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High Risk of Transmissible Disease and Mortality in Cancer, Advanced Cardiovascular Disease, and Hemodialysis Patients
Curator: Larry H Bernstein, MD, FCAP
This contribution is aimed at three situations of special concern with respect to transmission and handling of episodic bacteria or virus spread in hospital and ambulatory healthcare settings, where healthcare workers may be exposed and either become ill or are potential carriers of the disease. Not discussed is a report in the last week of an association between human papilloma virus (HPV), known to be associated with cervical cancer, and oropharyngeal cancer. In all of these situations, the patients at highest risk of death are immune compromized, carry a heavy burden of unbalanced oxidative stress, and have mitcochondrial dysfunction from unbalanced ubiquitination and repair.
Clostridium difficile colitis results from a disturbance of the normal bacterial flora of the colon, colonization by C difficile, and the release of toxins that cause mucosal inflammation and damage. Antibiotic therapy is the key factor that alters the colonic flora. C difficile infection primarily occurs in hospitalized patients.
Essential update: Fidaxomicin superior to vancomycin for cancer patients with C difficile
In a multicenter study including 1105 subjects with C difficile – associated diarrhea, 183 of whom had solid tumors or hematologic malignancies, fidaxomicin treatment was superior to vancomycin treatment in cancer patients, resulting in higher cure and sustained response rates, shorter time to resolution of diarrhea (TTROD), and fewer recurrences. Cure rates were lower overall in cancer patients than in others (79.2% vs 88.6%; P < 0.001).[2Whereas cure rates for noncancer patients were approximately the same with fidaxomicin as with vancomycin (88.5% vs 88.7%), those for cancer patients were higher with fidaxomicin than with vancomycin (85.1% vs 74.0%), though the difference was not statistically significant. Median TTRODs in noncancer patients were 54 hours with fidaxomicin and 58 with vancomycin; those in cancer patients were 74 and 123 hours, respectively. The risk of recurrence was approximately twice as high with vancomycin as with fidaxomicin, regardless of whether patients had cancer or not, but because both cure and recurrence outcomes were better with fidaxomicin than with vacomycin in cancer patients, the relative odds of sustained response at 28 days in these patients were more than 2.5-fold higher for fidaxomicin than for vancomycin.
Background
Clostridium difficile is a gram-positive, anaerobic, spore-forming bacillus that is responsible for the development of antibiotic-associated diarrhea and colitis. C difficile was first described in 1935 as a component of the fecal flora of healthy newborns and was initially not thought to be a pathogen. It was named difficile because it grows slowly and is difficult to culture. While early investigators noted that the bacterium produced a potent toxin, the role of C difficile in antibiotic-associated diarrhea and pseudomembranous colitis was not elucidated until the 1970s.
Approximately 20% of individuals who are hospitalized acquire C difficile during hospitalization, and more than 30% of these patients develop diarrhea. Thus, C difficile colitis is currently one of the most common nosocomial infections.
The diagnosis of C difficile colitis should be suspected in any patient with diarrhea who has received antibiotics within the previous 2 months and/or when diarrhea occurs 72 hours or more after hospitalization.
Pathophysiology
Colonization occurs by the fecal-oral route. C difficile forms heat-resistant spores that can persist in the environment for several months to years. Outbreaks of C difficile diarrhea may occur in hospitals and other outpatient facilities where contamination with spores is prevalent. Normal gut flora resists colonization and overgrowth with C difficile. Antibiotic use, which suppresses the normal flora, allows proliferation of C difficile.
Pathogenic strains of C difficile produce 2 distinct toxins. Toxin A is an enterotoxin, and toxin B is a cytotoxin. Both are high–molecular weight proteins capable of binding to specific receptors on the intestinal mucosal cells. Receptor-bound toxins gain intracellular entry where they catalyze a specific alteration of Rho proteins, small glutamyl transpeptidase (GTP)–binding proteins that assist in actin polymerization, cytoskeletal architecture, and cell movement. Both toxin A and toxin B appear to play a role in the pathogenesis of C difficile colitis in humans.
Epidemiology
Although the incidence of other nosocomial infections declined from 2000-2009, the number of hospitalized patients with any C difficile infection discharge diagnosis more than doubled, from approximately 139,000 to 336,600. The number of patients with a primary C difficile infection diagnosis more than tripled, from 33,000 to 111,000.
Among C difficile infections identified in the Centers for Disease Control and Prevention’s (CDC’s) Emerging Infections Program data in 2010, 94% were associated with receiving health care; of these, 75% had onset among persons not currently hospitalized, including recently discharged patients, outpatients, and nursing home residents
Physical examination may reveal the following in patients with the disorder:
Fever: Especially in more severe cases
Dehydration
Lower abdominal tenderness
Rebound tenderness: Raises the possibility of colonic perforation and peritonitis
Laboratory studies
Lab tests for evaluating patients with C difficile infection include the following:
Electrolytes: Dehydration and electrolyte imbalance may accompany severe disease
Albumin: Hypoalbuminemia and anasarca may accompany severe disease
Transthyretin is the serum protein of choice for a rapid onset diarrhea with dehydration leading to weight loss, dehydration, anasarca and sarcopenia, as it has a serum half-life of ~ 48 hrs rather than 21 days, and it is an accurate measure of lean body mass.
Complete blood count: Leukocytosis may be present
Stool examination: Stool may be Hemoccult positive in severe colitis, but grossly bloody stools are unusual; fecal leukocytes are present in about half of cases
Stool assays for C difficile, from the most to the least sensitive, include the following:
Stool culture: The most sensitive test (sensitivity, 90-100%; specificity, 84-100%), but the results are slow and may lead to a delay in the diagnosis if used alone
Glutamate dehydrogenase enzyme immunoassay (EIA): Very sensitive (sensitivity, 85-100%; specificity, 87-98%); this test detects the presence of glutamate dehydrogenase produced by C difficile
The stool cytotoxin test: Has a sensitivity of 70-100% and a specificity of 90-100%; a positive test result is the demonstration of a cytopathic effect that is neutralized by a specific antiserum
Enzyme immunoassay for detecting toxins A and B: Used in most labs; the sensitivity is moderate (79-80%), and the specificity is excellent (98%)
Latex agglutination technique: Another means of detecting glutamate dehydrogenase; the sensitivity of this test is poor (48-59%), although the specificity is 95-96%
Management
Treatment for C difficile infection varies according to its severity. Interventions include the following:
Asymptomatic carriers: No treatment necessary
Mild, antibiotic-associated diarrhea without fever, abdominal pain, or leukocytosis: Cessation may be the only treatment necessary
Mild to moderate diarrhea or colitis: Metronidazole (oral or intravenous) or vancomycin (oral) for 10 days
Severe disease: Vancomycin is considered to produce faster symptom resolution and fewer treatment failures than metronidazole; in fulminant cases, combined therapy with intravenous metronidazole and oral vancomycin may be considered
Relapse
Relapse occurs in 20-27% of patients treated with metronidazole or vancomycin. Once a patient has one relapse, the risk for a second relapse is 45%. Relapses should be treated as follows:
First relapse: The choice of antibiotic should be based on the severity of C difficile diarrhea/colitis
Subsequent relapses: For every relapse beyond the first, vancomycin (prolonged taper/pulsed regimen) is recommended to help clear persistent spores
Among various investigational therapies, fecal transplantation (fecal enemas or infusion of donor feces through a nasoduodenal tube) has been reported to repopulate the colonic flora and treat recurrent C difficile infection.
Both community-associated and hospital-acquired infections with Staphylococcus aureus have increased in the past 20 years, and the rise in incidence has been accompanied by a rise in antibiotic-resistant strains—in particular, methicillin-resistant S aureus (MRSA) and, more recently, vancomycin-resistant strains.
Essential update: Universal decolonization more effective than screening and isolation in reducing rates of MRSA
Daily washing of ICU patients with chlorhexidine-impregnated cloths reduced positive cultures of MRSA by 37% and reduced bloodstream infection by any pathogen by 44%, according to a study of 74,256 patients in 74 adult ICUs.
In the study, hospitals were randomized to 18 months of either screening for MRSA followed by isolation of positive patients, targeted decolonization of MRSA-positive patients and isolation, or universal decolonization of all ICU patients without screening. Decolonization was achieved via daily cleansing with chlorhexidine-impregnated cloths and 5 days of twice-daily intranasal mupirocin treatments. At baseline, there was no significant difference in the rate of MRSA infections between the 3 groups. However, patients who underwent universal decolonization showed a significantly larger decline between baseline and intervention periods than those in either of the targeted interventions. Universal decolonization led to a 37% drop in the rate of MRSA infections, while targeted decolonization led to a 25% decline and no significant change was seen in the screening and isolation group. There was no significant difference in outcomes between the targeted decolonization and the screening and isolation groups, while the difference between the universal decolonization and the screening and isolation groups was significant (P = .003). Universal decolonization also significantly reduced ICU-attributed bloodstream infections from any pathogen.
Management
Antibiotic regimens include the following:
Empiric therapy with penicillins or cephalosporins may be inadequate because of community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA)
Combination therapy with a penicillinase-resistant penicillin or cephalosporin (in case the organism is methicillin-sensitive S aureus [MSSA]) and clindamycin or a quinolone
Clindamycin, trimethoprim-sulfamethoxazole (TMP-SMX), rifampin, doxycycline, or a quinolone
TMP-SMX and rifampin in combination, rather than singly
Clindamycin (rather than TMP-SMX) may become the preferred outpatient antibiotic therapy in regions with a relatively low incidence of clindamycin resistance
The Infectious Diseases Society of America has published treatment guidelines for MRSA infection
Bacteremia
Daptomycin, with or without beta-lactams, controls S aureus bacteremia without worsening renal dysfunction. In a cohort of patients with mild or moderate renal insufficiency, more than 80% responded to treatment, with no detrimental effect on their kidneys. Currently, the combination of daptomycin with beta-lactams is recommended only as salvage therapy for refractory MRSA bacteremia.
The novel coronavirus outbreak in the Middle East is eerily similar to SARS, according to Trish Perl, MD, of the Johns Hopkins University School of Medicine, part of an international team, led by Ziad Memish, MD, of the World Health Organization in Riyadh, that looked into a cluster of 23 cases in hospitals in the east of Saudi Arabia. . “The illness pattern, the incubation period — there are a lot of eerie similarities,” Perl told MedPage Today. They reported online in the New England Journal of Medicine, that the virus, MERS-CoV, is related to the virus that caused the 2002-2003 SARS outbreak. The viruses both are coronaviruses and both lead to severe respiratory illness. Further, person-to-person transmission can take place in healthcare settings and can do so with “considerable morbidity.” One key difference, Perl and colleagues noted, is that — at least in the cluster they investigated — the fatality rate was 65%, markedly higher than the 8% or so seen in the SARS outbreak. On the other hand, that rate may fall if a large number of milder cases is detected, they noted. An outside expert, David Freedman, MD, of the University of Alabama at Birmingham, told MedPage Today that an open question has been whether MERS could spread within hospitals as easily as did SARS. The current study, he said, shows “unequivocally” that it can.
The report comes as the World Health Organization is reporting a total of 64 laboratory-confirmed cases of infection with MERS-CoV, including 38 deaths. Most reported cases have either occurred in the Middle East or have involved recent travel to the region. SARS was contained and eventually controlled by identifying cases vigorously and then isolating them to prevent transmission, Perl noted, and similar tactics — when they were applied in Saudi Arabia — appeared to have the same effect. The key in the epidemiological chain may have been Patient C, who had been undergoing long-term hemodialysis, and was admitted to hospital April 6 in the room next to Patient A. When Patient A developed a fever April 8, Patient C was still in the same room and developed fever himself 3 days later. He also had dialysis in the hospital’s outpatient hemodialysis unit twice after the onset of symptoms. Between April 14 and April 30, MERS was confirmed in nine more patients who were undergoing hemodialysis, including six who did so at times overlapping those of Patient C. All told, Patient C appears to have transmitted MERS directly to seven people, six in the dialysis unit and one in the intensive care unit, the researchers reported, while other infected people had more limited transmission and some did not pass on the disease at all.
Obtained after an outbreak this micrograph depicts Gram-positive Clostridium difficile bacteria. These C. difficile organisms were cultured from a stool sample obtained during an outbreak of gastrointestinal illness, and extracted using a .1µm filter. (Photo credit: Wikipedia)
English: Clostridium difficile toxin B rendered from PDB 2BVM (Photo credit: Wikipedia)
Combining Nanotube Technology and Genetically Engineered Antibodies to Detect Prostate Cancer Biomarkers
Writer, Curator: Stephen J. Williams, Ph.D.
Article ID #61: Combining Nanotube Technology and Genetically Engineered Antibodies to Detect Prostate Cancer Biomarkers. Published on 6/13/2013
WordCloud Image Produced by Adam Tubman
Article 9.4.Combining Nanotube Technology and Genetically Engineered Antibodies to Detect Prostate Cancer Biomarkers
Figure of Carbon Nanotube Transistor design with functionalized antibodies for biomarker detection. From paper of A.T. Johnson; used with permission from A.T. Johnson)
In a literature review of the current status of the breast cancer biomarker field[2], author Dr. Michael Duffy, from University College Dublin, pondered the clinical utility of breast cancer serum markers and suggested that due to lack of sensitivity and specificity none of available markers is of value for detection of early breast cancer however these biomarkers have been shown useful in monitoring patients with advanced disease. For instance high preoperative CA15-3 is indicative of adverse patient outcome. According to American Society of Clinical Oncology Expert Panel, however CA 15-3 may lack the sensitivity and disease specificity for breast cancer as a prognostic marker. For panel suggestions please click on the link below:
The same panel also concurred on the lack of prognostic value of other markers (for example CEA for colon cancer) but did agree that 66-73% of patients with advanced disease, who responded to therapy, showed reduction in these serum markers. Indeed, CA125, long associated as a biomarker for ovarian cancer, does not have the sensitivity and especially the disease specificity to be a stand-alone prognostic marker[3]. Therefore, although “omics” strategies have suggested multiple possible biomarkers for various cancers, a major issue in translating a putative biomarker to either:
1) a clinically validated (panel) of disease-relevant biomarkers or
2) biomarkers useful for therapeutic monitoring
is obtaining the specificity and sensitivity for detection in bio-specimens. As discussed below, this is being achieved with the merger of nanotechnology-based sensors and bioengineering of biomolecule.
For ASCO panel suggestions of biomarkers useful in Prostate cancer please see the link below:
Osteopontin is a phosphorylated glycoprotein secreted by activated macrophages, leukocytes, activated T lymphocytes and is present at sites of inflammation (for a review of OPN see [4]). Osteopontin interacts with several integrins and CD44 (a putative cancer stem cell marker). Binding of OPN to cell integrins mediates cell-matrix and cell-cell communication, stimulating adhesion, migration (through interaction with urokinase plasminogen activator {uPA}) and cell signaling pathways such as the HGF-Met pathway. Overexpression is found on a variety of cancers including breast, lung, colorectal, ovarian and melanoma[5]. And although OPN is detected in normal tissue, it is known that OPN over-expression can alter the malignant potential of tumor cells.
Roles of osteopontin in cancer include:
Binding to CD44
Increase in growth factor signaling (HGF/Met pathway)
Increase uPA activity- increase invasiveness
Angiogenesis thru binding with αvβ3 integrin and increased VEGF expression
Protection against apoptosis: OPN activates nuclear factor Κβ
Some researchers have suggested it could be a prognostic marker for breast and lung cancer while there have been conflicting reports as to whether OPN expression is correlated to malignant potential in prostate cancer[6]. Osteopontin is found on tumor infiltrating macrophages, which may contribute to OPN as a prognostic marker. Breast cancer patients (disseminated carcinomas) have 4-10 times higher serum levels of OPN than found in healthy patients, although there is no difference in pre- or post-menopausal women[7].
Piezoelectric sensors have been used by the same group at Fox Chase Cancer Center to detect serum levels of the HER2 protein in breast cancer patients, for the purpose of therapeutic monitoring after anti-HER2 antibody trastuzumab (Herceptin™) therapy. Lina Loo, in the laboratory of Dr. Gregory Adams showed the utility of using (scFv) to trastuzumab (anti-HER2) with pizo-electric nanotubes to accurately and reproducibly determine levels of serum HER2[8]. This method improved the sensitivity of serum HER2 detection over other methods such as:
However the advent of nanotechnology-based detection system combined with engineered affinity-based biomolecules has increased both the sensitivity and specificity of biomarker detection from complex fluids such as plasma and urine. The advent of multiple types of biosensors, including
has given the ability to measure, with enhanced sensitivity and specificity, putative biomarkers of disease in minute volumes of precious bio-samples.
The basic design of a biosensor is made of three components:
A recognition element (I.e. antibodies, nucleic acids, enzymes)
A signal transducer (electrochemical, optical, piezoelectric)
Signal processor (relays and displays)
In the journal ACS Nano Mitchel Lerner from Dr. Charlie Johnson’s laboratory at University of Pennsylvania in collaboration with Fox Chase Cancer researchers in the laboratory of Dr. Matthew Robinson, describe a piezoelectric detection system for quantifying levels of osteopontin (OPN), a putative biomarker for prostate cancer[1]. In this paper Dr. Robinson’s group at Fox Chase, genetically engineered a single chain variable fragment (scFv) protein {the binding portion of the antibody} which had high affinity for OPN. This scFv was attached to a carbon nanotube field-effect transistor (NT-FET), designed by Dr. Johnson’s group, using a chemical process called chemical functionalization {a process using diazonium salts to covalently attach scFV to NT-FET.
