13.2% of over 1000 masses at US-guided CNB and although an infrequent finding, the specificity for benignity was 99.3% and the false-negative rate was only 1.4%, with two malignancies among 142 masses in which the parallel artery and vein sign was identified (21).

Color and power Doppler US are also useful to evaluate cysts and complex cystic masses that contain a solid component. High-grade invasive cancer and metastatic lymph nodes may occasionally appear anechoic. Demonstration of flow within an otherwise simple appearing cyst, a complicated cyst, or a complex mass confirms the presence of a suspicious solid component, which requires biopsy. In addition, twinkle artifact seen with color Doppler US is useful to identify a biopsy marker clip or subtle echogenic microcalcifications (Fig 4). This Doppler color artifact occurs secondary to the presence of a strong reflecting granular surface and results in a rapidly changing mix of color adjacent to and behind the reflector (22). Care must be taken to avoid mistaking twinkle artifact for true vascular flow and, if in doubt, a spectral Doppler tracing can be obtained, as a normal vascular waveform will not be seen with a twinkle artifact.







At physical examination, it has long been recognized that malignant tumors tend to feel hard when compared with benign lesions. US elastography can be used to measure tissue stiffness with the potential to improve specificity in the diagnosis of breast masses. There are two forms of US elastography available today: strain and shear wave. With either technique, acoustic information regarding lesion stiffness is converted into a black-and-white or color-scaled image that can also be superimposed on top of a B-mode gray-scale image.

Strain elastography requires gentle compression with a US probe or natural motion (such as heart beat, vascular pulsation, or respiration) and results in tissue displacement, or strain. Strain (ie, tissue compression and motion) is decreased in hard tissues compared with soft tissue (23). The information obtained with strain elastography provides qualitative information, although strain ratios may be calculated by comparing the strain of a lesion to the surrounding normal tissue. Benign breast lesions generally have lower ratios in comparison to malignant lesions (24,25).

Shear-wave elastography is based on the principle of acoustic radiation force. With use of light transducer pressure, transient automatic pulses can be generated by the US probe, inducing transversely oriented shear waves in tissue. The US system captures the velocity of these shear waves, which travel faster in hard tissue compared with soft tissue (26). Shear-wave elastography provides quantitative information because the elasticity of the tissue can be measured in meters per second or in kilopascals, a unit of pressure.

Elastography features such as strain ratios, size ratios, shape, homogeneity, and maximum lesion stiffness may complement conventional US in the analysis of breast lesions. Malignant masses evaluated with elastography tend to be more irregular, heterogeneous, and typically appear larger at elastography than at grayscale imaging (Fig 5) (27,28). Although malignant lesions generally also exhibit maximum stiffness greater than 80–100 kPa (28,29), caution is necessary when applying these numerical values to lesion analysis. Berg et al (28) reported three cancers among 115 masses with maximum stiffness between 20 and 30 kPa, for a 2.6% malignancy rate; 25 cancers among 281 masses with maximum stiffness between 30 and 80 kPa, for an 8.9% malignancy rate; and 61 cancers among 153 masses with maximum stiffness between 80 and 160 kPa, for a 39.9% malignancy rate (28). Invasive cancers with high histologic grade, large tumor size, nodal involvement, and vascular invasion have also been shown to be significantly correlated with high mean stiffness at shear-wave elastography (30).



Elastography may be useful in improving the specificity of US evaluation of BI-RADS 3 and 4A lesions, including complicated cysts. Berg and colleagues (28) showed that by using qualitative shear-wave elastography and color assessment of lesion stiffness, oval shape, and a maximum elasticity value of less than 80 kPa, unnecessary biopsy of low-suspicion BI-RADS 4A masses could be reduced without a significant loss in sensitivity. Several investigators have proposed a variety of imaging classifications using strain elastography, mostly based on the color pattern (27,31,32). A “bull’s eye” artifact has also been described as a characteristic feature present in benign breast cysts, which may appear as a round or oval lesion with a stiff rim associated with two soft spots, one located centrally and the other posteriorly (33).

Despite these initial promising studies regarding the role of US elastography in the analysis of breast lesions, limitations do exist. Strain and shear-wave elastography are quite different methods of measuring breast tissue stiffness, and the application of these methods varies across different commercial manufacturers. Inter- and intraobserver variability may be relatively high because the elastogram may be affected by differences in degree and method of compression. With strain elastography, a quality indicator that is an associated color bar or numerical value may be helpful to ensure proper light compression. Shear-wave elastography has been shown to be less operator-dependent, as tissue compression is initiated by the US probe in a standard, reproducible fashion (34) and only light transducer pressure is necessary. In addition, there is currently no universal color-coding standard and, depending on the manufacturer and/or operator preference, stiff lesions may be arbitrarily coded to appear red while soft lesions appear blue, or vice versa. Some elastography features such as the “bull’s eye” artifact are only seen on specific US systems. Lesions deeper than 2 cm are less accurately characterized by means of elastography. Moreover, one must be aware that soft cancers and hard benign lesions exist. Therefore, careful correlation of elastography with B-mode US features and mammography is essential. Future studies and further technical advances, including the creation of more uniformity across different US manufacturers, will ultimately determine the usefulness of elastography in clinical practice.

Three-dimensional US

Both handheld and automated high-resolution linear 3D transducers are now available for use in breast imaging. With a single pass of the ultrasound beam, a 3D reconstructed image can be formed in the coronal, sagittal, and transverse planes, potentially allowing more accurate assessment of anatomic structures and tumor margins (Fig 6). Few studies regarding the performance of 3D US in the breast exist, but a preliminary study demonstrated improved characterization of malignant lesions (35). Automated supine whole-breast US using 3D technology is now widely available for use in the screening setting (see section on screening breast US). Three-dimensional US may also be used in addition to computed tomography for image-guided radiation therapy (36) and has a potential role in assessing tumor response to neoadjuvant chemotherapy.




US Features of Benign and Malignant Breast Lesions


Although for many years the main function of breast US was to differentiate cysts from solid masses, this differentiation can at times be problematic, particularly if the lesion is small or located deep in the breast. Simple cysts are defined as circumscribed, anechoic masses with a thin imperceptible wall and enhanced through transmission (provided spatial compounding is not used). By convention, simple cysts may also contain up to a single thin septation. Simple cysts are confidently characterized with virtually 100% accuracy at US (14,37), provided that they are not very small (< 5 mm in size) or not located in deep tissue. Complicated cysts are hypoechoic with no discernable Doppler flow, contain internal echoes, and may also exhibit indistinct margins, and/or lack posterior acoustic enhancement. Clustered microcysts consist of a cluster of tiny (<2–3 mm in size) anechoic foci with thin (< 0.5 mm in thickness) intervening septations.

Complicated cysts are very common sonographic findings and the majority are benign. In multiple studies, which evaluated over 1400 complicated cysts and microcysts, the malignancy rate ranged from 0% to 0.8% (3844). Most complicated cysts and clustered microcysts with a palpable or mammographic correlate are classified as BI-RADS 3 and require short-interval imaging follow-up or, occasionally, US-guided aspiration. However, in the screening US setting, if multiple and bilateral complicated and simple cysts are present (ie, at least three cysts with at least one cyst in each breast), these complicated cysts can be assessed as benign, BI-RADS 2, requiring no additional follow-up (38).

Complicated cysts should never demonstrate internal vascularity at color Doppler interrogation. The presence of a solid component, mural nodule, thickened septation, or thickened wall within a cystic mass precludes the diagnosis of a benign complicated cyst. These complex masses require biopsy, as some cancers may have cystic components. The application of compound imaging and harmonics, color Doppler, and potentially elastography may help differentiate benign complicated cysts from malignant cystic-appearing masses and reduce the need for additional follow-up or biopsy.

Solid Masses

Sonographic features of benign-appearing solid masses include an oval or ellipsoid shape, “wider-than-tall” orientation parallel to the skin, circumscribed margins, gentle and smooth (less than three) lobulations, as well as absence of any malignant features (2,45) (Fig 2b). Lesions with these features are commonly fibroadenomas or other benign masses and can often be safely followed, even if the mass is palpable (4648). Malignant features of solid masses include spiculations, angular margins, marked hypoechogenicity, posterior acoustic shadowing, microcalcifications, ductal extension, branching pattern, and 1–2-mm microlobulations (2,45) (Figs 1b,56). These are also often taller-than-wide lesions with a nonparallel orientation to the skin and may occasionally be associated with thickened Cooper ligaments and/or or skin thickening. Most cancers have more than one malignant feature, spiculation being the most specific and angular margins the most common (2).