Figure. Functionalization scheme for OPN attachment to carbon nanotubes. As figure 1 legend in paper states: “First, sp8 hybridized-sites are created o the nanotube sidewall by incubation in a diazonium salt solution. The carboxylic acid group is then activated by EDC and stabilized with NHS.ScFv antibody displaces the NHS and forms an amide bond. OPN epitope is shown in yellow and the C and N-terminuses are in orange and green respectively.” (used by permision for A.T. Charlie Johnson)
This system was then used to determine the selectivity and sensitivity of OPN from complex solutions.
Methods:
Nanotube (NT) design
Grown by catalytic vapor deposition
Electrical contacts patterned using photo-lithography
Atomic Force microscopy was used to verify structure of nanotube
Chemical Linking of scFv to nanotube
Diazonium treatment resulted in activation and subsequent stabilization of amino (NHS) side chain
Amine group on lysine of scFV displaced NHS group => covalent attachment of scFV to NT
Atomic Force Spectroscopy used to verify linkage of scFv to nanotube
Results showed there was
minimal non-specific binding of OPN to the scFv
system allowed for detection limit of 1 pg/ml OPN (pictogram/milliliter) or 30 fM (fentomolar) in a phosphate buffered saline solution.
Only a minute volume (10 µl) of sample is needed
Sensor able to measure million-fold range of OPN concentrations ( from 10-3 to 103 ng/mL OPN)
Two experiments were conducted to determine the specificity of OPN to the antibody-detection system.
1st experiment
– scFv functionalized sensor was incubated in a solution of high concentration of BSA (450 mg/ml) to approximate nonspecific proteins in patient samples
– minimal signal was detected
2nd experiment
– Functionalized NT-FET devices with a scFv based on the HER2 therapeutic antibody trastuzumab
– There was no binding of OPN to anti-HER2 devices
– Therefore anti OPN (23C3) scFv-functionalized carbon nanotube sensors exhibit high levels of specificity to OPN
The authors conclude “the functionalization procedure described here is expected to be generalizable to any antibody containing an accessible amine group, and to result in biosensors appropriate for detection of corresponding complementary proteins at fM concentrations”.
I had the opportunity to speak with co-author Dr. Matthew Robinson, Assistant Professor in the Developmental Therapeutics Program at Fox Chase Cancer Center about the next steps for this work. Dr. Robinson mentioned that “at this point we have not looked in patient samples yet but our plan is to move in that direction. We need to establish sensitivity/specificity in increasingly complex samples (e.g. spiked normal serum and retrospectively in patient serum with known levels of biomarkers).”
Cancer patients often present a complex metabolic profile. The paper notes that OPN has a pI (isoelectric point) of 4.2, which would result in a negative charge at physiologically normal pH of 7.6. I asked Dr. Robinson about if changes in metabolic profile could hinder OPN binding to the NT-FET system would require some preprocessing of blood samples. Dr. Robinson agreed “that confounding variables such as additional diseases but even things like diet (i.e. is fasting necessary) need to be addressed before this platform is ready for use in clinical setting. It is likely that sample prep will be needed to remove albumin, lower salt concentrations, etc. This could end up being problematic for biomarkers that are unstable and would degrade over the time necessary for sample prep. It is also possible that sample prep to remove albumin and other background factors could result in loss of biomarkers. This will need to be determined on a case-by-case basis with validated testing methods.” One useful advantage of this system is the possibility of measuring multiple biomarkers, clinically important as studies has suggested that
multiple markers result in the higher sensitivity/specificity for many infrequent cancers, such as ovarian. Dr. Robinson agrees “that panels of biomarkers are likely to be better at early detection and diagnosis. In principle the platform that we describe can be set up to allow for detection of multiple biomarkers at a time. From the biology end of things we have built antibodies against 3 different prostate cancer biomarkers for that purpose.”
Dr. Johnson commented on the ability of the platform allowed for the simultaneous detection of multiple biomarkers, noting that ”the platform is compatible with the measurement of multiple biomarkers through the use of multiple devices, each functionalized with their own antibody.”
ASCO guidelines Expert Panel on Tumor Biomarkers 2007 Updatefor Breast Cancer:
Published in JCO, Vol. 25, Issue 12 (April 20), 2007: 1596-1605
References:
1. Lerner MB, D’Souza J, Pazina T, Dailey J, Goldsmith BR, Robinson MK, Johnson AT: Hybrids of a genetically engineered antibody and a carbon nanotube transistor for detection of prostate cancer biomarkers. ACS nano 2012, 6(6):5143-5149.
5. Brown LF, Berse B, Van de Water L, Papadopoulos-Sergiou A, Perruzzi CA, Manseau EJ, Dvorak HF, Senger DR: Expression and distribution of osteopontin in human tissues: widespread association with luminal epithelial surfaces. Molecular biology of the cell 1992, 3(10):1169-1180.
6. Thoms JW, Dal Pra A, Anborgh PH, Christensen E, Fleshner N, Menard C, Chadwick K, Milosevic M, Catton C, Pintilie M et al: Plasma osteopontin as a biomarker of prostate cancer aggression: relationship to risk category and treatment response.British journal of cancer 2012, 107(5):840-846.
7. Brown LF, Papadopoulos-Sergiou A, Berse B, Manseau EJ, Tognazzi K, Perruzzi CA, Dvorak HF, Senger DR: Osteopontin expression and distribution in human carcinomas. The American journal of pathology 1994, 145(3):610-623.
8. Loo L, Capobianco JA, Wu W, Gao X, Shih WY, Shih WH, Pourrezaei K, Robinson MK, Adams GP: Highly sensitive detection of HER2 extracellular domain in the serum of breast cancer patients by piezoelectric microcantilevers. Analytical chemistry 2011, 83(9):3392-3397.
Other posts from this site on Biomarkers, Cancer, and Nanotechnology include:
Imaging of Non-tumorous and Tumorous Human Brain Tissues
Reporter and Curator: Dror Nir, PhD
The point of interest in the article I feature below is that it represents a potential building block in a future system that will use full-field optical coherence tomography during brain surgery to improve the accuracy of cancer lesions resection. The article is featuring promising results for differentiating tumor from normal brain tissue in large samples (order of 1–3 cm2) by offering images with spatial resolution comparable to histological analysis, sufficient to distinguish microstructures of the human brain parenchyma. Easy to say, and hard to make…:) –> Intraoperative apparatus to guide the surgeon in real time during resection of brain tumors.
Imaging of non-tumorous and tumorous human brain tissues with full-field optical coherence tomography
A prospective study was performed on neurosurgical samples from 18 patients to evaluate the use of full-field optical coherence tomography (FF-OCT) in brain tumor diagnosis.
FF-OCT captures en face slices of tissue samples at 1 μm resolution in 3D to a penetration depth of around 200 μm. A 1 cm2 specimen is scanned at a single depth and processed in about 5 min. This rapid imaging process is non-invasive and requires neither contrast agent injection nor tissue preparation, which makes it particularly well suited to medical imaging applications.
Temporal chronic epileptic parenchyma and brain tumors such as meningiomas, low-grade and high-grade gliomas, and choroid plexus papilloma were imaged. A subpopulation of neurons, myelin fibers and CNS vasculature were clearly identified. Cortex could be discriminated from white matter, but individual glial cells such as astrocytes (normal or reactive) or oligodendrocytes were not observable.
This study reports for the first time on the feasibility of using FF-OCT in a real-time manner as a label-free non-invasive imaging technique in an intraoperative neurosurgical clinical setting to assess tumorous glial and epileptic margins.
Abbreviations
FF-OCT, full field optical coherence tomography;
OCT, optical coherence tomography
Keywords
Optical imaging; Digital pathology; Brain imaging; Brain tumor; Glioma
1. Introduction
1.1. Primary CNS tumors
Primary central nervous system (CNS) tumors represent a heterogeneous group of tumors with benign, malignant and slow-growing evolution. In France, 5000 new cases of primary CNS tumors are detected annually (Rigau et al., 2011). Despite considerable progress in diagnosis and treatment, the survival rate following a malignant brain tumor remains low and 3000 deaths are reported annually from CNS tumors in France (INCa, 2011). Overall survival from brain tumors depends on the complete resection of the tumor mass, as identified through postoperative imaging, associated with updated adjuvant radiation therapy and chemotherapy regimen for malignant tumors (Soffietti et al., 2010). Therefore, there is a need to evaluate the completeness of the tumor resection at the end of the surgical procedure, as well as to identify the different components of the tumor interoperatively, i.e. tumor tissue, necrosis, infiltrated parenchyma (Kelly et al., 1987). In particular, the persistence of non-visible tumorous tissue or isolated tumor cells infiltrating brain parenchyma may lead to additional resection.
For low-grade tumors located close to eloquent brain areas, a maximally safe resection that spares functional tissue warrants the current use of intraoperative techniques that guide a more complete tumor resection. During awake surgery, speech or fine motor skills are monitored, while cortical and subcortical stimulations are performed to identify functional areas (Sanai et al., 2008). Intraoperative MRI provides images of the surgical site as well as tomographic images of the whole brain that are sufficient for an approximate evaluation of the abnormal excised tissue, but offers low resolution (typically 1 to 1.5 mm) and produces artifacts at the air-tissue boundary of the surgical site.
Histological and immunohistochemical analyses of neurosurgical samples remain the current gold standard method used to analyze tumorous tissue due to advantages of sub-cellular level resolution and high contrast. However, these methods require lengthy (12 to 72 h), complex multiple steps, and use of carcinogenic chemical products that would not be technically possible intra-operatively. In addition, the number of histological slides that can be reviewed and analyzed by a pathologist is limited, and it defines the number and size of sampled locations on the tumor, or the surrounding tissue.
To obtain histology-like information in a short time period, intraoperative cytological smear tests are performed. However tissue architecture information is thereby lost and the analysis is carried out on only a limited area of the sample (1 mm × 1 mm).
Intraoperative optical imaging techniques are recently developed high resolution imaging modalities that may help the surgeon to identify the persistence of tumor tissue at the resection boundaries. Using a conventional operating microscope with Xenon lamp illumination gives an overall view of the surgical site, but performance is limited by the poor discriminative capacity of the white light illumination at the surgical site interface. Better discrimination between normal and tumorous tissues has been obtained using fluorescence properties of tumor cells labeled with preoperatively administered 5-ALA. Tumor tissue shows a strong ALA-induced PPIX fluorescence at 635 nm and 704 nm when the operative field is illuminated with a 440 nm-filtered lamp. More complete resections of high-grade gliomas have been demonstrated using 5-ALA fluorescence guidance (Stummer et al., 2000), however brain parenchyma infiltrated by isolated tumor cells is not fluorescent, reducing the interest of this technique when resecting low-grade gliomas.
Refinement of this induced fluorescence technique has been achieved using a confocal microscope and intraoperative injection of sodium fluorescein. A 488 nm laser illuminates the operative field and tissue contact analysis is performed using a handheld surgical probe (field of view less than 0.5 × 0.5 mm) which scans the fluorescence of the surgical interface at the 505–585 nm band. Fluorescent isolated tumor cells are clearly identified at depths from 0 to 500 μm from the resection border (Sanai et al., 2011), demonstrating the potential of this technique in low-grade glioma resection.
Reviewing the state-of-the-art, a need is identified for a quick and reliable method of providing the neurosurgeon with architectural and cellular information without the need for injection or oral intake of exogenous markers in order to guide the neurosurgeon and optimize surgical resections.
1.2. Full-field optical coherence tomography
Introduced in the early 1990s (Huang et al., 1991), optical coherence tomography (OCT) uses interference to precisely locate light deep inside tissue. The photons coming from the small volume of interest are distinguished from light scattered by the other parts of the sample by the use of an interferometer and a light source with short coherence length. Only the portion of light with the same path length as the reference arm of the interferometer, to within the coherence length of the source (typically a few μm), will produce interference. A two-dimensional B-scan image is captured by scanning. Recently, the technique has been improved, mainly in terms of speed and sensitivity, through spectral encoding (De Boer et al., 2003, Leitgeb et al., 2003 and Wojtkowski et al., 2002).
A recent OCT technique called full-field optical coherence tomography (FF-OCT) enables both a large field of view and high resolution over the full field of observation (Dubois et al., 2002 and Dubois et al., 2004). This allows navigation across the wide field image to follow the morphology at different scales and different positions. FF-OCT uses a simple halogen or light-emitting diode (LED) light source for full field illumination, rather than lasers and point-by-point scanning components required for conventional OCT. The illumination level is low enough to maintain the sample integrity: the power incident on the sample is less than 1 mW/mm2 using deep red and near infrared light. FF-OCT provides the highest OCT 3D resolution of 1.5 × 1.5 × 1 μm3 (X × Y × Z) on unprepared label-free tissue samples down to depths of approximately 200 μm–300 μm (tissue-dependent) over a wide field of view that allows digital zooming down to the cellular level. Interestingly, it produces en face images in the native field view (rather than the cross-sectional images of conventional OCT), which mimic the histology process, thereby facilitating the reading of images by pathologists. Moreover, as for conventional OCT, it does not require tissue slicing or modification of any kind (i.e. no tissue fixation, coloration, freezing or paraffin embedding). FF-OCT image acquisition and processing time is less than 5 min for a typical 1 cm2 sample (Assayag et al., in press) and the imaging performance has been shown to be equivalent in fresh or fixed tissue (Assayag et al., in press and Dalimier and Salomon, 2012). In addition, FF-OCT intrinsically provides digital images suitable for telemedicine.
In the CNS, published studies that evaluate OCT (Bizheva et al., 2005, Böhringer et al., 2006, Böhringer et al., 2009, Boppart, 2003 and Boppart et al., 1998) using time-domain (TD) or spectral domain (SD) OCT systems had insufficient resolution (10 to 15 μm axial) for visualization of fine morphological details. A study of 9 patients with gliomas carried out using a TD-OCT system led to classification of the samples as malignant versus benign (Böhringer et al., 2009). However, the differentiation of tissues was achieved by considering the relative attenuation of the signal returning from the tumorous zones in relation to that returning from healthy zones. The classification was not possible by real recognition of CNS microscopic structures. Another study showed images of brain microstructures obtained with an OCT system equipped with an ultra-fast laser that offered axial and lateral resolution of 1.3 μm and 3 μm respectively (Bizheva et al., 2005). In this way, it was possible to differentiate malignant from healthy tissue by the presence of blood vessels, microcalcifications and cysts in the tumorous tissue. However the images obtained were small (2 mm × 1 mm), captured on fixed tissue only and required use of an expensive large laser thereby limiting the possibility for clinical implementation.
Other studies have focused on animal brain. In rat brain in vivo, it has been shown that optical coherence microscopy (OCM) can reveal neuronal cell bodies and myelin fibers (Srinivasan et al., 2012), while FF-OCT can also reveal myelin fibers (Ben Arous et al., 2011), and movement of red blood cells in vessels (Binding et al., 2011).
En face images captured with confocal reflectance microscopy can closely resemble FF-OCT images. For example, a prototype system used by Wirth et al. (2012) achieves lateral and axial resolution of 0.9 μm and 3 μm respectively. However small field size prevents viewing of wide-field architecture and slow acquisition speed prohibits the implementation of mosaicking. In addition, the poorer axial resolution and lower penetration depth of confocal imaging in comparison to FF-OCT limit the ability to reconstruct cross-sections from the confocal image stack.
This study is the first to analyze non-tumorous and tumorous human brain tissue samples using FF-OCT.
2. Materials and methods
2.1. Instrument
The experimental arrangement of FF-OCT (Fig. 1A) is based on a configuration that is referred to as a Linnik interferometer (Dubois et al., 2002). A halogen lamp is used as a spatially incoherent source to illuminate the full field of an immersion microscope objective at a central wavelength of 700 nm, with spectral width of 125 nm. The signal is extracted from the background of incoherent backscattered light using a phase-shifting method implemented in custom-designed software. This study was performed on a commercial FF-OCT system (LightCT, LLTech, France).
Capturing “en face” images allows easy comparison with histological sections. The resolution, pixel number and sampling requirements result in a native field of view that is limited to about 1 mm2. The sample is moved on a high precision mechanical platform and a number of fields are stitched together (Beck et al., 2000) to display a significant field of view. The FF-OCT microscope is housed in a compact setup (Fig. 1B) that is about the size of a standard optical microscope (310 × 310 × 800 mm L × W × H).