There is, however, considerable overlap between these benign and malignant US features and careful scanning technique, as well as direct correlation with mammography, is essential. For example, some high-grade invasive ductal carcinomas with central necrosis, as well as the well-differentiated mucinous and medullary subtypes, may present as circumscribed, oval, hypoechoic masses that may look like complicated cysts with low-level internal echoes at US. Benign focal fibrous breast tissue or postoperative scars can appear as irregular shadowing masses on US images. Furthermore, while echogenic lesions are often benign and frequently represent lipomas or fibrous tissue, echogenic cancers do rarely occur (Figs 78) (49,50). The presence of a single malignant feature, despite the presence of multiple benign features, precludes a benign classification and mandates biopsy, with the exception of fat necrosis and postoperative scars exhibiting typical benign mammographic features. Likewise, a mass with a benign US appearance should be biopsied if it exhibits any suspicious mammographic features.




 Ductal Carcinoma in Situ

Ductal carcinoma in situ (DCIS) is characteristically associated with microcalcifications detected at mammography, but may also be detected at US since they are often associated with a subtle hypoechoic mass, which may indicate an invasive mammographically occult component. US features associated with DCIS most commonly include a hypoechoic mass with an irregular shape, microlobulated margins, no posterior acoustic features, and no internal vascularity. Ductal abnormalities, intracystic lesions, and architectural distortions may also be present (5153). Noncalcified DCIS manifesting as a solid mass at US is more frequently found in non–high-grade than high-grade DCIS, which is more often associated with microcalcifications and ductal changes (54). US can depict microcalcifications, particularly those in clusters greater than 10 mm in size and located in a hypoechoic mass or a ductlike structure (Fig 9) (55). Malignant calcifications are more likely to be detected sonographically than are benign calcifications, which may be obscured by surrounding echogenic breast tissue (55,56). Although US is inferior to mammography in the detection of suspicious microcalcifications, the main benefit of US detection of DCIS is to identify the invasive component and guide biopsy procedures.





Breast US in Clinical Practice

Current indications for breast US as recommended by the American College of Radiology Practice Guidelines include the evaluation of palpable abnormalities or other breast symptoms, assessment of mammographic or MR imaging–detected abnormalities, and evaluation of breast implants (57). Additionally, US is routinely used for guidance during interventional procedures, treatment planning for radiation therapy, screening in certain groups of women, and evaluation of axillary lymph nodes. Much literature has been written on these uses and a comprehensive discussion is beyond the scope of this article. A few important and timely topics, however, will be reviewed.




The BI-RADS US lexicon was introduced in 2003, and subsequently, there have been several studies assessing the accuracy of BI-RADS US classification of breast lesions. Low to moderate interobserver agreement has been found in the description of margins (especially noncircumscribed margins), echogenicity, and posterior acoustic features. Abdullah et al (58) reported low interobserver agreement especially for small masses and for malignant masses. Given the importance of margin analysis in the characterization of benign and malignant lesions, this variability is potentially problematic. Studies have also shown variable results in the use of the final assessment categories. In clinical settings, Raza et al (46) showed inconsistent use of the BI-RADS 3 (probably benign) category in 14.0% of cases when biopsy was recommended. Abdullah et al also demonstrated fair and poor interobserver agreement for BI-RADS 4 (suspicious for malignancy) a, b, and c subcategories (58). However, Henig et al (59) reported more promising results, with malignancy rates in categories 3, 4, and 5 to be similar to those seen with mammographic categorization (1.2%, 17%, and 94%, respectively).


 Evaluation of Mammographic Findings

Targeted US is complementary to diagnostic mammography because of its ability to differentiate cystic and solid lesions.US is also useful in the work up of subtle asymmetries, as it can help identify or exclude the presence of an underlying mass. True hypoechoic lesions can often be differentiated from prominent fat lobules by scanning in multiple planes, because true lesions usually do not blend or elongate into adjacent tissue. With the introduction of digital breast tomosynthesis for mammographic imaging, US will play yet another important role. As mammographic lesions can often be detected, localized, and have adequate margin assessment on 3D images, patients with lesions detected on digital breast tomosynthesis images at screening may often be referred directly to US, avoiding additional mammographic imaging and its associated costs and radiation exposure (Fig 10). This will place an even greater importance on high-quality US.