2.2. Imaging protocol
All images presented in this study were captured on fresh brain tissue samples from patients operated on at the Neurosurgery Department of Sainte-Anne Hospital, Paris. Informed and written consent was obtained in all cases following the standard procedure at Sainte-Anne Hospital from patients who were undergoing surgical intervention. Fresh samples were collected from the operating theater immediately after resection and sent to the pathology department. A pathologist dissected each sample to obtain a 1–2 cm2 piece and made a macroscopic observation to orientate the specimen in order to decide which side to image. The sample was immersed in physiological serum, placed in a cassette, numbered, and brought to the FF-OCT imaging facility in a nearby laboratory (15 min distant) where the FF-OCT images were captured. The sample was placed in a custom holder with a coverslip on top (Fig. 1C, D). The sample was raised on a piston to rest gently against the coverslip in order to flatten the surface and so optimize the image capture. The sample is automatically scanned under a 10 × 0.3 numerical aperture (NA) immersion microscope objective. The immersion medium is a silicone oil of refractive index close to that of water, chosen to optimize index matching and slow evaporation. The entire area of each sample was imaged at a depth of 20 μm beneath the sample surface. This depth has been reported to be optimal for comparison of FF-OCT images to histology images in a previous study on breast tissue (Assayag et al., in press). There are several reasons for the choice of imaging depth: firstly, histology was also performed at approximately 20 μm from the edge of the block, i.e. the depth at which typically the whole tissue surface begins to be revealed. Secondly, FF-OCT signal is attenuated with depth due to multiple scattering in the tissue, and resolution is degraded with depth due to aberrations. The best FF-OCT images are therefore captured close to the surface, and the best matching is achieved by attempting to image at a similar depth as the slice in the paraffin block. It was also possible to capture image stacks down to several hundred μm in depth (where penetration depth is dependent on tissue type), for the purpose of reconstructing a 3D volume and imaging layers of neurons and myelin fibers. An example of such a stack in the cerebellum is shown as a video (Video 2) in supplementary material. Once FF-OCT imaging was done, each sample was immediately fixed in formaldehyde and returned to the pathology department where it underwent standard processing in order to compare the FF-OCT images to histology slides.
2.3. Matching FF-OCT to histology
The intention in all cases was to match as closely as possible to histology. FF-OCT images were captured 20 μm below the surface. Histology slices were captured 20 μm from the edge of the block. However the angle of the inclusion is hard to control and so some difference in the angle of the plane always exists when attempting matching. Various other factors that can cause differences stem from the histology process — fixing, dehydrating, paraffin inclusion etc. all alter the tissue and so precise correspondence can be challenging. Such difficulties are common in attempting to match histology to other imaging modalities (e.g. FF-OCT Assayag et al., in press; OCT Bizheva et al., 2005; confocal microscopy Wirth et al., 2012).
An additional parameter in the matching process is the slice thickness. Histology slides were 4 μm in thickness while FF-OCT optical slices have a 1 μm thickness. The finer slice of the FF-OCT image meant that lower cell densities were perceived on the FF-OCT images (in those cases where individual cells were seen, e.g. neurons in the cortex). This difference in slice thickness affects the accuracy of the FF-OCT to histology match. In order to improve matching, it would have been possible to capture four FF-OCT slices in 1 μm steps and sum the images to mimic the histology thickness. However, this would effectively degrade the resolution, which was deemed undesirable in evaluating the capacities of the FF-OCT method.
3. Results
18 samples from 18 adult patients (4 males, 14 females) of age range 19–81 years have been included in the study: 1 mesial temporal lobe epilepsy and 1 cerebellum adjacent to a pulmonary adenocarcinoma metastasis (serving as the non-tumor brain samples), 7 diffuse supratentorial gliomas (4 WHO grade II, 3 WHO grade III), 5 meningiomas, 1 hemangiopericytoma, and 1 choroid plexus papilloma. Patient characteristics are detailed in Table 1.
3.1. FF-OCT imaging identifies myelinated axon fibers, neuronal cell bodies and vasculature in the human epileptic brain and cerebellum
The cortex and the white matter are clearly distinguished from one another (Fig. 2). Indeed, a subpopulation of neuronal cell bodies (Fig. 2B, C) as well as myelinated axon bundles leading to the white matter could be recognized (Fig. 2D, E). Neuronal cell bodies appear as dark triangles (Fig. 2C) in relation to the bright surrounding myelinated environment. The FF-OCT signal is produced by backscattered photons from tissues of differing refractive indices. The number of photons backscattered from the nuclei in neurons appears to be too few to produce a signal that allows their differentiation from the cytoplasm, and therefore the whole of the cell body (nucleus plus cytoplasm) appears dark.
Myelinated axons are numerous, well discernible as small fascicles and appear as bright white lines (Fig. 2E). As the cortex does not contain many myelinated axons, it appears dark gray. Brain vasculature is visible (Fig. 2F and G), and small vessels are distinguished by a thin collagen membrane that appears light gray. Video 1 in supplementary material shows a movie composed of a series of en face 1 μm thick optical slices captured over 100 μm into the depth of the cortex tissue. The myelin fibers and neuronal cell bodies are seen in successive layers.
The different regions of the human hippocampal formation are easily recognizable (Fig. 3). Indeed, CA1 field and its stratum radiatum, CA4 field, the hippocampal fissure, the dentate gyrus, and the alveus are easily distinguishable. Other structures become visible by zooming in digitally on the FF-OCT image. The large pyramidal neurons of the CA4 field (Fig. 3B) and the granule cells that constitute the stratum granulosum of the dentate gyrus are visible, as black triangles and as small round dots, respectively (Fig. 3D).
In the normal cerebellum, the lamellar or foliar pattern of alternating cortex and central white matter is easily observed (Fig. 4A). By digital zooming, Purkinje and granular neurons also appear as black triangles or dots, respectively (Fig. 4C), and myelinated axons are visible as bright white lines (Fig. 4E). Video 2 in supplementary material shows a fly-through movie in the reconstructed axial slice orientation of a cortex region in cerebellum. The Purkinje and granular neurons are visible down to depths of 200 μm in the tissue.
3.2. FF-OCT images distinguish meningiomas from hemangiopericytoma in meningeal tumors
The classic morphological features of a meningioma are visible on the FF-OCT image: large lobules of tumorous cells appear in light gray (Fig. 5A), demarcated by collagen-rich bundles (Fig. 5B) which are highly scattering and appear a brilliant white in the FF-OCT images. The classic concentric tumorous cell clusters (whorls) are very clearly distinguished on the FF-OCT image (Fig. 5D). In addition the presence of numerous cell whorls with central calcifications (psammoma bodies) is revealed (Fig. 5F). Collagen balls appear bright white on the FF-OCT image (Fig. 5H). As the collagen balls progressively calcify, they are consumed by the black of the calcified area, generating a target-like image (Fig. 5H). Calcifications appear black in FF-OCT as they are crystalline and so allow no penetration of photons to their interior.
Mesenchymal non-meningothelial tumors such as hemangiopericytomas represent a classic differential diagnosis of meningiomas. In FF-OCT, the hemangiopericytoma is more monotonous in appearance than the meningiomas, with a highly vascular branching component with staghorn-type vessels (Fig. 6A, C).
The choroid plexus papilloma appears as an irregular coalescence of multiple papillas composed of elongated fibrovascular axes covered by a single layer of choroid glial cells (Fig. 7). By zooming in on an edematous papilla, the axis appears as a black structure covered by a regular light gray line (Fig. 7B). If the papilla central axis is hemorrhagic, the fine regular single layer is not distinguishable (Fig. 7C). Additional digital zooming in on the image reveals cellular level information, and some nuclei of plexus choroid cells can be recognized. However, cellular atypia and mitosis are not visible. These represent key diagnosis criteria used to differentiate choroid plexus papilloma (grade I) from atypical plexus papilloma (grade II).
3.4. FF-OCT images detect the brain tissue architecture modifications generated by diffusely infiltrative gliomas
Contrary to the choroid plexus papillomas which have a very distinctive architecture in histology (cauliflower-like aspect), very easily recognized in the FF-OCT images (Fig. 7A to G), diffusely infiltrating glioma does not present a specific tumor architecture (Fig. 8) as they diffusely permeate the normal brain architecture. Hence, the tumorous glial cells are largely dispersed through a nearly normal brain parenchyma (Fig. 8E). The presence of infiltrating tumorous glial cells attested by high magnification histological observation (irregular atypical cell nuclei compared to normal oligodendrocytes) is not detectable with the current generation of FF-OCT devices, as FF-OCT cannot reliably distinguish the individual cell nuclei due to lack of contrast (as opposed to lack of resolution). In our experience, diffuse low-grade gliomas (less than 20% of tumor cell density) are mistaken for normal brain tissue on FF-OCT images. However, in high-grade gliomas (Fig. 8G–K), the infiltration of the tumor has occurred to such an extent that the normal parenchyma architecture is lost. This architectural change is easily observed in FF-OCT and is successfully identified as high-grade glioma, even though the individual glial cell nuclei are not distinguished.
4. Discussion
We present here the first large size images (i.e. on the order of 1–3 cm2) acquired using an OCT system that offer spatial resolution comparable to histological analysis, sufficient to distinguish microstructures of the human brain parenchyma.
Firstly, the FF-OCT technique and the images presented here combine several practical advantages. The imaging system is compact, it can be placed in the operating room, the tissue sample does not require preparation and image acquisition is rapid. This technique thus appears promising as an intraoperative tool to help neurosurgeons and pathologists.
Secondly, resolution is sufficient (on the order of 1 μm axial and lateral) to distinguish brain tissue microstructures. Indeed, it was possible to distinguish neuron cell bodies in the cortex and axon bundles going towards white matter. Individual myelin fibers of 1 μm in diameter are visible on the FF-OCT images. Thus FF-OCT may serve as a real-time anatomical locator.
Histological architectural characteristics of meningothelial, fibrous, transitional and psammomatous meningiomas were easily recognizable on the FF-OCT images (lobules and whorl formation, collagenous-septae, calcified psammoma bodies, thick vessels). Psammomatous and transitional meningiomas presented distinct architectural characteristics in FF-OCT images in comparison to those observed in hemangiopericytoma. Thus, FF-OCT may serve as an intraoperative tool, in addition to extemporaneous examination, to refine differential diagnosis between pathological entities with different prognoses and surgical managements.
Diffuse glioma was essentially recognized by the loss of normal parenchyma architecture. However, glioma could be detected on FF-OCT images only if the glial cell density is greater than around 20% (i.e. the point at which the effect on the architecture becomes noticeable). The FF-OCT technique is therefore not currently suitable for the evaluation of low tumorous infiltration or tumorous margins. Evaluation at the individual tumor cell level is only possible by IDH1R132 immunostaining in IDH1 mutated gliomas in adults (Preusser et al., 2011). One of the current limitations of the FF-OCT technique for use in diagnosis is the difficulty in estimating the nuclear/cytoplasmic boundaries and the size and form of nuclei as well as the nuclear-cytoplasmic ratio of cells. This prevents precise classification into tumor subtypes and grades.
To increase the accuracy of diagnosis of tumors where cell density measurement is necessary for grading, perspectives for the technique include development of a multimodal system (Harms et al., 2012) to allow simultaneous co-localized acquisition of FF-OCT and fluorescence images. The fluorescence channel images in this multimodal system show cell nuclei, which increase the possibility of diagnosis and tumor grading direct from optical images. However, the use of contrast agents for the fluorescence channel means that the multimodal imaging technique is no longer non-invasive, and this may be undesirable if the tissue is to progress to histology following optical imaging. This is a similar concern in confocal microscopy where use of dyes is necessary for fluorescence detection (Wirth et al., 2012).
In its current form therefore, FF-OCT is not intended to serve as a diagnostic tool, but should rather be considered as an additional intraoperative aid in order to determine in a short time whether or not there is suspicious tissue present in a sample. It does not aim to replace histological analyses but rather to complement them, by offering a tool at the intermediary stage of intraoperative tissue selection. In a few minutes, an image is produced that allows the surgeon or the pathologist to assess the content of the tissue sample. The selected tissue, once imaged with FF-OCT, may then proceed to conventional histology processing in order to obtain the full diagnosis (Assayag et al., in press and Dalimier and Salomon, 2012).
Development of FF-OCT to allow in vivo imaging is underway, and first steps include increasing camera acquisition speed. First results of in vivo rat brain imaging have been achieved with an FF-OCT prototype setup, and show real-time visualization of myelin fibers (Ben Arous et al., 2011) and movement of red blood cells in vessels (Binding et al., 2011). To respond more precisely to surgical needs, it would be preferable to integrate the FF-OCT system into a surgical probe. Work in this direction is currently underway and preliminary images of skin and breast tissue have been captured with a rigid probe FF-OCT prototype (Latrive and Boccara, 2011).
In conclusion, we have demonstrated the capacity of FF-OCT for imaging of human brain samples. This technique has potential as an intraoperative tool for determining tissue architecture and content in a few minutes. The 1 μm3 resolution and wide-field down to cellular-level views offered by the technique allowed identification of features of non-tumorous and tumorous tissues such as myelin fibers, neurons, microcalcifications, tumor cells, microcysts, and blood vessels. Correspondence with histological slides was good, indicating suitability of the technique for use in clinical practice for tissue selection for biobanking for example. Future work to extend the technique to in vivo imaging by rigid probe endoscopy is underway.
The following are the supplementary data related to this article.
Video 1. Shows a movie composed of a series of en face 1 μm thick optical slices captured over 100 μm into the depth of the cortex tissue. The myelin fibers and neuronal cell bodies are seen in successive layers. Field size is 800 μm × 800 μm.
Video 2. Shows a fly-through movie in the reconstructed cross-sectional orientation showing 1 μm steps through a 3D stack down to 200 μm depth in cerebellum cortical tissue. Purkinje and granular neurons are visible as dark spaces. Field size is 800 μm × 200 μm.
Acknowledgments
The authors wish to thank LLTech SAS for use of the LightCT Scanner.
Sleep apnea and non-invasive positive pressure breathing
Curator: Larry H Bernstein, MD, FCAP
UPDATED on 10/24/2019
Researchers identify genetic variations linked to oxygen drops during sleep
“This study highlights the advantage of using family data in searching for rare variants, which is often missed in genome-wide association studies,” said James Kiley, Ph.D., director of the Division of Lung Diseases at NHLBI. “It showed that, when guided by family linkage data, whole genome sequence analysis can identify rare variants that signal disease risks, even with a small sample. In this case, the initial discovery was done with fewer than 500 samples.”
Notably, 51 of the 57 genetic variants influence and regulate human lung fibroblast cells, a type of cell producing scar tissue in the lungs, according to study author Xiaofeng Zhu, Ph.D., professor at the Case Western Reserve University School of Medicine, Cleveland.
“This is important because Mendelian Randomization analysis, a statistical approach for testing causal relationship between an exposure and an outcome, shows a potential causal relationship between how the DLC1 gene modifies fibroblasts cells and the changes in oxygen levels during sleep,” he said.
Obstructive sleep apnea is caused by a blockage of the airway. This may occur when the soft tissue in the rear of the throat collapses and closes during sleep. Sleep apnea causes SNORING, intermittent cessation of breathing during sleep, which the person having the sleep disturbance may be unaware of. This results in reawaking and restless sleep, and concomitantly, daytime fatigue. Obstructive sleep apnea accounts for 85% of cases. According to some studies, one in every 15 Americans is affected by this condition, and only a small percentage of them get treated.
Treatment(s)
Weight loss and diabetic control might be sufficient for some who have a mild condition. There are also breathing exercises, and the placement of an orthodontic specially fitted mouth guard that flattens the posterior mouth during sleep. Those who have moderate to severe sleep apnea may require assisted beathing during sleep, or surgery. The standard treatments are CPAP (continuous positive airway pressure ) or BiPAP (Bilevel positive airway pressure), the first being most commonly used. However, the effectiveness is influenced by body positioning during sleep. Many patients are unable to adjust to the CPAP mask, which has to fit snugly over the mouth and nose.
A recently introduced surgical procedure that has gained wide use is transoral robotic surgery (TORS).
The use of da Vinci® robot-assisted surgery for treatment of obstructive sleep apnea is revolutionary due to the minimally invasive nature of the procedure. The surgeon guides the robotic arms in through the patient’s mouth, and a high-definition [3D] camera allows the surgeon to perfectly visualize areas of the mouth and throat without any open incisions. The surgery focuses on reducing the size of the base of the tongue. Patients are assessed during an in-office examination, which includes a review of recent sleep studies, and an evaluation with a scope to identify the level and nature of obstruction.
The sleep apnea procedure (TORS) involves the actual surgery and a 1-2 day hospital stay after the surgery. Full recovery is expected to take about three weeks. A sleep study is then conducted about three months after surgery to ensure that the procedure was successful.
About CPAP
Continuous positive airway pressure or CPAP is used both in hospitals for newborn babies or those who suffer from respiratory failure, and in the home. The device works by increasing pressure in the airway, preventing collapse while breathing in. The CPAP machine has tubing, a setting for the pressure, and a mask that covers the mouth and nose, delivering the air pressure into the nasal passages. The right air pressure for a patient is prescribed by the sleep physician after conducting a detailed overnight study of the patient’s breathing pattern. Such a prescribed air pressure is termed as ‘titrated pressure’. The CPAP machine, set at the prescribed air pressure , blows air at the titrated pressure, maintaining the air passage open for uninterrupted breathing during sleep.
CPAP Side Effects
Nasal Congestion: Use of CPAP machines may cause nasal congestion. Some patients may experience nasal irritation or a runny nose too. This is because of the fact that the nose humidifies the air that passes through it and the air from CPAP machine dries up the nose. The body reacts by producing more mucus in the nose, which leads to nasal congestion. In some patients, there will be no mucus production and this results in dry nose, which cause nasal irritation, burning or sneezing. CPAP machines with inbuilt humidifier may help you address this problem. Other problems are ear pressure and difficulty from a deviated nasal septum.
CPAP Alternatives
Only 23% of individuals suffering from sleep apnea succeed in getting used to CPAP. A popular alternative to this machine are the intraoral dental appliances that consist of two U-shaped plates that are joined to form a hinge. These can be custom-made by a dentist or an orthodontist. It adjusts the lower jaw and tongue of a user, so that the air passage does not collapse while sleeping. There are lingual tabs that hold the appliance in place.