Evaluation of the Symptomatic Patient:Palpable Masses, Breast Pain, and Nipple Discharge

US is essential in the evaluation of patients with the common clinical complaint of either a palpable mass or focal persistent breast pain. Unlike focal breast pain, which may be occasionally associated with benign or malignant lesions, diffuse breast pain (bilateral or unilateral), as well as cyclic breast pain, requires only clinical follow-up, as it is usually physiologic with an extremely low likelihood of malignancy (60,61). In patients with isolated focal breast pain, the role of sonography may be limited to patient reassurance (61). In women younger than 30 years of age, with a palpable lump or focal breast pain, US is the primary imaging test, with a sensitivity and negative predictive value of nearly 100% (62). Symptomatic women older than 30 years usually require both US and mammography, and in these patients, the negative predictive value approaches 100% (63,64). Lehman et al (65) demonstrated that in symptomatic women aged 30–39 years, the risk of malignancy was 1.9% and the added value of adjunct mammography in addition to US was low. Identification of a benign-appearing solid lesion at US in a symptomatic woman can negate the need for needle biopsy, as many of these masses can safely be monitored with short-interval follow-up US (4648), usually performed at 6 months. A suspicious mass identified at US can promptly undergo biopsy with US guidance.

US can also be used as an alternative or an addition to ductography in patients who present with unilateral, spontaneous bloody, clear, or serosanguinous nipple discharge (66). Among women with worrisome nipple discharge, ductography can demonstrate an abnormality in 59%–82% of women (67,68), MR imaging may demonstrate a suspicious abnormality in 34% of women (68), and US has been shown to demonstrate a subareolar mass or an intraductal mass or filling defect in up to 14% of women (67). If US can be used to identify a retroareolar mass or an intraductal mass, US-guided biopsy can be performed and ductography may be avoided (Fig 11). US may be limited, however, as small peripherally located intraductal masses or masses without an associated dilated duct may not be identified. Therefore, galactography, MR imaging, and/or major duct excision may still be necessary in the symptomatic patient with a negative US examination.


Finally, in the pregnant or lactating patient who presents with a palpable breast mass, focal breast pain, or bloody nipple discharge, US is also the initial imaging modality of choice. Targeted US examination in these patients can be used to identify most benign and malignant masses, including fibroadenomas, galactocoeles, lactating adenomas, abscesses, and invasive carcinomas. In a recent study by Robbins et al (69), a negative predictive value of 100% was found among 122 lesions evaluated with US in lactating, pregnant, or postpartum women. This is much higher than the pregnancy-associated breast cancer sensitivity of mammography, which has been reported in the range of 78%–87% (70,71). The diminished sensitivity of mammography is likely due to increased parenchymal density seen in these patients. However, since lactating breast parenchyma is more echogenic than most breast masses, hypoechoic breast cancers are more readily detected at US in pregnant patients.



Supplemental Screening Breast US

Because of the known limitations of mammography, particularly in women with dense breast tissue, supplemental screening with whole-breast US, in addition to mammography, is increasingly gaining widespread acceptance. Numerous independent studies have demonstrated that the addition of a single screening or whole-breast US examination in women with dense breast tissue at mammography will yield an additional 2.3–4.6 mammographically occult cancers per 1000 women (7280). Mammographically occult cancers detected on US images are generally small node-negative invasive cancers (Fig 12) (81). However, few studies have investigated the performance of incident screening breast US, and the optimal screening US interval is unknown. Berg and colleagues (82) recently demonstrated that incident annual supplemental screening US in intermediate- and high-risk women with mammographically dense breast tissue enabled detection of an additional 3.7 cancers per 1000 women screened.


Handheld screening breast US is highly operator-dependent and the majority of screening breast US studies have relied on physician-performed examinations. As per the ACRIN 6666 protocol, a normal screening US examination should consist of a minimum of one image in each quadrant and one behind the nipple (83). Two studies have also demonstrated that technologist-performed handheld screening breast US can achieve similar cancer detection rates (76,78).

Automated whole-breast US is a recently developed alternative to traditional handheld screening breast US, in which standardized, uniform image sets may be readily obtained by a nonradiologist. Automated whole-breast US systems may utilize a standard US unit and a linear-array transducer attached to a computer-guided mechanical arm or a dedicated screening US unit with a 15-cm wide transducer (84,85). With these systems, over 3000 overlapping sagittal, transverse, and coronal images are obtained and available for later review by the radiologist, with associated 3D reconstruction. The advantages include less operator dependence, increased radiologist efficiency, and increased reproducibility, which could aid in follow-up of lesions.