CPAP Vs. BiPAP – Difference between CPAP and BiPAP
The Continuous Positive Airway Pressure (CPAP) machine gives a predetermined level of pressure. It releases a gust of compressed air through a hose which is connected to the nose mask. The continuous air pressure is what keeps the upper airway open. Thus, air pressure prevents obstructive sleep apnea, which occurs as a result of narrowing of the air passage due to the relaxation of upper respiratory tract muscles while the patient sleeps. It assists in increasing the flow of oxygen by keeping the airway open.
The Bilevel Positive Airway Pressure (BiPAP) is a patented, non-invasive ventilation machine. As the name suggest, it delivers two levels of pressure. Inspiratory Positive Airway Pressure (IPAP) is a high level of pressure, applied when the patient inhales. Expiratory Positive Airway Pressure (EPAP), a low level of pressure exerted during exhalation. BiPAP is used to treat central sleep apnea and severe obstructive sleep apnea, and It is prescribed for patients who suffer from respiratory and heart diseases.
Patients using the CPAP have to exert extra force against the air flow while exhaling, whereas with the BiPAP, the airway pressure is set at high and low levels, making it more user-friendly.
Relationship of sleep apnea syndrome to other complicating conditions
Sixteen of 22 obese diabetics of an apneic cohort had severe and six had moderate obstructive sleep apnea syndrome. The cohort had an average of 44.6 + 21.9 apneic or hypopneic events per hour averaging 23.3 + 5.9 seconds, with oxygen saturation of 73.5 + 9.5% (normal 94%). The patients had retinopathy manifesting multiple nerve-fiber layer infarcts, at least 3 in each eye, and more than 6 infarcts in most eyes, with microvascular leakage and macular edema. This finding was rare among the cohort without sleep apnea.
Laparoscopic surgery has been associated with ventilator complications, contingent on cardiac and respiratory comorbidities, and body habitus., particularly morbidly obese patients receiving general anesthesia. The EZ PAP positive airway pressure system is an easily used, disposable device that delivers CPAP air flow from an oxygen flow meter, and has been predicted to improve oxygenation, reducxe CO2 retention, and lower the risk of respiratory complications postoperatively. Patients in the EZ PAP group demonstrated improvement in ventilator effort in the first few hours postoperatively, but the measured benefit did not exceed 4 hours. Interventions must be aimed at improvement for longer periods.
Sleep apnea is well documented to negatively affect neurocognitive and neuropsychiatric functioning, including memory, attention, mood, and anxiety. It has been identified as a risk for developing Alzheimer’s disease, and TBI (traumatic brain injury) is a risk factor for developing dementia, expetially in those with the apolipoprotein epsilon 4 allele. The majority of sleep apnea are male and TBI is common in veterans of combat, the increased incidence of sleep disordered breathing in TBI patients (SDB in TBI in 50-70% of patients) is of interest to the Department of Veterans Affairs. A recent review by O’Hara et al. found that sleep apnea interacted with APOE ε4 and carried increased risk for poor cognitive performance. Moreover, SNPs within the APOE gene (rs157580, rs405509, rs769455, and rs7412) all showed associations with OSA in children, with age and BMI as covariates. This suggests that the interaction between TBI, OSA, and APOE genotype is quite complex. Studies indicate that CPAP/BiPAP can be effective in reducing the sleep apnea and the cognitive sequelae. The question is raised as to whether the treatment of OSA might only target APOE ε4 carriers, but it is important to recognize that chronic pulmonary disease that increases hypoxia would factor in.
Treatment of Obstructive Sleep Apnea Reduces the Risk of Atrial Fibrillation Recurrence After Catheter Ablation
Objectives The aim of this study was to examine the effect of continuous positive airway pressure (CPAP) therapy on atrial fibrillation (AF) recurrence in patients with obstructive sleep apnea (OSA) undergoing pulmonary vein isolation (PVI).
Background OSA is a predictor of AF recurrence following PVI, but the impact of CPAP therapy on PVI outcome in patients with OSA is unknown.
Methods Among 426 patients who underwent PVI between 2007 and 2010, 62 patients had a polysomnography-confirmed diagnosis of OSA. While 32 patients were “CPAP users” the remaining 30 patients were “CPAP nonusers.” The recurrence of any atrial tachyarrhythmia, use of antiarrhythmic drugs, and need for repeat ablations were compared between the groups during a follow-up period of 12 months. Additionally, the outcome of patients with OSA was compared to a group of patients from the same PVI cohort without OSA.
Results CPAP therapy resulted in higher AF-free survival rate (71.9% vs. 36.7%; p = 0.01) and AF-free survival off antiarrhythmic drugs or repeat ablation following PVI (65.6% vs. 33.3%; p = 0.02). AF recurrence rate of CPAP-treated patients was similar to a group of patients without OSA (HR: 0.7, p = 0.46). AF recurrence following PVI in CPAP nonuser patients was significantly higher (HR: 2.4, p < 0.02) and similar to that of OSA patients managed medically without ablation (HR: 2.1, p = 0.68).
Conclusions CPAP is an important therapy in OSA patients undergoing PVI that improves arrhythmia free survival.
Comment: . The current study extends similar benefits to those undergoing catheter ablation to those undergoing elective cardioversion of atrial fibrillation with a better long term success when OSA patients are treated with CPAP.
A putative relationship between OSA and diabetic macular edema associated with optic nerve fiber layer infarcts.
Unver YB, Yavuz GSA, Stafford CA, Sinclair SH.
The Open Sleep Journal 2009;2:11-19. 1874-6209/09 http://www.benthamscience.com/open/toslpj/articles/V002/11TOSLPJ.pdf
Continuous positive airway pressure devices for the treatment of obstructive sleep apnea-hypopnea syndrome: a systematic review and economic analysis.
McDaid C, Griffin S, Weatherly H, Duree K, et al.
High Technology Assessment 2009; 13(4):1-136 http://dx.doi.org/10.3310/hta13040
Sleep apnea, apolipoprotein epsilon 4 allele, and TBI: Mechanism for cognitive dysfunction and development of dementia.
O’Hara R, Luzon A, Hubbard J, Zeitzer JM.
J Rehab Res Develop 2009; 46(6):837-850. http://dx.doi.org/10.1682/JRRD.2008.10.0140
English: The Cycle of Obstructive Sleep Apnea – OSA (Photo credit: Wikipedia)
English: This is my own machine of which I took the picture. (Photo credit: Wikipedia)
Young Innovator Develops bCPAP to Save Babies Lives (Photo credit: USAID_IMAGES)
English: Medical report showing the duration and frequency of sleep apnea of a test subject. Duration and frequencies are sorted by the sleeper’s position in bed. Français : Analyse de la durée et du nombre d’apnées en fonction de la position du dormeur. (Photo credit: Wikipedia)
In a previous posting I commented on the problem of hs cTn use and the on site ED performance of cardiac treadmill (done in Europe)
prior to a decision of CT scan (not done in US).
Acute Chest Pain/ER Admission: Three Emerging Alternatives to Angiography and PCI – Corus CAD, hs cTn, CCTA
We examine the emergence of Alternatives to Angiography and PCI as most common strategy for ER admission with listed cause of Acute Chest Pain. The Goal is to use methods that will improve the process to identify for an Interventional procedure only the patients that a PCI is a must to have.
Alternative #1: Corus® CAD
Alternative #2: High-Sensitivity Cardiac Troponins in Acute Cardiac Care
Alternative #3: Coronary CT Angiography for Acute Chest Pain
After presenting the the Three alternatives, the Editorial by R.F. Redberg, Division of Cardiology, UCSF, will be analyzed.
Alternative #1: First-Line Test to Help Clinicians Exclude Obstructive CAD as a Cause of the Patient’s Symptoms
Corus® CAD, a blood-based gene expression test, demonstrated high accuracy with both a high negative predictive value (96 percent) and high sensitivity (89 percent) for assessing obstructive coronary artery disease (CAD) in a population of patients referred for stress testing with myocardial perfusion imaging (MPI).
COMPASS enrolled stable patients with symptoms suggestive of CAD who had been referred for MPI at 19 U.S. sites. A blood sample was obtained in all 431 patients prior to MPI and Corus CAD gene expression testing was performed with study investigators blinded to Corus CAD test results.Following MPI, patients underwent either invasive coronary angiography orcoronary CT angiography, gold-standard anatomical tests for the diagnosis of coronary artery disease.
Alternative #2: High-Sensitivity Cardiac Troponins in Acute Cardiac Care
Recommendations for the use of cardiac troponin (cTn) measurement in acute cardiac care have recently been published.[1] Subsequently, a high-sensitivity (hs) cTn T assay was introduced into routine clinical practice.[2] This assay, as others, called highly sensitive, permits measurement of cTn concentrations in significant numbers of apparently illness-free individuals. These assays can measure cTn in the single digit range of nanograms per litre (=picograms per millilitre) and some research assays even allow detection of concentrations <1 ng/L.[2–4] Thus, they provide a more precise calculation of the 99th percentile of cTn concentration in reference subjects (the recommended upper reference limit [URL]). These assays measure the URL with a coefficient of variation (CV) <10%.[2–4]The high precision of hs-cTn assays increases their ability to determine small differences in cTn over time. Many assays currently in use have a CV >10% at the 99th percentile URL limiting that ability.[5–7] However, the less precise cTn assays do not cause clinically relevant false-positive diagnosis of acute myocardial infarction (AMI) and a CV <20% at the 99th percentile URL is still considered acceptable.[8]
We believe that hs-cTn assays, if used appropriately, will improve clinical care. We propose criteria for the clinical interpretation of test results based on the limited evidence available at this time.
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4. Todd J, Freese B, Lu A, Held D, Morey J, Livingston R, Goix P. Ultrasensitive flow based immunoassays using single-molecule counting. Clin Chem 2007; 53:1990–1995.
5. van de Kerkhof D, Peters B, Scharnhorst V. Performance of Advia Centaur second-generation troponin assay TnI-Ultra compared with the first-generation cTnI assay. Ann Clin Biochem 2008; 45:316–317.
6. Lam Q, Black M, Youdell O, Spilsbury H, Schneider HG. Performance evaluation and subsequent clinical experience with the Abbott automated Architect STAT Troponin-I assay. Clin Chem 2006; 52:298–300.
7. Tate JR, Ferguson W, Bais R, Kostner K, Marwick T, Carter A. The determination of the 99th percentile level for troponin assays in an Australian reference population. Ann Clin Biochem 2008; 45:275–288.
8. Jaffe AS, Apple FS, Morrow DA, Lindahl B, Katus HA. Being rational about (im)-precision: a statement from the Biochemistry Subcommittee of the Joint European Society of Cardiology/American College of Cardiology Foundation/American Heart Association/World Heart Federation Task Force for the definition of myocardial infarction. Clin Chem 2010; 56:921–943.
Hoffmann et al. (July 26 issue)1 conclude that, among patients with low-to-intermediate-risk acute coronary syndromes, the incorporation of coronary computed tomographic angiography (CCTA) improves the standard evaluation strategy.2 However, it may be difficult to generalize their results, owing to different situations on the two sides of the Atlantic and the availability of high-sensitivity troponin T assays in Europe. In the United States, the Food and Drug Administration has still not approved a high-sensitivity troponin test, and patients in the Rule Out Myocardial Infarction/Ischemia Using Computer Assisted Tomography (ROMICAT-II) trial only underwent testing with the conventional troponin T test. As we found in the biomarker substudy in the ROMICAT-I trial, a single high-sensitivity troponin T test at the time of CCTA accurately ruled out acute myocardial infarction (negative predictive value, 100%) (Table 1TABLE 1Results of High-Sensitivity Troponin T Testing for the Diagnosis of Acute Coronary Syndromes in ROMICAT-I.).3 In addition, patients with acute myocardial infarction can be reliably identified, with up to 100% sensitivity, with the use of two high-sensitivity measurements of troponin T within 3 hours after admission.4,5
It seems plausible to assume that the incorporation of high-sensitivity troponin T assays in this trial would have outperformed CCTA. Therefore, it is important to assess the performance of such testing and compare it with routine CCTA testing in terms of length of stay in the hospital and secondary end points, especially cumulative costs and major adverse coronary events at 28 days.
Januzzi JL Jr, Bamberg F, Lee H, et al. High-sensitivity troponin T concentrations in acute chest pain patients evaluated with cardiac computed tomography. Circulation2010;121:1227-1234
Keller T, Zeller T, Ojeda F, et al. Serial changes in highly sensitive troponin I assay and early diagnosis of myocardial infarction. JAMA 2011;306:2684-2693
Thygesen K, Mair J, Giannitsis E, et al. How to use high-sensitivity cardiac troponins in acute cardiac care. Eur Heart J 2012;33:2252-2257
Author/Editor Response
In response to Karakas and Koenig: we agree that high-sensitivity troponin T assays may permit more efficient care of low-risk patients presenting to the emergency department with acute chest pain1 and may also have the potential to identify patients with unstable angina because cardiac troponin T levels are associated with the degree and severity of coronary artery disease.2 Hence, high-sensitivity troponin T assays performed early may constitute an efficient and safe gatekeeper for imaging. CCTA, however, may be useful for ruling out coronary artery disease in patients who have cardiac troponin T levels above the 99th percentile but below levels that are diagnostic for myocardial infarction. The hypothesis that high-sensitivity troponin T testing followed by CCTA, as compared with other strategies, may enable safe and more efficient treatment of patients in the emergency department who are at low-to-moderate risk warrants further assessment. The generalizability of our data to clinical settings outside the United States may also be limited because of differences in the risk profile of emergency-department populations and the use of nuclear stress imaging.3
Udo Hoffmann, M.D., M.P.H.
Massachusetts General Hospital, Boston, MA uhoffmann@partners.org
W. Frank Peacock, M.D.
Baylor College of Medicine, Houston, TX
James E. Udelson, M.D.
Tufts Medical Center, Boston, MA
Since publication of their article, the authors report no further potential conflict of interest.
Than M, Cullen L, Reid CM, et al. A 2-h diagnostic protocol to assess patients with chest pain symptoms in the Asia-Pacific region (ASPECT): a prospective observational validation study. Lancet 2011;377:1077-1084
Januzzi JL Jr, Bamberg F, Lee H, et al. High-sensitivity troponin T concentrations in acute chest pain patients evaluated with cardiac computed tomography. Circulation2010;121:1227-1234
Alternative #3: Coronary CT Angiography for Acute Chest Pain
The Study concluded:
There was increased diagnostic testing and higher radiation exposure in the CCTA group, with no overall reduction in the cost of care.
Coronary CT Angiography versus Standard Evaluation in Acute Chest Pain
Udo Hoffmann, M.D., M.P.H., Quynh A. Truong, M.D., M.P.H., David A. Schoenfeld, Ph.D., Eric T. Chou, M.D., Pamela K. Woodard, M.D., John T. Nagurney, M.D., M.P.H., J. Hector Pope, M.D., Thomas H. Hauser, M.D., M.P.H., Charles S. White, M.D., Scott G. Weiner, M.D., M.P.H., Shant Kalanjian, M.D., Michael E. Mullins, M.D., Issam Mikati, M.D., W. Frank Peacock, M.D., Pearl Zakroysky, B.A., Douglas Hayden, Ph.D., Alexander Goehler, M.D., Ph.D., Hang Lee, Ph.D., G. Scott Gazelle, M.D., M.P.H., Ph.D., Stephen D. Wiviott, M.D., Jerome L. Fleg, M.D., and James E. Udelson, M.D. for the ROMICAT-II Investigators
It is unclear whether an evaluation incorporating coronary computed tomographic angiography (CCTA) is more effective than standard evaluation in the emergency department in patients with symptoms suggestive of acute coronary syndromes.
METHODS
In this multicenter trial, we randomly assigned patients 40 to 74 years of age with symptoms suggestive of acute coronary syndromes but without ischemic electrocardiographic changes or an initial positive troponin test to early CCTA or to standard evaluation in the emergency department on weekdays during daylight hours between April 2010 and January 2012. The primary end point was length of stay in the hospital. Secondary end points included rates of discharge from the emergency department, major adverse cardiovascular events at 28 days, and cumulative costs. Safety end points were undetected acute coronary syndromes.
RESULTS
The rate of acute coronary syndromes among 1000 patients with a mean (±SD) age of 54±8 years (47% women) was 8%. After early CCTA, as compared with standard evaluation, the mean length of stay in the hospital was reduced by 7.6 hours (P<0.001) and more patients were discharged directly from the emergency department (47% vs. 12%, P<0.001). There were no undetected acute coronary syndromes and no significant differences in major adverse cardiovascular events at 28 days. After CCTA, there was more downstream testing and higher radiation exposure. The cumulative mean cost of care was similar in the CCTA group and the standard-evaluation group ($4,289 and $4,060, respectively; P=0.65).
CONCLUSIONS
In patients in the emergency department with symptoms suggestive of acute coronary syndromes, incorporating CCTA into a triage strategy improved the efficiency of clinical decision making, as compared with a standard evaluation in the emergency department, but it resulted in an increase in downstream testing and radiation exposure with no decrease in the overall costs of care. (Funded by the National Heart, Lung, and Blood Institute; ROMICAT-II ClinicalTrials.gov number, NCT01084239.)
Roe MT, Harrington RA, Prosper DM, et al. Clinical and therapeutic profile of patients presenting with acute coronary syndromes who do not have significant coronary artery disease. Circulation 2000;102:1101-1106
Miller JM, Rochitte CE, Dewey M, et al. Diagnostic performance of coronary angiography by 64-row CT. N Engl J Med 2008;359:2324-2336
Budoff MJ, Dowe D, Jollis JG, et al. Diagnostic performance of 64-multidetector row coronary computed tomographic angiography for evaluation of coronary artery stenosis in individuals without known coronary artery disease: results from the prospective multicenter ACCURACY (Assessment by Coronary Computed Tomographic Angiography of Individuals Undergoing Invasive Coronary Angiography) trial. J Am Coll Cardiol 2008;52:1724-1732
Marano R, De Cobelli F, Floriani I, et al. Italian multicenter, prospective study to evaluate the negative predictive value of 16- and 64-slice MDCT imaging in patients scheduled for coronary angiography (NIMISCAD-Non Invasive Multicenter Italian Study for Coronary Artery Disease). Eur Radiol 2009;19:1114-1123
Meijboom WB, Meijs MF, Schuijf JD, et al. Diagnostic accuracy of 64-slice computed tomography coronary angiography: a prospective, multicenter, multivendor study. J Am Coll Cardiol 2008;52:2135-2144
Hoffmann U, Bamberg F, Chae CU, et al. Coronary computed tomography angiography for early triage of patients with acute chest pain: the ROMICAT (Rule Out Myocardial Infarction using Computer Assisted Tomography) trial. J Am Coll Cardiol 2009;53:1642-1650
Hollander JE, Chang AM, Shofer FS, et al. One-year outcomes following coronary computerized tomographic angiography for evaluation of emergency department patients with potential acute coronary syndrome. Acad Emerg Med 2009;16:693-698
Rubinshtein R, Halon DA, Gaspar T, et al. Usefulness of 64-slice cardiac computed tomographic angiography for diagnosing acute coronary syndromes and predicting clinical outcome in emergency department patients with chest pain of uncertain origin. Circulation2007;115:1762-1768
Schlett CL, Banerji D, Siegel E, et al. Prognostic value of CT angiography for major adverse cardiac events in patients with acute chest pain from the emergency department: 2-year outcomes of the ROMICAT trial. JACC Cardiovasc Imaging 2011;4:481-491
Goldstein JA, Chinnaiyan KM, Abidov A, et al. The CT-STAT (Coronary Computed Tomographic Angiography for Systematic Triage of Acute Chest Pain Patients to Treatment) trial. J Am Coll Cardiol 2011;58:1414-1422
Litt HI, Gatsonis C, Snyder B, et al. CT angiography for safe discharge of patients with possible acute coronary syndromes. N Engl J Med 2012;366:1393-1403
Shreibati JB, Baker LC, Hlatky MA. Association of coronary CT angiography or stress testing with subsequent utilization and spending among Medicare beneficiaries. JAMA2011;306:2128-2136
Hoffmann U, Truong QA, Fleg JL, et al. Design of the Rule Out Myocardial Ischemia/Infarction Using Computer Assisted Tomography: a multicenter randomized comparative effectiveness trial of cardiac computed tomography versus alternative triage strategies in patients with acute chest pain in the emergency department. Am Heart J2012;163:330-338
Abbara S, Arbab-Zadeh A, Callister TQ, et al. SCCT guidelines for performance of coronary computed tomographic angiography: a report of the Society of Cardiovascular Computed Tomography Guidelines Committee. J Cardiovasc Comput Tomogr 2009;3:190-204
Gerber TC, Carr JJ, Arai AE, et al. Ionizing radiation in cardiac imaging: a science advisory from the American Heart Association Committee on Cardiac Imaging of the Council on Clinical Cardiology and Committee on Cardiovascular Imaging and Intervention of the Council on Cardiovascular Radiology and Intervention. Circulation 2009;119:1056-1065
von Ballmoos MW, Haring B, Juillerat P, Alkadhi H. Meta-analysis: diagnostic performance of low-radiation-dose coronary computed tomography angiography. Ann Intern Med2011;154:413-420[Erratum, Ann Intern Med 2011;154:848.]
Achenbach S, Marwan M, Ropers D, et al. Coronary computed tomography angiography with a consistent dose below 1 mSv using prospectively electrocardiogram-triggered high-pitch spiral acquisition. Eur Heart J 2010;31:340-346
Than M, Cullen L, Reid CM, et al. A 2-h diagnostic protocol to assess patients with chest pain symptoms in the Asia-Pacific region (ASPECT): a prospective observational validation study. Lancet 2011;377:1077-1084
In the EDITORIAL by Redberg RF. Dr. Redberg, Cardiology Division, UCSF made the following points in:
Six million people present to ER annually with Acute Chest Pain, most have other diseases that Heart.
Current diagnostic methods lead to admission to the hospital, unnecessary stays and over-treatment – improvement of outcomes is needed.
Rule Out Myocardial Infarction Using Computer Assisted Tomography II (ROMICAT-II) 100 patients were randomly assigned to CCTA group or Standard Diagnosis Procedures Group in the ER which involved Stress Test in 74%.
CRITIQUE and Study FLAWS in MGH Study:
ROMICAT-II enrolled patients only during “weekday daytime hours, no weekend or nights when the costs are higher.
Assumption that a diagnostic test must be done before discharge for low-to-intermediate-risk patients is unproven and probably unwarranted.. No evidence that the tests performed let to improved outcomes.
Events rate for patient underwent CCTA, Stress test or no testing at al were less that 1% to have an MI, no one died. Thus, it is impossible to assign a benefit to the CCTA Group. So very low rates were observed in other studies
CCTA patients were exposed to substantial dose of Radiation, , contrast die,
Patients underwent ECG and Negative Troponin, no evidence that additional testing further reduced the risk.
Average age of patients: 54, 47% women.Demographic Characteristics with low incidence of CAD, NEJM, 1979; 300:1350-8
Risk of Cancer from radiation in younger population is higher, same in women.
Hoffmann’s Study: Radiation burden was clinically significant: Standard Evaluation Group: (4.7+-8.4 mSv), CCTA: (13.9+-10.4 mSv), exposure of 10 mSv have been projected to lead to 1 death from Cancer per 2000 persons, Arch Intern Med 2009; 169:2071-7
Middle Age women, increased risk of Breast Cancer from radiation, Arch Intern Med 2012 June 11 (ePub ahead of Print)
ROMICAT-II study: discharge diagnosis Acute Coronary Syndrome – less than 10%
CCTA Group: more tests, more radiation, more interventions tht the standard-evaluation group.
Choose Wisely Campaign – order test only when the benefit will exceed the risks
Dr. Redberd advocates ECG and Troponin, if NORMAL, no further testing.
Epicrisis on Part 1
Redberg’s conclusions are correct for the initial screening. The issue has been whether to do further testing for low or intermediate risk patients.
The most intriguing finding that is not at all surprising is that the CCTA added very little in the suspect group with small or moderate risk. My original studies using a receiver operator characteristic curve were very good, although some patients with CRF or ESRD had extremely high values. The ultra sensitive troponin threw the Area Under the ROC out the window, under the assumption that a perfect assay would exclude AMI, or any injury to the heart. The improved assay does pick up minor elevations of troponin in the absence of MI as a result of plaque rupture. It is possible that 50% of these elevations need medical attention, but then the question is an out of hospital referral or admission and further workup. I have discussed this at some length on several occasions with Dr. Jaffe at Mayo Clinic.
Many of those with minor or intermediate elevation have significant renal insufficiency, but they might also be in CKD Class 3 and not 1 or 2. The coexistence of Type 2 diabetes would go into the standard assessment, but is not mentioned in the study with respect to immediate admission or outcome 28 days after discharge.
The hs troponin I has been in daily use on the Ortho J&J (formerly Kodak) for about 2 years, and the QC standards are very high. I expected the Roche hs-TnT assay to be in use in US as well, but there may have been delays. Januzzi , Jaffe, and Fred Aplle would be involved in the evaluation in the US, but Paul Collinson in UK, Katus and Mair in Germany, and other Europena centers certainly have been using the Roche Assay.
The biggest problem in these studies is as my mentor called my attention to – the frontrunners aren’t going to support a nose-to-nose up front study. Given that a diagnosis requires more information at minimal cost, especially when diagnosis of the heart that are not MI have to be evaluated as well, it is incomprehensibe to me that such information as
mean arterial blood pressure,
natriuretic peptides,
the calculated EGFR are not used in the evaluation.
It is quite impossible to clear the deck when you have patients who don’t have
ST elevation,
depression, or
T-wave inversion who are seen for vague
(not to mention long QT abnormalities).
predordial tightness or shortness of breath
pain that resembles gall bladder.
Is this an indication of the obsolescence of the RCT.
A Retrospective Quality and Cost Driven Audit on Effect of hs cTn Assay with On-Site CT Followup. (No treadmill availability)
A retrospective multisite study showed that doing the hs cTn followed by CT on-site was a good choice for US.
I also considered the selective release of
low- moderate-risk patients cardiology followup in a timely manner.
This report is an excellent analysis of my point by Korley and Jaffe in Medscape, and satisfies some several years discussion
I have had with Dr. Jaffe, at Mayo Clinic. He pointed out the importance of
Type 1 and Type 2 AMI
at a discussion with Dr. Fred Apple at a meeting of the Amer Assn for Clinical Chemistry that he fully elaborates on here.
It is really a refinement of other proposals that are being discussed. It is also timely because hs cTnI is already being used
widely in the US, while there might be a holdup on the hs cTnT.
Highlights
Need for a Universally Accepted Nomenclature
Defining Uniform Criteria for Reference Populations
Discriminating Between Acute and Nonacute Causes of hs-cTn Elevations
Distinguishing Between Type 1 and Type 2 AMI
Analytical Imprecision in Cardiac Troponin Assays
Ruling Out AMI
Investigating the Causes of Positive Troponin Values in Non-AMI Patients
Risk Stratifying Patients With Nonacute Coronary Syndrome Conditions
Conclusions
Abstract
It is only a matter of time before the use of high-sensitivity cardiac
troponin assays (hs-cTn) becomes common throughout the United
States. In preparation for this inevitability, this article raises a number
of important issues regarding these assays that deserve consideration.
These include: the need for
the adoption of a universal nomenclature; the importance
of defining uniform criteria for reference populations;
the challenge of discriminating between acute and nonacute
causes of hs-cTn elevations, and
factors influencing the analytical precision of hs-cTn;
ascertaining the optimal duration of the rule-out period for AMI;
the need for further evaluation to determine the causes
of a positive hs-cTn in non-AMI patients; and
the use of hs-cTn to risk-stratify patients with disease conditions
other than AMI.
This review elaborates on these critical issues as a means of
educating clinicians and researchers about them.
Introduction
Recently, clinicians have begun to use the recommended cut-off values
for current generation cardiac troponin (cTn) assays:
the 99th percentile upper reference limit (URL).
Previously, there was reluctance to use these cut-off values because
of cTn elevations from non-acute ischemic heart disease conditions.
Thus, there was a tendency to use cut-off values for troponin that equated with the
prior gold standard diagnosis developed with less sensitive markers
creatinine kinase-MB isoenzyme (CK-MB) or
the lowest value at which assay achieved a 10%
coefficient of variation (CV),
which would reduce false-positive elevations (without plaque rupture).
The use of the 99th percentile URL increases the ability of these assays to detect both
acute myocardial infarction (AMI) and
structural cardiac morbidities.[1]
This change in practice should not be confused with
newer-generation high-sensitivity assays.
Improvements in the analytic performance of cTn assays have resulted in
superior sensitivity and precision.
Improved sensitivity occurs because of
more sensitive antigen binding and detection antibodies,
increases in the concentration of the detection probes on the tag antibodies,
increases in sample volume, and buffer optimization.[2]
Assays now are able to measure
10-fold lower concentrations with high precision
(a CV <10% at the 99th percentile of the URL).
The high-sensitivity cardiac troponin T (hs-cTnT) assay is already in clinical use
throughout most of the world. It is only a matter of time before high- sensitivity
assays are approved for use in the United States. In preparation for this, as well as
using the 99th percentile URL with contemporary assays,
there are a number of important issues that deserve consideration. Key concepts are included in (Table 1).
Table 1: Key ConceptsThere is a need to develop a universal nomenclature for troponin assays.There is a need for uniform criteria for selecting reference populations.The optimal delta criteria for distinguishing between acute and chronic cardiac injury remain unclear and are likely to be assay-specific.Distinguishing between type 1 and type 2 AMI is challenging, and more type 2 AMIs will be detected with hsTn assays.Factors affecting the analytical precision of troponin assays (including how we collect samples) will become more important with the use of hs-cTn assays.The optimal duration for ruling out AMI remains unclear;
novel approaches to this issue are being developed.
Elevated hs-cTn, regardless of the cause, has important
prognostic implications and deserves additional evaluation;
Many cases of chronic elevations can be evaluated in an outpatient setting.
Hs-cTn can be used to
risk-stratify patients with non-ACS cardiovascular comorbidities.
Need for a Universally Accepted Nomenclature
The literature is replete with terms used to refer to cTn assays.
We advocate the use of the term “high-sensitivity cardiac troponin assays” (hs-cTn) for
cTn assays that v measure cardiac troponin values in
in at least 50% of a reference population.[2,3]
This policy has now been embraced by the journal Clinical Chemistry. High-sensitivity
assays can be further categorized as well (Table 2) with respect to generations of cTn.
Table 2. Classification of High-Sensitivity Cardiac Troponin Assays
Category
Description
First Generation Able to measure cTn in
50%–75% of a reference population
Second Generation Able to measure cTn in
75%–95% of a reference population
Third Generation Able to measure cTn in > 95% a reference population
Adapted from Apple and Collinson (3)
Ideally, assays should have a CV of <10% at the 99th percentile value.
Assays that do not achieve this level are less sensitive which protects against
false-positive results, and they can be used.[4]
Defining Uniform Criteria for Reference Populations There is a lack of consistency in the types and numbers of subjects that constitute a reference
population.[2] Often, participants are included after simple screening by check list but without a
physical examination,
electrocardiogram, or
laboratory testing.
At other times, a
normal creatinine and/or a normal natriuretic peptide value is required.
Imaging to detect structural heart disease is rarely used.
Because it is known that
gender,
age,
race,
renal function,
heart failure, and
structural heart disease, including
increased left ventricular (LV) mass
are associated with increased cTn concentrations,[5,6,7] An assay’s 99th percentile value depends on the composition of the reference group. Thus, the more criteria used, the lower the reference values (Figure 1).[5]
LVEF > 50%; normal lung function; and no significant
valvular heart disease,
LVH,
diastolic HF, or
regional wall-motion abnormalities on ECHO.
The appropriate reference value to use clinically also is far from a settled issue.
It might be argued that
using a higher 99th percentile value for the elderly
allows comparison of the patient to his or her peers, but
in raising the cut-off value, if the increases are caused by comorbidities,
those who are particularly healthy will be disadvantaged.[8]
Gender and ethnicity are not comorbidities, and we would urge that those should be taken into account.
Regardless of the assay, there will need to be
99th percentile values for men that are different for women.[2]
The reference population for assay validation studies should ideally be based on –
demographic characteristics that mirror the U.S. population and include subjects whose
blood pressure,
serum glucose, and
creatinine and
natriuretic peptide values are
within the normal reference range and
who take no cardiac medications.
These subjects should be
free from structural heart disease,
documented by echocardiography,
cardiac magnetic resonance imaging (MRI) or
computed tomography (CT) angiography.
Meeting these criteria will be a major challenge, especially for older individuals.
A conjoint pool of samples collected with manufacturers’ support so that all methods were derived from an
identical patient population for their reference ranges would be ideal.
[However, the method of collection and possible freeze-thaw effects is unavoidable].
One large national effort might be advantageous over multiple efforts.
Discriminating Between Acute and Nonacute Causes of hs-cTn Elevations
With the ability to precisely measure small concentrations of cTn,
clinicians will be faced with the challenge of distinguishing patients
who have acute problems from those with chronic elevations from other causes.
Using the fourth-generation cTnT assay, approximately 0.7% of patients in
the general population have modest elevations >99th percentile URL.[11]
In the same population, this number was 2% with the hs-cTnT assay.[6] Only
half of them had documentation (even with imaging) of cardiac abnormalities.
If the prevalence of a positive cTnT is 2% in the general population,
it will likely be 10% or 20% in the emergency department (ED)
and even higher in hospitalized patients, as
these patients often have cardiac comorbidities.
Measurement of changes in hs-cTn over time (δ hs-cTn)
improves the specificity of hs-cTn for the diagnosis of acute cardiac injury.[12,13]
However, it does so at the cost of sensitivity. With contemporary assays, differences
in analytical variation have been used to define an increasing pattern.
At elevated values, CV for most assays is in the range of 5% to 7%, so
a change of 20% ensures that a given change is not caused
by analytical variation alone.[10]
At values near the 99th percentile URL, higher change values are necessary.[13] The situation with hs-cTn assays is much more complex, as follows:
1. Change criteria are unique for each assay.
2. It will be easy to misclassify patients with coronary artery disease who may present with a noncardiac cause of chest pain
but have elevated values.
They could be having unstable ischemia or elevations caused by structural cardiac abnormalities and noncardiac discomfort.
If hs-cTn is rising significantly, the issue is easy but
if the values are not rising, a diagnosis of AMI still might be made.
If so, some patients may be included as having AMI without a changing pattern.
This occurred in 14% patients studied by Hammarsten et al.[14]
If patients with elevated hs-cTn without a changing pattern are not called AMI,
should they be called patients with “unstable angina and cardiac injury” or patients with structural heart disease and noncardiac chest pain?