A multi-institutional study has shown that supplemental automated whole-breast US can depict an additional 3.6 cancer per 1000 women screened, similar to physician-performed handheld screening US (85). However, disadvantages include the limited ability to scan the entire breast, particularly posterior regions in large breasts, time-consuming review of a large number of images by the radiologist, and the need to recall patients for a second US examination to re-evaluate indeterminate findings. Moreover, few investigators have compared the use of handheld with automated breast US screening. A single small recent study by Chang et al (86) demonstrated that of 14 cancers initially detected at handheld screening, only 57%–79% were also detected by three separate readers on automated whole-breast US images, with the two cancers missed by all three readers at automated whole-breast US, each less than 1 cm in size.

The use of supplemental screening breast US, performed in addition to mammography, remains controversial despite proof of the ability to detect small mammographically occult cancers. US has limited value for the detection of small clustered microcalcifications without an associated mass lesion. Low positive predictive values of biopsies performed of less than 12% have been consistently reported (77,87). No outcome study has been able to demonstrate a direct decrease in patient mortality due to the detection of these additional small and mammographically occult cancers. This would require a long, randomized screening trial, which is not feasible. Rationally, however, the early detection and treatment of additional small breast cancers should improve outcomes and reduce overall morbidity and mortality. Many insurance companies will not reimburse for screening breast US and historically, this examination has not been widely accepted in the United States.

Nevertheless, because of both the known efficacy of supplemental screening breast US and overall increased breast cancer awareness, more patients and clinicians are requesting this examination. In fact, some states now mandate that radiologists inform women of their breast density and advise them to discuss supplemental screening with their doctors. Although supplemental screening breast MR imaging is usually preferred for women who are at very high risk for breast cancer (ie, women with a lifetime risk of over 20%, for example those women who are BRCA positive or have multiple first-degree relatives with a history of premenopausal breast cancer), screening breast US should be considered in women at very high risk for breast cancer who cannot tolerate breast MR imaging, as well as those women with dense breast tissue and intermediate risk (ie, lifetime risk of 15%–20%, for example those women whose only risk factor is a personal history of breast cancer or previous biopsy of a high-risk lesion), or even average risk. Future studies are needed to establish strategies to reduce false-positive results and continue to optimize both technologist-performed handheld screening US and automated whole-breast US in women with mammographically dense breast tissue.


 Use of US for MR Imaging–depicted Abnormalities

MR imaging of the breast is now an integral part of breast imaging, most commonly performed to screen high-risk women and to further assess the stage in patients with newly diagnosed breast cancers. While MR has a higher sensitivity than mammography for detecting breast cancer, the specificity is relatively low (88). Lesions detected on MR images are often mammographically occult, but many can be detected with targeted US (Fig 13). Besides further US characterization of an MR imaging–detected lesion, US may be used to guide intervention for lesions initially detected at MR imaging. US-guided biopsies are considerably less expensive, less time consuming, and more comfortable for the patient than MR imaging–guided biopsies.



Some suspicious lesions detected at MR imaging will represent invasive ductal or lobular cancers, but many may prove to be intraductal disease, which can be challenging to detect at US. Meticulous scanning technique is required for an MR imaging–directed US examination, with knowledge of subtle sonographic signs and close correlation with the MR imaging findings and location. Precontrast T1 images are helpful to facilitate localization of lesions in relation to fibroglandular tissue (89). Because MR imaging abnormalities tend to be vascular, increased vascularity may also assist in detection of a subtle sonographic correlate (90). Having the MR images available for simultaneous review while performing the US examination will ideally permit such associative correlation. At the authors’ facility, computer monitors displaying images from the picture archiving and communication system are available in all US rooms for this purpose.

Recent studies have shown that 46%–71% of lesions at MR imaging can be detected with focused US (9094). Enhancing masses detected on MR images are identified on focused US images in 58%–65% of cases compared with nonmass enhancement, which is identified on focused US images in only 12%–32% of cases (9092). Some studies have shown that US depiction of an MR imaging correlate was independent of size (91,93,95). However, Meissnitzer et al (92) showed that size dependence is also important: For masses 5 mm or smaller, only 50% were seen, versus 56% for masses 6–10 mm, 73% for masses 11–15 mm, and 86% for masses larger than 15 mm. Likewise, this study also demonstrated that for nonmass lesions, a US correlate was found for 13% of those measuring 6–10 mm, 25% of those 11–15 mm, and 42% of those larger than 15 mm (92). In addition, many of these studies determined that when a sonographic correlate was discovered, the probability of malignancy was increased (9092). Since typical US malignant features such as spiculation and posterior shadowing may be absent and the pretest probability is higher for MR imaging–detected lesions, a lower threshold for biopsy should be considered when performing MR imaging–directed US compared with routine targeted US (90) or screening US.