Perhaps both exist?
3. The release of biomarkers is flow-dependent.Thus, there may not always be rapid access to the circulation. An area of injury distal to a totally occluded vessel (when collateral channels close) may be different in terms of the dynAMIcs of
hs-cTn change than an intermittently occluded coronary artery.
4. Conjoint biological and analytical variation can be measured.
They are assay-dependent, and the reference change values range from 35% to 85%.[2]
The use of criteria less than that (which may be what is needed clinically) will thus
likely include individuals with changes caused by
conjoint biological and analytical variation alone.
This has been shown to be the case in
many patients with nonacute cardiovascular diagnoses.[14,15]
5. Most evaluations have attempted to define the optimal delta, often with receiver operator curve analysis. Such an approach is based on the concept that sensitivity and specificity deserve equivalent weight.[But higher deltas improve specificity more and lower ones improve sensitivity and it is not clear that all physicians want the same tradeoffs in this regard.]ED physicians often prefer high-sensitivity so that their miss rate is low (<1%),[16] whereas hospital clinicians want increased specificity. This tension will need to be addressed in defining the optimal delta.
6. The delta associated with AMI may be different from that associated with other cardiac injury.[14] In addition, women have less marked elevations of cTn in response to coronary artery disease[17] and in earlier studies were less apt to have elevated values.[18] Given their pathology is at times different,
it may be that different metrics may be necessary based on gender
7. Some groups have assumed that if a change is of a given magnitude over 6 hours, it can be divided by 6 and the 1-h values can be used.
This approach is not data driven, and biomarker release is more likely to be discontinuous rather than continuous.[19]
In addition, the values obtained with this approach are too small to be distinguished from a lack of change with most assays.
These issues pose a major challenge even for defining the ideal delta change value and provide the reasons why
the use of this approach will reduce sensitivity[20,21] (Figure 2).
Defining the Optimal Delta: Tension Between Sensitivity and Specificity
There is a reciprocal relationship between sensitivity and specificity. With marked percentage changes,
specificity is improved at the expense of sensitivity, and
at lower values, the opposite occurs.
In addition, there is controversy in regard to the metrics that should be used with high-sensitivity assays.
The Australian-New Zealand group proposed
a 50% change for hs-cTnT for values below 53 ng/l and
a 20% change above that value.[22]
The 20% change is much less than conjoint biological and analytical variation.
A number of publications have suggested the superiority of
absolute δ cTn compared to relative δ cTn in discriminating between AMI and non-AMI causes of elevated cTn.[23,24,25]
The utility of the absolute or relative δ cTn appears to depend on the initial cTn concentration, and
the major benefit may be at higher values.[23]
A recent publication by Apple et al.[26] calculates deltas in several different ways with a contemporary assay and
provides a template for how to do such studies optimally.[26]
If all studies were carried out in a similar fashion, it would help immensely. In the long run, institutions will need to
define the approach they wish to take. We believe this discussion is a critical one and should include
laboratory,
ED, and
cardiology professionals.
Distinguishing Between Type 1 and Type 2 AMI
Although δ cTn is helpful in distinguishing between AMI and nonacute causes of Tn release,
it may or may not be useful in discerning type 1 from type 2 AMI.
As assay sensitivity increases, it appears that the frequency of type 2 AMI increases.
Making this distinction is not easy.
Type 1 AMI is caused by a primary coronary event, usually plaque rupture.
It is managed acutely with aggressive anticoagulation and
revascularization (percutaneous coronary intervention or coronary artery bypass).[10]
Type 2 AMI typically evolves secondary to ischemia from an oxygen demand/supply mismatch
severe tachycardia and
hypo- or hypertension and the like,
with or without a coronary abnormality.
These events usually are treated by addressing the underlying abnormalities.
They are particularly common in patients who are
critically ill and those who
are postoperative.[27]
However, autopsy studies from patients with postoperative AMI often manifest plaque rupture.[28]
Thus, the more important events, even if less common, may be type 1 AMIs. Type 2 events
seem more common in women, who tend to have
more endothelial dysfunction,
more plaque erosion, and
less fixed coronary artery disease.[28-30]
Additional studies are needed to determine how best to make this clinical distinction.
For now, clinical judgment is recommended.
Analytical Imprecision in Cardiac Troponin Assays
All analytical problems will be more critical with hs-cTn assays. Cardiac troponin I (cTnI) and cardiac troponin T (cTnT) are measured using enzyme linked immune- sorbent assays.
quantification of hs-cTn can be influenced by interference by reagent antibodies to analyte (cTn), leading to false- positive or negative results.[31]
Autoantibodies to cTnI or cTnT are found in 5% to 20% of individuals and can reduce detection of cTn.[32,33]
Additionally, fetal cTn isoforms can be re-expressed in diseased skeletal muscle and detected by the cTnT assays, resulting in false-positive values.[34]
Several strategies, including the use of
blocking reagents,
assay redesign, and use of
antibody fragments,
have been used to reduce interference.[35–36]
There are differences in measured cTn values based on specimen type (serum versus heparinized plasma versus EDTA plasma).
In addition, hemolysis may affect the accuracy of cTn measurement,[37] and with blood draws from peripheral IV lines, common in ICU.
Ruling Out AMI
Studies evaluating the diagnostic performance of hs-cTn assays for the early diagnosis of AMI usually define AMI on
the basis of a rising and/or falling pattern of current generation cTn values.[21,38]
However, defining AMI on the basis of the less sensitive current generation assay results in an underestimation of the true prevalence of AMI and
an overestimation of negative predictive value of the experimental assay.
shortens the time it takes to rule in all the AMIs and
to definitively exclude AMI as it
ignores the new AMIs more sensitively detected by the hs-cTn assay.
Thus, in the study by Hammarsten et al.,[14]
the time to exclude all AMIs was 8.5 hours when all of the AMIs detected
with the high-sensitivity assay were included, whereas
others that do not include these additional events report this can be done
in 3 to 4 hours.[21,29,38]
In our view, Hammarsten is correct.
This does not mean that hs-cTn cannot help in excluding AMI. Body et al.[39] reported that patients who present with undetectable values (less than the LOB of the hs-cTnT assay) were unlikely to have adverse events during follow-up. If that group of patients is added to those who present later than 6 hours, then perhaps a significant proportion of patients
with possible acute coronary syndrome (ACS) could
have that diagnosis excluded with the initial value.[40]
studies need to continue to evaluate cTn values for at least 6 h
to define the frequency of additional AMIs detected in that manner.
Using follow-up evaluations of patients with small event rates
who are likely to have additional care during the follow-up period are likely to be underpowered.
It may be that better initial risk stratification may help with this, as recently reported.[16,41]
Low-risk patients who have good follow-up after an ED visit
may be a group that can be released as early as 2 h after presentation.[16]
Investigating the Causes of Positive Troponin Values in Non-AMI Patients
Elevated Tn values (including those obtained with high-sensitivity assays) are associated with
a 2-fold higher risk for longer-term all-cause mortality and
cardiovascular death than a negative troponin values.[6,42-44]
This association is dose-dependent.
If values are rising, they are indicative of acute cardiac injury.
Those patients should be admitted because the risk is often short-term. However,
if the values are stable, assuming the timing of any acute event would
allow detection of a changing pattern,
the risk, although substantive, in our view, often plays out in the longer term.[44]
Many of these individuals, assuming they are doing well clinically, can be evaluated outside of the hospital, in our view.
However, because such elevations are an indicator of a subclinical
cardiovascular injury, such evaluations should be early and aggressive.
Data from several studies suggest that there may well be risk far below the 99th percentile URL value.
Thus, it may evolve that patients in the upper ranges of the normal range also require some degree of cardiovascular evaluation.
Risk Stratifying Patients With Nonacute Coronary Syndrome Conditions
Patients who have a rising pattern of values have a higher risk of mortality than those with negative values regardless of the cause.
Investigations are ongoing to determine how well results from hs-cTn testing help to risk-stratify patients with
pulmonary embolism,[45]
congestive heart failure,[46]
sepsis,[47]
hypertensive emergency,[48] and
chronic obstructive pulmonary disease.[49]
Presently, the studies suggest that cTn values classify patients into clinically relevant risk subgroups. Studies are needed
to evaluate the incremental prognostic benefit of hs-cTn.
Conclusions
Routine use of hs-cTn assays in the United States is inevitable. These assays hold
the promise of
improving the sensitivity of AMI diagnoses,
shortening the duration of AMI evaluation and
improving the risk stratification of other noncardiac diagnoses.
However, to be able to fully realize their potential, additional studies are needed to address the
knowledge gaps we have identified. In the interim, clinicians need to
learn how to use the 99th% URL and
the concept of changing values
John Adan, MD, FACC
In 2008 CMS commissioned Yale University to analyze 30 days mortality after myocardial infarction in their hospitals.
The study has been based on review of medical records. Consensus criteria for diagnosis of myocardial infarction include
clinical symptoms,
EKG,
troponins,
CK MB,
ECHO,
cath,
histopathology, etc.
How the reviewed hospitals performed diagnostic coding is unknown. In clinical practice we are bombarded by consults
for elevated troponins due to causes other than myocardial infarction, like
pneumonia,
accelerated hypertension,
arrhythmias,
renal failure, etc.
The metric started out over 19%. Now it is below 15%, on average.
typical changes in CK-MB and cardiac troponin in Acute Myocardial Infarction (Photo credit: Wikipedia)
Phosphotungstic acid-haematoxylin staining demonstrating contraction band necrosis in an individual that had a myocardial infarction (heart attack). (Photo credit: Wikipedia)
Causes and imaging features of false positives and false negatives on 18F-PET/CT in oncologic imaging
Author and Curator: Dror Nir, PhD
Article 11.4.1 Causes and imaging features of false positives and false negatives on 18FPET CT in oncologic imaging
Early this year I have posted on: Whole-body imaging as cancer screening tool; answering an unmet clinical need? F-PET/CT was discussed in this post as a leading modality in that respect. Here I report on an article dedicated to the sources for misdiagnosis; i.e. false negatives and false positives when applying this technology:
18F-FDG is a glucose analogue that is taken up by a wide range of malignancies. 18F-FDG PET-CT is now firmly established as an accurate method for the staging and restaging of various cancers. However, 18F-FDG also accumulates in normal tissue and other non-malignant conditions, and some malignancies do not take up F18-FDG or have a low affinity for the tracer, leading to false-positive and false-negative interpretations.
Methods
PET-CT allows for the correlation of two separate imaging modalities, combining both morphological and metabolic information. We should use the CT to help interpret the PET findings. In this article we will highlight specific false-negative and false-positive findings that one should be aware of when interpreting oncology scans.
Results
We aim to highlight post-treatment conditions that are encountered routinely on restaging scans that can lead to false-positive interpretations. We will emphasise the importance of using the CT component to help recognise these entities to allow improved diagnostic accuracy.
Conclusion
In light of the increased use of PET-CT, it is important that nuclear medicine physicians and radiologists be aware of these conditions and correlate the PET and CT components to avoid misdiagnosis, over staging of disease and unnecessary biopsies.
Introduction
[18F] 2-fluoro-2deoxy-D-glucose (18F-FDG) PET-CT imaging has become firmly established as an excellent clinical tool in the diagnosis, staging and restaging of cancer. 18F-FDG (a glucose analog) is taken up by cells via glucose transporter proteins. The glucose analog then undergoes phosphorylation by hexokinase to FDG-6 phosphate. Unlike glucose, FDG-phosphate does not undergo further metabolism and so becomes trapped in the cell as the cell membrane is impermeable to FDG-6 phosphate following phosphorylation [1].
Malignant tumors have a higher metabolic rate and generally express higher numbers of specific membrane transporter proteins than normal cells. This results in increased uptake of 18F-FDG by tumor cells and forms the basis of FDG-PET imaging [2]. Glucose however acts as a basic energy substrate for many tissues, and so 18F-FDG activity can be seen both physiologically and in benign conditions. In addition, not all tumors take up FDG [3–5]. The challenge for the interpreting physician is to recognize these entities and avoid the many pitfalls associated with 18F-FDG PET-CT imaging.
In this article we discuss false-positive and false-negative 18F-FDG PET-CT findings, common and atypical physiological sites of FDG uptake, and benign pathological causes of FDG uptake. We will focus on post-treatment conditions that can result in false-positive findings. We will highlight the importance of utilizing the CT component of the study, not only for attenuation correction but also in the interpretation of the study. The CT component of 18F-FDG PET-CT imaging can provide high-resolution anatomical information, which enables more accurate staging and assessment. For the purposes of this article, we refer to the descriptive terms “false-positive” and “false-negative” findings in the context of oncology imaging.
The authors acknowledge that there are recognized causes of FDG uptake that are not related to malignancy; however in this paper we refer to false-positive findings as FDG uptake that is not tumor related.
Patient preparation
Tumor uptake of FDG is reduced in the presence of raised serum glucose as glucose competes with FDG for uptake by the membrane transporter proteins. In order to prevent false-negative results, it is necessary for the patient to fast for at least 4–6 h prior to the procedure [6]. Induction of a euglycamic hypoinsulinaemic state also serves to reduce the uptake of glucose by the myocardium and skeletal muscle. In the fasting state, the decreased availability of glucose results in predominant metabolism of fatty acids by the myocardium. This reduces the intensity of myocardial uptake and prevents masking of metastatic disease within the mediastinum [6].
The radiotracer is administered intravenously (dose dependent on both the count rate capability of the system used and the patient’s weight), and the patient is left resting in a comfortable position during the uptake phase (60–90 min). Patient discomfort and anxiety can result in increased uptake in skeletal muscles of the neck and paravertebral regions. Muscular contraction immediately prior to or following injection can result in increased FDG activity in major muscle groups [6].
Patients are placed in a warm, quiet room with little stimulation, as speech during the uptake phase is associated with increased FDG uptake in the laryngeal muscles [7].
At our institution we perform the CT component with arms up except for head and neck studies where the arms are placed down by the side. This minimizes artifacts on CT. Depending on the type of cancer, oral contrast to label the bowel and intravenous contrast may also be given. The CT is performed with a full dose similar to a diagnostic CT, and lungs are analyzed following reconstruction with a lung algorithm. The PET scan is performed with 3–4 min per bed position; however the time per bed position will vary in different centers depending on both the dose of FDG administered and the specifications of the camera used for image acquisition. It is beyond the scope of this article to provide detailed procedure guidelines for 18F-FDG PET-CT imaging, and for this purpose we refer the reader to a comprehensive paper by Boellaard et al. [8].
Technical causes of false positives
Misregistration artifact
The evaluation of pulmonary nodules provides a unique challenge for combined PET-CT scanning due to differences in breathing patterns between CT and PET acquisition periods. CT imaging of the thorax is classically performed during a breath-hold; however PET images are acquired during tidal breathing, and this can contribute significantly to misregistration of pulmonary nodules on fused PET-CT images. Misregistration is particularly evident at the lung bases, which can lead to difficulty differentiating pulmonary nodules from focal liver lesions (Fig. 1) [9].
Fig. 1
18F-FDG PET-CT performed in a 65-year-old male with colorectal cancer. On the coronal PET images, a focus of increased FDG uptake is seen at the right lung base (black arrow). Contrast CT does not show any pulmonary nodules but does demonstrate a liver metastasis in the superior aspect of the right lobe of the liver (yellow arrow)
Acquiring CT imaging of the thorax during quiet respiration can help to minimize misregistration artifacts. It is also important to correlate your PET and CT findings by scrolling up and down to make sure that lesions match.
Injected clot
A further diagnostic pitfall in staging of intrathoracic disease can be caused by injected clot. Injection of radioactive clot following blood withdrawal into the syringe at the time of radiotracer administration can result in pulmonary hotspots [10]. The absence of a CT correlate for a pulmonary hotspot should raise the possibility of injected clot; however this is a diagnosis of exclusion, and it is important to carefully evaluate the adjacent slices to ensure the increased radiotracer activity does not relate to misregistration of a pulmonary nodule or hilar lymph node. The area of abnormal radiotracer uptake should also be closely evaluated on subsequent restaging CT to ensure there has been no interval development of an anatomical abnormality in the region of previously diagnosed injected clot (Fig. 2) [11].
Fig. 2
18F-FDG PET-CT performed in a 28-year-old male with an osteosarcoma of the femur. A focus of increased FDG uptake (yellow arrow) is identified in the left lower lobe with no CT correlate (a). A 3-month follow-up CT thorax again does not demonstrate any pulmonary nodules confirming that the uptake seen originally on the PET-CT was due to injected clot (b)
Injection artifact
Leakage of radiotracer into the subcutaneous tissues at the injection site or tissued injection can result in subcutaneous tracking of FDG along lymphatic channels in the arm. This can result in spurious uptake in axillary nodes distal to the injection site [12]. Careful attention must be paid to the technical aspects of the study to ensure accurate staging. Injection at the side contralateral to the site of disease is advised where feasible to allow differentiation between artifactual and metastatic uptake, particularly in breast cancer patients. The side of injection should also be clearly documented during administration of radiotracer, and this information should be available to the reader in order to ensure pathological FDG uptake is not spuriously attributed to injection artifact (Fig. 3).
Fig. 3
18F-FDG PET-CT performed in a 56-year-old woman with colorectal cancer. Some low grade FDG uptake is identified in non-enlarged right axillary nodes (yellow arrow) consistent with injection artifact
Imaging of metallic implants
The use of CT for attenuation correction negates the need for traditional transmission attenuation correction, reducing scanning time. There are however technical factors relating to the use of CT imaging for attenuation correction, which lead to artefacts when imaging metal [9]. The presence of metal implants in the body produces streak artifact on CT imaging and degrades image quality. When CT images are used for attenuation correction, the presence of metal results in over attenuation of PET activity in this region and can result in artifactual ‘hot spots.’ Metal prostheses, dental fillings, indwelling ports and breast expanders and sometimes contrast media are common causes of streak artifact secondary to high photon absorption and can cause attenuation correction artifacts [9]. In order to avoid false positives, particularly when imaging metallic implants careful attenuation should be paid to the nonattenuation corrected images, which do not produce this artifact.
Sites of physiological FDG uptake
Physiological uptake in a number of organs is readily recognized and rarely confused with malignancy. These include cerebral tissue, the urinary system, liver and spleen. Approximately 20% of administered activity is renally excreted in the 2 h post-injection resulting in intense radiotracer activity in the renal collecting systems, ureters and bladder [13]. In order to minimize the intensity of renal activity, patients are advised to void prior to imaging. Moderate physiological FDG uptake is noted in the liver, spleen, GI tract and salivary glands. Uptake in the cecum and right colon tends to be higher than in the remainder of the colon due to the presence of glucose-avid lymphocytes [14].
Other sites of physiological FDG activity can be confused with malignancy. Examples include activity within brown fat, adrenal activity, uterus and ovaries.
Brown fat
FDG uptake in hyper-metabolic brown adipose tissue is well recognized as a potential source of false positive in 18F-FDG PET-CT imaging. The incidence of FDG uptake in brown fat has been reported as between 2.5–4% [15, 16].
Hypermetabolic brown fat is more commonly identified in children than in adults and is more prevalent in females than in males. It occurs more frequently in patients with low body mass index and in cold weather [15].
Glucose accumulation within brown fat is increased by sympathetic stimulation as brown fat is innervated by the sympathetic nervous system. In view of this, administration of oral propranolol is advised by some authors as it has been shown to reduce the uptake of FDG by brown fat [17]. This is not performed at our institution; however, attempts are made to reduce FDG uptake in brown fat by maintaining a warm ambient temperature and providing patients with blankets during the uptake phase.
The typical distribution of brown fat in a bilateral symmetric pattern in the supraclavicular and neck regions is rarely confused with malignancy. In cases where hypermetabolic brown fat is seen to surround lymph nodes, the CT images should be separately evaluated to allow morphological assessment of the lymph nodes. The classical CT features of pathological replacement of lymph nodes should be sought, namely increased short axis diameter, loss of the fatty hilum and loss of the normal concavity of the lymph node. If the morphology of the lymph node is entirely normal, malignancy can be confidently excluded and the increased uptake attributed to brown fat [18].
Atypical brown fat in the mediastinum can be misinterpreted as nodal metastases and has been identified in the paratracheal, paraoesophageal, prevascular regions, along the pericardium and in the interatrial septum. Extramediastinal sites of brown fat uptake include the paravertebral regions, perinephric, perihepatic and subdiaphragmatic regions and in the intraatrial septum [16].
The absence of an anatomical lesion on CT imaging in areas of FDG uptake should raise the possibility of brown fat to the reader. Careful evaluation of the CT images must be performed to confirm the presence of adipose tissue in the anatomical region correlating to the increased FDG activity on 18F-FDG PET before this activity be attributed to brown fat.
An awareness of the possibility of brown fat in atypical locations is vital to avoid overstaging, and correlation with CT imaging increases reader confidence in differentiating brown fat from malignancy (Fig. 4).
Fig. 4
18F-FDG PET-CT surveillance scan performed in a 36-year-old male with a history of seminoma. Symmetrical uptake is noted in the neck, supraclavicular fossa and paravertebral regions consistent with typical appearance of brown fat activity (black arrow). Brown fat uptake is also seen in the left supradiaphragmatic region and left paraoesophageal region (yellow arrow) (a). 18F-FDG PET-CT performed in a 48-year-old male with a history of colorectal cancer. Increased FDG uptake is noted within brown fat associated with lipomatous hypertrophy of the intra-atrial septum (b)
Uterine and ovarian uptake
In premenopausal women endometrial uptake of FDG varies cyclically and is increased both at ovulation and during the menstrual phase of the cycle with mean SUV values of 3.5–5 [19]. Endometrial uptake in postmenopausal women is abnormal and warrants further investigation; however benign explanations for increased FDG uptake include recent curettage, uterine fibroids and endometrial polyps [19].
Benign ovarian uptake of FDG in premenopausal women can be associated with ovulation. In postmenopausal women, ovarian uptake of FDG should be further investigated (Fig. 5).
Fig. 5
18F-FDG PET-CT performed in a 42-year-old premenopausal female with breast cancer. She was scanned during menstruation. FDG uptake is noted within metastatic right axillary nodes (black arrow). Increased FDG uptake is also noted within the endometrial canal of the uterus (yellow arrow), which is thickened on CT, consistent with active menstruation (a). 18F-FDG PET-CT performed in the same 42-year-old woman at a different stage in her menstrual cycle showing resolution of the previously identified uterine uptake (yellow arrow) (b)
Adrenal uptake
18F-FDG PET imaging is commonly used for evaluation of adrenal masses in patients with diagnosed malignancies. Similarly incidental adrenal lesions are commonly identified on staging 18F-FDG PET-CT imaging. The positive predictive value of 18F-FDG PET-CT evaluation of adrenal lesions has been reported as high as 95% with a similarly high negative predictive value of 94% [20].
Causes of false-positive adrenal lesions include angiomyolipoma, adrenal hyperplasia and adrenal adenomas (up to 5%) [21, 24]. FDG activity greater than that of the liver is generally associated with malignancy; however benign lesions have been reported with greater activity than liver [21].
Evaluation of the CT component can provide additional diagnostic information with identification of HU attenuation values of <10 on noncontrast CT for adrenal adenomas or fat-containing myelolipomata [21].
Symmetrical intense FDG activity with no identifiable abnormality on CT is associated with benign physiological FDG uptake (Fig. 6).
Fig. 6
18F-FDG PET-CT performed in a 50-year-old woman with inflammatory breast cancer. Diffuse increased FDG uptake is noted within the right breast (yellow arrow) and in a right axillary node (black arrow), consistent with malignancy (a). Increased symmetrical uptake is also noted within both adrenal glands with no abnormal correlate on CT (yellow arrow) (b). Post-chemotherapy PET-CT performed 5 months later demonstrates resolution of the activity within the breast, increased uptake in the bone marrow consistent with post treatment effect (black arrow) and persistent increased uptake in the adrenal glands (yellow arrow), confirming benign physiological activity (c)
Thyroid uptake
Thyroid uptake is incidentally identified on 18F-FDG PET imaging with a frequency of almost 4%, with a diffuse uptake pattern in roughly half of cases and a focal pattern in the remainder [22]. The majority of diffuse uptake represents chronic thyroiditis, multinodular goiter or Graves’ disease, whereas focal uptake is associated with a risk of malignancy that ranges from 30.9–63.6% in published studies [22, 23]. Focal thyroid uptake requires further investigation with ultrasound and tissue biopsy.
Uptake in the gastrointestinal tract
The pattern of physiological uptake within the GI tract is highly variable. Low-grade linear uptake is likely related to smooth muscle activity and swallowed secretions. More focal increased uptake in the distal esophagus is sometimes seen with Barrett’s esophagus. In view of this, referral for OGD may be reasonable in cases of increased uptake in the distal esophagus [14, 24].
The typical pattern of FDG uptake in the stomach is of low-grade activity in a J-shaped configuration. Small bowel typically demonstrates mild heterogeneous uptake throughout. Common pitfalls of small bowel evaluation relate to spuriously high uptake in underdistened or overlapping loops of bowel [14, 25].
Within the colon, FDG uptake is highly variable, however can be quite avid particularly in the cecum, right colon and rectosigmoid regions. Focal areas of FDG activity within the colon that are of greater intensity than background liver uptake should raise the suspicion of a colonic neoplasm (Fig. 7) [25, 26].
Fig. 7
18F-FDG PET-CT restaging scan performed in a 65-year-old female with a history of breast cancer. Incidental focal uptake is identified in the ascending colon where some abnormal thickening is seen on the CT component (yellow arrow). Colonoscopy confirmed the presence of a T3 adenocarcinoma
In a review of over 3,000 patients’ focal areas of abnormal FDG uptake within the gastrointestinal tract (GIT) were identified in 3% of cases of staging 18F-FDG PET-CT studies.
Incidental malignant lesions were identified in 19% of these patients with pre-malignant lesions including adenomas in 42% of the patients [27]. In view of this endoscopy referral is recommended in the absence of a clear benign correlate for focal areas of avid uptake on CT imaging.
Treatment-related causes of false-positive uptake
There are a number of conditions that can occur in patients undergoing treatment for cancer. When imaging these patients to assess for response, we often see these treatment-related conditions. It is important to recognize the imaging features to avoid misdiagnosis.
Thymus/thymic hyperplasia
Thymic hyperplasia post-chemotherapy is a well-described phenomenon. It is generally seen in children and young adults at a median of 12 months post chemotherapy [28]. The presence of increased FDG uptake in the anterior mediastinum can be attributed to thymic hyperplasia by identification of a triangular soft tissue density seen retrosternally on CT with a characteristic bilobed anatomical appearance [29]. In the presence of thymic hyperplasia, there is generally preservation of the normal shape of the gland despite an increase in size [30].
Superior mediastinal extension of thymic tissue is an anatomical variant that has been described in children and young adults (Fig. 8).
Fig. 8
A 3.5-year-old boy with abdominal Burkitt’s lymphoma. Coronal 18F-FDG PET scan obtained 5 months after completion of treatment shows increased activity in the thymus in an inverted V configuration and in superior thymic extension (white arrow). Note physiologic activity within the right neck in the sternocleidomastoid muscle (a). Axial CT image from the same 18F-FDG PET-CT study performed 5 months after treatment shows a nodule (white arrow) anteromedial to the left brachiocephalic vein (b). Axial fusion image shows that the FDG activity in the superior mediastinum corresponds to this enlarged nodule anteromedial to left brachiocephalic vein (white arrow) (c). Axial fusion image shows increased activity in an enlarged thymus consistent with thymic hyperplasia (white arrow; standardized uptake value 3.0) of similar intensity to activity in superior mediastinum (d)
It presents as a soft tissue nodule anteromedial to the left brachiocephalic vein and represents a remnant of thymic tissue along the path of migration in fetal life. In patients with thymic hyperplasia, a superior mediastinal nodule in this location may represent accessory thymic tissue. An awareness of this physiological variant is necessary to prevent misdiagnosis [28].
G-CSF changes
Granulocyte colony-stimulating factor is a glycoprotein hormone that regulates proliferation and differentiation of granulocyte precursors. It is used to accelerate recovery from chemotherapy-related neutropaenia in cancer patients. Intense increased FDG uptake is commonly observed in the bone marrow and spleen following GCSF therapy; however the bone marrow response to GCSF can be differentiated from pathological infiltration by its intense homogeneous nature without focally increased areas of FDG uptake. Increased FDG uptake attributable to GCSF uptake rapidly decreases following completion of therapy and generally resolves within a month (Fig. 9).
Fig. 9
18F-FDG PET-CT performed in a 46-year-old male post four cycles of chemotherapy for lymphoma and 2 weeks post administration of G-CSF. Note the diffuse homogeneous increased uptake throughout the bone marrow and the increased uptake in the spleen (yellow arrow)
Marked uptake in the bone marrow can also be seen following chemotherapy, reflecting marrow activation [31, 32].
Radiation pneumonitis
Inflammatory morphological changes in the radiation field post-irradiation of primary or metastatic lung tumor can result in false-positive diagnosis. Radiation pneumonitis typically occurs following high doses of external beam radiotherapy (>40 Gy). In the acute phase (1–8 weeks) radiation pneumonitis is characterized by ground-glass opacities and patchy consolidation. This can commonly lead to a misdiagnosis of infection. Chronic CT appearances of fibrosis and traction bronchiectasis in the radiation field allow correct interpretation of increased FDG uptake as radiation pneumonitis as opposed to disease recurrence [33, 34]. Other organs are also sensitive to radiation, and persistent uptake due to inflammatory change can persist for up to 1 year. It is important to elicit a history of radiation from the patient and to correlate the increased uptake with the CT findings to avoid missing a disease recurrence (Fig. 10).
Fig. 10
18F18-FDG PET-CT performed in a 52-year-old male with newly diagnosed esophageal carcinoma. Increased FDG uptake is identified within the esophagus (black arrow) and an upper abdominal lymph node (yellow arrow), consistent with malignancy (a). 18F18-FDG PET-CT performed 6 weeks post-completion of radiotherapy for esophageal carcinoma. Linear increased uptake is identified along the mediastinum in the radiation port (black arrow). This corresponds to areas of ground-glass change on CT (yellow arrow) consistent with acute radiation change (b)
Infection
Bone marrow suppression places chemotherapy patients at increased risk of infection.
Inflammatory cells such as neutrophils and activated macrophages at the site of infection or inflammation actively accumulate FDG [35].
In the post-therapy setting it has been reported that up to 40% of FDG uptake occurs in non-tumor tissue [12]. Infection is one of the most common causes of false-positive 18F-FDG PET-CT findings post-chemotherapy. Chemotherapy patients are susceptible to a wide variety of infections, including upper respiratory chest infections, pneumonia, colitis and cholecystitis. Reactivation of tuberculous infection can occur in immunocompromised patients post,chemotherapy, and correlation with CT imaging can prevent misdiagnosis in suspected cases.
Atypical infections such as cryptococcosis and pneumocystis can also present as false-positives on FDG imaging (Fig. 11) [36].
Fig. 11
18F-FDG PET-CT performed in a 57-year-old male 2 weeks following chemotherapy for lung cancer. Increased FDG uptake is noted within the cecum (black arrow). On CT there is some thickening of the cecal wall and stranding of the pericecal fat (yellow arrow) consistent with typhilits
Surgery and radiotherapy
There are inherent challenges in the interpretation of 18F-FDG PET-CT imaging in the postoperative patient. Non-tumor-related uptake of FDG is frequently identified in post-operative wound sites, at colostomy sites or at the site of post-radiation inflammatory change. 18F-FDG PET-CT imaging during the early postoperative/post-radiotherapy period may result in overstaging of patients because of non-neoplastic uptake of FDG [12]. Careful evaluation of the CT component in this setting is vital as CT imaging can provide valuable additional information regarding benign inflammatory conditions commonly encountered in the postoperative setting such as abscesses or wound infection. These conditions are often readily apparent on CT, particularly when oral and/or IV contrast CT is administered.
The reader should also bear in mind that avid uptake of FDG at postoperative/post radiotherapy sites may mask malignant FDG uptake in neighboring structures. In order to minimize non-tumoral uptake of FDG, it is advisable to allow at least 6 weeks post-surgery or completion of radiotherapy prior to performing staging 18F-FDG PET-CT [24].
Talc pleurodesis
Talc pleurodesis is a commonly performed procedure for the treatment of persistent pneumothorax or pleural effusion. The fibrotic/inflammatory reaction results in increased FDG uptake on 18F-FDG PET imaging with corresponding high-density areas of pleural thickening on CT. SUV values of between 2–16.3 have been seen years after the procedure [37].
When increased FDG uptake is indentified in the pleural space in a patient with a known history of pleurodesis, correlation with CT is recommended to detect pleural thickening of increased attenuation that suggests talc rather than tumor.
It is extremely important that a comprehensive history with relevant surgical interventions is available to the reader in order to ensure accurate diagnosis and staging (Fig. 12).
Fig. 12
18F-FDG PET-CT performed in a 69-year-old male with a history of non-Hodgkin’s lymphoma. The patient had a previous talc pleurodesis for a persistent left pleural effusion. Increased FDG activity is identified within the left pleura (black arrow). CT demonstrates a pleural effusion with high density material along the left pleural surface consistent with talc (yellow arrow)
Flare phenomenon
Bone healing is mediated by osteoblasts, and an early increase in osteoblast activity on successful treatment of metastatic disease has been described [38]. “Bone flare” refers to a disproportionate increase in bone lesion activity on isotope bone scan despite evidence of a therapeutic response to treatment in other lesions and has been well described in breast, prostate and lung tumors. ‘Flare phenomenon’ has also been described on 18F-FDG PET-CT in patients with lung and breast cancer who are receiving chemotherapy [39].
Differentiating between increased FDG uptake due to flare response and true disease progression may not be possible in the early post-treatment studies. While it is recognized that bone flare is a rare phenomenon, an increase in baseline skeletal activity and appearance of new bone lesions despite apparent response or stable disease elsewhere should be interpreted with caution to avoid erroneously suggesting progressive disease.
Osteonecrosis
Osteonecrosis or avascular necrosis has been well described as a complication of combination chemotherapy treatment, especially where it includes intermittent high-dose corticosteroids (e.g., lymphoma patients) [40]. Commonly encountered sites include the hip and less frequently the proximal humerus. Occasionally we can see a discrete entity known as jaw osteonecrosis. Patients receiving IV bisphosphonates for the management of bone metastases are at an increased risk of developing this [41]. The development of osteonecrosis in the mandible is frequently preceded by tooth extraction. Radiographic findings that may be visualized on CT include osteosclerosis, dense woven bone, thickened lamina dura and sub-periosteal bone deposition [42]. FDG uptake can be seen in areas of osteonecrosis (Fig. 13).