Because lesions are often very subtle at MR-directed US examination and because of differences in patient positioning during the two examinations, careful imaging–histologic correlation is required when performing US-guided biopsy of MR imaging–detected abnormalities. For lesions sampled with a vacuum-assisted device and US guidance, Sakamoto et al (96) found a higher rate of false-negative biopsy results for MR imaging–detected lesions than for US-detected lesions, suggesting that precise US-MR imaging correlation may not have occurred. Meissnitzer et al (92) showed that although 91% of MR imaging–detected lesions had an accurate US correlate, 9% were found to be inaccurate. With ever-improving techniques and experience in breast US, the US visualization of MR imaging–detected abnormalities will likely continue to improve. Nevertheless, if a suspicious lesion is not identified sonographically, MR imaging–guided biopsy should still be performed, because the malignancy rate of sonographically occult MR imaging–detected lesions has been shown to range from 14% to 22% (91,95).



Preoperative Staging of Cancer with US

Breast MR imaging has been shown to be more sensitive than US in the detection of additional foci of mammographically occult disease in women with newly diagnosed breast cancer (9799). Nevertheless, when a highly suspicious mass is identified at mammography and US, immediate US evaluation of the remainder of the ipsilateral breast, the contralateral breast, and the axilla should be considered. If additional lesions are identified, preoperative staging with MR imaging can be avoided and US-guided biopsy can be promptly performed, saving the patient valuable time and expense (100). In a study by Moon et al (101), of 201 patients with newly diagnosed breast cancer, staging US demonstrated mammographically occult multifocal or multicentric disease in 28 patients (14%) and contralateral breast cancers in eight patients (4%), resulting in a change in therapy in 32 patients (16%).

US can also be used to identify abnormal axillary, supraclavicular, and internal mammary lymph nodes. Abnormal lymph nodes characteristically demonstrate focal or diffuse cortical thickening (≥3 mm in thickness), a round (rather than oval or reniform) shape, loss of the echogenic fatty hilum and/or nonhilar, disorganized, irregular blood vessels (102,103) (Fig 14). A positive US-guided CNB or fine-needle aspiration of a clinically abnormal axillary lymph node in a patient with a known breast cancer can aid patient management, by avoiding the need for sentinel node biopsy and allowing the patient instead to proceed directly to axillary lymph node dissection or neoadjuvant chemotherapy.



 Interventional Breast US

US-guided interventional procedures have increased in volume in recent years and US is now the primary biopsy guidance technique used in many breast imaging centers. Most palpable lesions, as well as lesions detected at mammography, MR imaging, or screening US, can be sampled with US. With current high-resolution transducers, even suspicious intraductal microcalcifications may be detected and sampled.

While US-guided procedures require technical skills that must be developed and can be challenging, once mastered this technique allows precise real-time sampling of the lesion, which is not possible with either stereotactic or MR imaging–guided procedures. US-guided procedures do not require ionizing radiation or intravenous contrast material. US procedures are more tolerable for patients than stereotactic (104) or MR imaging–guided procedures because US-guided procedures are faster and more comfortable, as breast compression and uncomfortable biopsy coils or tables are not necessary and the procedure may be performed with the patient supine (104106).

Most literature has shown that automated 14-gauge CNB devices are adequate for the majority of US-guided biopsies (107115). Image-guided CNB is preferable to fine-needle aspiration cytology of breast masses because of superior sensitivity, specificity, and diagnostic accuracy (116). DCIS, malignant invasion, and hormone receptor status of invasive breast cancers can be determined with CNB samples, but not with fine-needle aspiration cytology. Fine-needle aspiration may be performed, however, in complicated cysts and symptomatic simple cysts. In these cases, the cyst aspirate fluid can often be discarded; cytology is usually only necessary if the fluid is frankly bloody (117).

The choice of performing fine-needle aspiration or CNB of a suspicious axillary lymph node depends on radiologist preference and the availability of an experienced cytopathologist, although CNB is usually more accurate than fine-needle aspiration biopsy (118,119). Fine-needle aspiration may be preferred for suspicious deep lymph nodes in proximity to the axillary vessels, whereas CNB may be preferred in large nodes with thickened cortices, particularly if determination of hormone receptor status or immunohistochemistry is desired, since more tissue is required for these assays. If lymphoma is suspected, a core should be placed in saline and also in conventional formalin.

While the underestimation rate of malignancy can be considerable for high-risk lesions such as atypical hyperplasia, such histology is not commonly found in lesions undergoing US-guided CNB. Multiple studies have shown a false-negative rate for US CNB biopsy of around 2%–3% (107115). Although the contiguous and larger samples obtained with a vacuum-assisted biopsy device undoubtedly reduce sampling error, the vacuum-assisted biopsy is a more expensive and more invasive procedure (109). In the authors’ experience, vacuum-assisted US biopsy is to be considered for small masses, intraductal or intracystic lesions, or lesions with subtle microcalcifications. These may be difficult to adequately sample with a spring-loaded automatic firing device. Alternatively, for more accurate sampling of such challenging cases, as well as some axillary lymph nodes and masses smaller than 1 cm in size, automated CNB needles designed to place the inner trough of the needle within a lesion before firing can be utilized (Fig 15). With this technique, the sampling trough of the CNB needle can be clearly visualized within the lesion before the overlying outer sheath is fired. Regardless of needle choice, a postbiopsy clip marker should be placed followed by a postbiopsy mammogram to document clip position. This will assist with follow-up imaging, facilitating mammography and/or MR imaging correlation.




There has been recent interest in the percutaneous removal of benign breast lesions by using US-guided vacuum-assisted biopsy. While in general, proved benign concordant lesions can safely remain in the breast, some patients desire removal. Percutaneous US-guided removal with a vacuum-assisted biopsy device can replace surgical removal in some cases, particularly for small lesions (1 cm in size or less). Several reports have shown promising results demonstrating rates of complete lesion excision, varying from 61% to 94% (120124). Dennis et al (125) demonstrated that vacuum-assisted US-guided biopsy could be used to excise intraductal lesions resulting in resolution of problematic nipple discharge in 97% of patients. Even on long-term follow-up, most studies show low rates of residual masses, more commonly observed in larger fibroadenomas.


 Intraoperative Breast US

The use of two-dimensional and 3D intraoperative US may decrease the incidence of positive margins and decrease re-excision rates (126130) particularly in the setting of lumpectomy for palpable cancers, when US is used to assess the adequacy of surgical margins to determine the need for additional tissue removal. Similarly, intraoperative US has also been utilized to improve detection and removal of metastatic lymph nodes during sentinel lymph node assessment (131).


Future Directions

Intravenous US microbubble contrast agents have been used to enhance US diagnosis by means of analysis, enhancement patterns, the rates of uptake and washout, and identification of tumor angiogenesis. In addition, preliminary research has shown that intravenous US contrast agents may be able to depict tissue function with the potential to deliver targeted gene therapy to selected tumor cells (132). However, there are currently no intravenous US contrast agents approved for use in breast imaging by the U.S. Food and Drug Administration. Other potential advances in breast US include fusion imaging, which involves the direct overlay of correlative MR imaging with targeted US. Another evolving area is that of US computer-aided detection, which may be of particular benefit when combined with automated whole-breast screening US.



Technical advances in US now allow comprehensive US diagnosis, management, and treatment of breast lesions. Optimal use of US technology, meticulous scanning technique with careful attention to lesion morphology, and recognition and synthesis of findings from multiple imaging modalities are essential for optimal patient management. In the future, as radiologists utilize US for an ever-increasing scope of indications, become aware of the more subtle sonographic findings of breast cancer, and apply newly developing tools, the value of breast US will likely continue to increase and evolve.



  • • Breast US is operator dependent; knowledge and understanding of the various technical options currently available are important for image optimization and accurate diagnosis.
  • • US is an interactive, dynamic modality and real-time scanning is necessary to assess subtle findings associated with malignancy.
  • • Ability to synthesize the information obtained from the breast US examination with concurrent mammography, MR imaging, and clinical breast examination is necessary for accurate diagnosis.
  • • The use of screening breast US in addition to mammography, particularly in women with dense breast tissue, is becoming more widely accepted in the United States.
  • • Breast US guidance is the primary biopsy method used in most breast imaging practices, and the radiologist should be familiar with various biopsy devices and techniques to adequately sample any breast mass identified at US.


Disclosures of Conflicts of Interest: R.J.H. No relevant conflicts of interest to disclose. L.M.S. Financial activities related to the present article: none to disclose. Financial activities not related to the present article: educational consultant in vascular US to Philips Healthcare; payment for lectures on breast US from Educational Symposia; payment for development of educational presentations from Philips Healthcare. Other relationships: none to disclose. L.E.P. Financial activities related to the present article: none to disclose. Financial activities not related to the present article: consultant to Hologic. Other relationships: none to disclose.


BI-RADS = Breast Imaging and Reporting Data System

CNB = core needle biopsy

DCIS = ductal carcinoma in situ

3D = three dimensional


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Following (or not) the guidelines for use of imaging in management of prostate cancer.

Writer and curator: Dror Nir, PhD

Over diagnosis and over treatment is a trend of the last two decades. It leads to increase in health-care costs and human-misery.

The following headline on Medscape; Swedes Show That We Can Improve Imaging in Prostate Cancer elicited my curiosity.

I was expecting “good news” – well, not this time!

In spite the “general language” the study that the above mentioned headline refers to is not addressing the global use of imaging in prostate cancer patients’ pathway but is specific to use of radionuclide bone-scans as part of patients’ staging.  The “bad-news” are that realization that the Swedish government had to invest many man-years to achieve “success” in reducing unnecessary use of such imaging in low risk patients. Moreover, the paper reveals under-use of such imaging technology for staging high risk prostate cancer patients.

Based on this paper, one could come to the conclusion that in reality, we are facing long lasting non-conformity with established guidelines related to the use of “full-body” imaging as part of the prostate cancer patients’ pathway in Europe and USA.

Here is a link to the original paper:

Prostate Cancer Imaging Trends After a Nationwide Effort to Discourage Inappropriate Prostate Cancer Imaging, Danil V. MakarovStacy LoebDavid UlmertLinda DrevinMats Lambe and Pär Stattin Correspondence to: Pär Stattin, MD, PhD, Department of Surgery and Perioperative Sciences, Urology and Andrology, Umeå University, SE- 901 87 Umeå, Sweden (e-mail:par.stattin@urologi.umu.se).

JNCI J Natl Cancer Inst (2013)doi: 10.1093/jnci/djt175


For convenience, here are the highlights:











  • In 1998, the baseline low-risk prostate cancer imaging rate in Sweden was 45%. Per the NCCN guidelines (7), none of these men should have received bone imaging unless they presented with symptoms suggestive of bone pain (8,24). In the United States, the imaging rate among men with low-risk prostate cancer has been reported to be 19% to 74% in a community cohort and 10% to 48% in a Surveillance Epidemiology and End Results (SEER)–Medicare cohort (10–13,16). It is challenging to compare these rates directly across the two countries because the NPCR aggregates all staging imaging into one variable. However, our sampling revealed that 88% of those undergoing imaging had at least a bone scan, whereas only 11% had any CTs and 10% had any MRI. This suggests that baseline rates of bone scan among low-risk men in Sweden were similar to those among their low-risk counterparts in the United States, whereas rates of axial imaging were likely much lower. During the study period, rates of prostate cancer imaging among low-risk men in Sweden decreased to 3%, substantially lower than those reported in the United States at any time.

  • Miller et al. describe a decline in imaging associated with a small-scale intervention administered in three urology practices located in the United States participating in a quality-improvement consortium. Our study’s contribution is to demonstrate that a similar strategy can be applied effectively at a national scale with an associated decline in inappropriate imaging rates, a finding of great interest for policy makers in the United States seeking to improve health-care quality.

  • In 1998, the baseline high-risk prostate cancer imaging rates in Sweden were 63%, and decreased by 43% in 2008 (rising slightly to 47% in 2009). Based on our risk category definitions and the guidelines advocated in Sweden, all of these men should have undergone an imaging evaluation (8,24). Swedish rates of prostate cancer imaging among men with high-risk disease are considerably lower than those reported from the SEER–Medicare cohort, where 70% to 75% underwent bone scan and 57% to 58% underwent CT (13,16). These already low rates of imaging among men with high-risk prostate cancer only decreased further during the NPCR’s effort to promote guideline-concordant imaging. Clearly in both countries, imaging for high-risk prostate cancer remains underused despite the general overuse of imaging and numerous guidelines encouraging its appropriate use (3–9).

Similar items I have covered on this this Open Access Online Scientific Journal:


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