Fig. 13
18F-FDG PET-CT performed in a 46-year-old gentleman with a history of non-Hodgkin’s lymphoma. Increased FDG uptake is identified in the right proximal humerus (black arrow). CT of the area demonstrates a corresponding vague area of sclerosis (yellow arrow). Biopsy of the area yielded osteonecrosis with no evidence of metastatic disease
Insufficiency fractures
Pelvic insufficiency fractures have been described following irradiation for gynecological, colorectal, anal and prostate cancer. They commonly occur within 3–12 months post-radiation treatment, and osteoporosis is often a precipitating factor. FDG uptake in insufficiency fractures ranges from mild and diffuse to intense and heterogeneous. The maximum SUV values are variable with reported values of between 2.4–7.2 [43]. Differentiating insufficiency fractures from bone metastases can prove challenging; however they are often bilateral and occur in characteristic locations within the radiation field—sacral ala, pubic rami and iliac bones. Biopsy of insufficiency fractures can lead to irreparable damage and so careful correlation of 18F-FDG PET imaging with the CT component along with radiation history is vital for correct diagnosis. CT allows evaluation of the bone cortex and adjacent soft tissues, which can confirm the diagnosis of a pathological fracture or a metastatic deposit.
Follow-up of suspected insufficiency fractures demonstrates a reduction in FDG uptake over time (Fig. 14) [43].
Fig. 14
18F-FDG PET-CT performed in a 46-year-old female, 3 years post-chemo-radiation for cervical carcinoma. Low grade FDG uptake is identified in the left acetabulum and right pubic bone (black arrow). CT demonstrates pathological fractures in these areas consistent with insufficiency fractures (yellow arrow)
Sarcoidosis
Sarcoidosis is a chronic multisystem disorder characterized by non-caseating granulomas and derangement of normal tissue architecture [36]. Sarcoidosis has been reported in association with a variety of malignancies either synchronously or post-chemotherapy. Aggregation of inflammatory cells post-chemotherapy is associated with accumulation of FDG, and the intensity of FDG uptake may correlate with disease activity [36].
When suspected disease recurrence presents with signs and symptoms compatible with sarcoidosis (i.e., mediastinal and bihilar lymphadenopathy), this must be excluded by clinical, radiological and pathological correlation to prevent mistreatment (Fig. 15).
Fig. 15
18F-FDG PET-CT performed in a 67-year-old male for restaging of laryngeal carcinoma. Increased FDG uptake is noted in the left lower neck and left mediastinum (black arrow). CT demonstrates lymphadenopathy in these areas (yellow arrow), some of which are calcified. Biopsy of the left lower neck node confirmed sarcoidosis
FDG-PET negative tumors
There are a number of malignancies that can be FDG-PET negative. Examples include bronchoalveolar carcinoma and carcinoid tumors in the lung, renal cell carcinomas and hepatomas, mucinous tumors of the GIT and colon, and low grade lymphomas [3, 44–48]. Careful evaluation of the CT component of the study however will prevent a misdiagnosis (Fig. 16).
Fig. 16
18F-FDG PET-CT performed in a 52-year-old female with breast cancer and chronic hepatitis. On the CT component a hyper-enhancing mass is identified in segment 4 of the liver (yellow arrow). No increased FDG activity is identified in this area on the PET component. Biopsy of the mass confirmed the diagnosis of a hepatocellular carcinoma
Osteoblastic metastases
Bone metastases are diagnosed in up to 85% of patients with advanced breast cancer, leading to significant morbidity and mortality. Sclerotic bone metastases are commonly associated with breast carcinoma [49].18F-FDG PET imaging is superior to nuclear bone scan in detection of osteolytic breast metastases; however it commonly fails to diagnose osteoblastic or sclerotic metastases [50]. Review of bony windows on CT imaging allows identification of sclerotic metastases and ensures accurate staging of metastatic bone disease (Fig. 17).
Fig. 17
Staging 18F-FDG PET-CT performed in a 45-year-old female with newly diagnosed breast cancer. CT demonstrates multiple small sclerotic foci in the spine and pelvis (yellow arrow), consistent with bony metastases. These are FDG negative on the PET component of the study
Discussion/conclusion
18F-FDG PET imaging has dramatically changed cancer staging, and findings of restaging studies commonly effect changes in treatment protocols. 18F-FDG however is not tumor specific. As interpreting physicians we need to be aware of these false positives and false negatives. In this review we have outlined atypical physiological sites of FDG uptake along with common causes of FDG uptake in benign pathological conditions, many of which are treatment related. With 18F-FDG PET-CT we have the advantage of two imaging modalities. The PET component gives us functional information and the CT, anatomical data. We have discussed the importance of dual-modality imaging and correlation with CT imaging of the above conditions. Furthermore CT imaging provides important diagnostic information in evaluation of tumors that poorly concentrate FDG. In light of the increased reliance of 18F-FDG PET-CT for cancer staging, it is vital that radiologists and nuclear medicine physicians be aware of pitfalls in 18F-FDG PET-CT imaging and correlate PET and CT components to avoid misdiagnosis, overstaging of disease and unnecessary biopsies.
Other research papers related to the use of 18F-PET in management of cancer were published on this Scientific Web site:
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Article 2.7 Finding the Genetic Links in Common Disease: Caveats of Whole Genome Sequencing Studies
In the November 23, 2012 issue of Science, Jocelyn Kaiser reports (Genetic Influences On Disease Remain Hidden in News and Analysis)[1] on the difficulties that many genomic studies are encountering correlating genetic variants to high risk of type 2 diabetes and heart disease. At the recent American Society of Human Genetics annual 2012 meeting, results of several DNA sequencing studies reported difficulties in finding genetic variants and links to high risk type 2 diabetes and heart disease. These studies were a part of an international effort to determine the multiple genetic events contributing to complex, common diseases like diabetes. Unlike Mendelian inherited diseases (like ataxia telangiectasia) which are characterized by defects mainly in one gene, finding genetic links to more complex diseases may pose a problem as outlined in the article:
Variants may be so rare that massive number of patient’s genome would need to be analyzed
For most diseases, individual SNPs (single nucleotide polymorphisms) raise risk modestly
Hard to find isolated families (hemophilia) or isolated populations (Ashkenazi Jew)
Disease-influencing genes have not been weeded out by natural selection after human population explosion (~5000 years ago) resulted in numerous gene variants
What percentage variants account for disease heritability (studies have shown this is as low as 26% for diabetes with the remaining risk determined by environment)
Although many genome-wide-associations studies have found SNPs that have causality to increasing risk diseases such as cancer, diabetes, and heart disease, most individual SNPs for common diseases raise risk by about only 20-40% and would be useless for predicting an individual’s chance they will develop disease and be a candidate for a personalized therapy approach. Therefore, for common diseases, investigators are relying on direct exome sequencing and whole-genome sequencing to detect these medium-rare risk variants, rather than relying on genome-wide association studies (which are usually fine for detecting the higher frequency variants associated with common diseases).
Three of the many projects (one for heart risk and two for diabetes risk) are highlighted in the article:
Sequenced 5,300 exomes of type 2 diabetes patients and controls from five ancestry groups SNP in PAX4 gene associated with disease in East Asians No low-frequency variant with large effect though
After sequencing 2700 patient’s exomes and whole genome no new rare variants above 1.5% frequency with a strong effect on diabetes risk
A nice article by Dr. Sowmiya Moorthie entitled Involvement of rare variants in common disease can be found at the PGH Foundation site http://www.phgfoundation.org/news/5164/ further discusses this conundrum, and is summarized below:
“Although GWAs have identified many SNPs associated with common disease, they have as yet had little success in identifying the causative genetic variants. Those that have been identified have only a weak effect on disease risk, and therefore only explain a small proportion of the heritable, genetic component of susceptibility to that disease. This has led to the common disease-common variant hypothesis, which predicts that common disease-causing genetic variants exist in all human populations, but each individual variant will necessarily only have a small effect on disease susceptibility (i.e. a low associated relative risk).
An alternative hypothesis is the common disease, many rare variants hypothesis, which postulates that disease is caused by multiple strong-effect variants, each of which is only found in a few individuals. Dickson et al. in a paper in PLoS Biology postulate that these rare variants can be indirectly associated with common variants; they call these synthetic associations and demonstrate how further investigation could help explain findings from GWA studies [Dickson et al. (2010) PLoS Biol. 8(1):e1000294][3]. In simulation experiments, 30% of synthetic associations were caused by the presence of rare causative variants and furthermore, the strength of the association with common variants also increased if the number of rare causative variants increased. “
Figure from Dr. Moorthie’s article showing the problem of “finding one in many”.
(please click to enlarge)
Indeed, other examples of such issues concerning gene variant association studies occur with other common diseases such as neurologic diseases and obesity, where it has been difficult to clearly and definitively associate any variant with prediction of risk.
For example, Nuytemans et. al.[4] used exome sequencing to find variants in the vascular protein sorting 3J (VPS35) and eukaryotic transcription initiation factor 4 gamma1 (EIF4G1) genes, tow genes causally linked to Parkinson’s Disease (PD). Although they identified novel VPS35 variants none of these variants could be correlated to higher risk of PD. One EIF4G1 variant seemed to be a strong Parkinson’s Disease risk factor however there was “no evidence for an overall contribution of genetic variability in VPS35 or EIF4G1 to PD development”.
However there seems to be more luck with strategies focused on analyzing intronic sequence rather than exome sequence. Jocelyn Kaiser’s Science article notes this in a brief interview with Harry Dietz of Johns Hopkins University where he suspects that “much of the missing heritability lies in gene-gene interactions”. Oliver Harismendy and Kelly Frazer and colleagues’ recent publication in Genome Biology http://genomebiology.com/content/11/11/R118 support this notion[5]. The authors used targeted resequencing of two endocannabinoid metabolic enzyme genes (fatty-acid-amide hydrolase (FAAH) and monoglyceride lipase (MGLL) in 147 normal weight and 142 extremely obese patients.
These patients were enrolled in the CRESCENDO trial and patients analyzed were of European descent. However, instead of just exome sequencing, the group resequenced exome AND intronic sequence, especially focusing on promoter regions. They identified 1,448 single nucleotide variants but using a statistical filter (called RareCover which is referred to as a collapsing method) they found 4 variants in the promoters and intronic areas of the FAAH and MGLL genes which correlated to body mass index. It should be noted that anandamide, a substrate for FAAH, is elevated in obese patients. The authors did note some issues though mentioning that “some other loci, more weakly or inconsistently associated in the original GWASs, were not replicated in our samples, which is not too surprising given the sample size of our cohort is inadequate to replicate modest associations”.
2. Tennessen JA, Bigham AW, O’Connor TD, Fu W, Kenny EE, Gravel S, McGee S, Do R, Liu X, Jun G et al: Evolution and functional impact of rare coding variation from deep sequencing of human exomes.Science 2012, 337(6090):64-69.
4. Nuytemans K, Bademci G, Inchausti V, Dressen A, Kinnamon DD, Mehta A, Wang L, Zuchner S, Beecham GW, Martin ER et al: Whole exome sequencing of rare variants in EIF4G1 and VPS35 in Parkinson disease. Neurology 2013, 80(11):982-989.
5. Harismendy O, Bansal V, Bhatia G, Nakano M, Scott M, Wang X, Dib C, Turlotte E, Sipe JC, Murray SS et al: Population sequencing of two endocannabinoid metabolic genes identifies rare and common regulatory variants associated with extreme obesity and metabolite level. Genome biology 2010, 11(11):R118.
Other posts on this site related to Genomics include:
9. Is it Hypertension or Physical Inactivity: Cardiovascular Risk and Mortality – New results in 3/2013.
Summary By Justin D. Pearlman MD ME PhD MA FACC
1. Physiology of Circulation and Role of Arterial Elasticity
Simplistically, high blood pressure stems from too much volume (salt water) for the vascular space, or conversely, too little space for the volume. Biological signals, such as endothelin, hypoxia, acidosis, nitric oxide, can modify vascular volume by constricting muscles in blood vessel walls. Less simplistically the physics of circulation are governed by numerous factors, with essentials detailed below.
The vascular space has two major circuits: pulmonary (lungs) and systemic (body).
Compliance (C) relates change in volume (ΔV) to change in pressure (ΔP) as a measure of the strength of elasticity, where elasticity summarizes the intrinsic forces that return to original shape after deformation: C = ΔV/ΔP . Those values can be estimated by ultrasound imaging with Doppler blood velocity estimation, by MRI, or invasively. Related properties can also be measured, such as wave propagation time or fractional flow reserve.
The vascular system is dynamic, with frequency components and reactive elements. The fundamental frequency is governed by the heart rate delivering a stroke volume forward into the vasculature; a heart rate of 60/minute corresponds to the frequency of 1 Hertz (1 cycle/second). The pressure rise due to the ejection of stroke volume is called the pulse pressure.
Numerous factors affect blood flow, including blood composition (affected by anemia or blood dilution), leakiness of vessels, elasticity, wave propagation, streamlines, viscosity, osmotic pressure (affected by protein deficiency and other factors),
In a static system, the driving force relates linearly flow by way of resistance (R in units of dyn·s·cm−5): V=IR (Ohm’s law).
Pulmonary:
Systemic:
In a dynamic, reactive system, the relation between the driving potential (pressure gradient), and current (blood flow) is governed by a differential equation. However, use of complex numbers and exponentials recovers simplicity similar to Ohm’s law:
Variables take the form , where t is time, s is a complex parameter, and A is a complex scalar. Complex values simply mean two dimensional, e.g., magnitude (as in resistance) plus phase shift (to account for reactive components).
Complex version of Ohm’s law: where V and I are the complex scalars in the voltage and current respectively and Z is the complex impedance.
Frequency dependent “resistance” is captured by the term impedance.
Breathing in increases the return of blood to the heart, adding to pulse variation.
where PPmax and PPmin are the maximum and minimum pulse pressures determined during a single respiratory cycle
SVV(%) = 100% × [(SVmax − SVmin)/SVmean]
where SVmax and SVmin are the maximum and minimum standard deviation of arterial pressure about the mean arterial pressure during a single respiratory cycle
The nervous system provides both stimulants and inhibitors (sympathetic and vagal nerves) to regulate blood vessel wall muscle tone and also heart rate. Many medications, and anesthetic agents in particular, reduce those responses to stimuli, so the vessels dilate, vascular impedance lowers, pressures drop, and autoregulation is impaired.
Diuretics aim to decrease volume of circulating fluid, vasodilators aim to increase the vascular space, and elasticity treatments will aim to preserve or improve the ability to accommodate changes in volume of fluid.
Vessel dilation near the skin promotes heat loss.
Vascular elasticity is impaired by atherosclerosis, menopause, and endothelial dysfunction (impaired nitric oxide signals response, impaired endothelin response).
Elastance in a cyclic pressure system of systole-diastole (contraction-dilation) presents impedance as a pulsatile load on the heart. Inotropy describes the generation of pressure by cardiac contraction, lusiotropy the compliance of the heart to accept filling with minimal back pressure to the lungs. Chronic exposure to elevated vascular impedance leads to impairment of lusiotropy (diastolic failure, stiff heart) and inotropy (systolic failure, weak heart).
Diuretics enhance renal excretion of sodium. Sodium is the major determinant of circulating volume. Too much blood volume for the amount of vascular space elevates blood pressure. Clinical trials show that use of diuretics to lower blood pressure can prevent strokes, non-inferior to vasodilators and recommended as first line agents.
The most common prescriptions, a mild diuretic, hydrochlorothiazide (HCTZ), is known to improve blood vessel compliance by reducing cell turgor, which explains why its full onset of benefit as well as its slow offset when stopped can take more than one month.
Chlorthalidone – Some evidence suggests that chlorthalidone may be superior to hydrochlorothiazide for the treatment of hypertension. However, a recent study concluded: chlorthalidone in older adults was not associated with fewer adverse cardiovascular events or deaths than hydrochlorothiazide. However, it was associated with a greater incidence of electrolyte abnormalities, particularly hypokalemia.
Alternatively, the pressure can be lowered by increasing the vascular space for a given vascular volume. Examples of mediators for arterial tone (degree of dilation) include nitric oxide, prostacyclin and endothelin.
These work by blocking certain nerve and hormonal signals to the heart and blood vessels, thus lowering blood pressure. Frequently prescribed beta blockers include
metoprolol (Lopressor, Toprol XL)
carvedilol (Coreg)
nadolol (Corgard)
penbutolol (Levatol).
Metabolized nebivololincreases vascular NO production, involves endothelial ß2-adrenergic receptor ligation, with a subsequent rise in endothelial free [Ca2+]i and endothelial NO synthase–dependent NO production
Angiotensin-converting enzyme (ACE) inhibitors
These allow blood vessels to widen by preventing the hormone angiotensin from affecting blood vessels. Frequently prescribed ACE inhibitors include captopril (Capoten), lisinopril (Prinivil, Zestril) and ramipril (Altace).
Angiotensin II receptor blockers
These help blood vessels relax by blocking the action of angiotensin. Frequently prescribed angiotensin II receptor blockers include losartan (Cozaar), olmesartan (Benicar) and valsartan (Diovan).
Another very commonly prescribed drug class of medication counteracts hardening of arteries.
Atheroma lipids have enzyme systems that explicitly disassemble cholesterol esters and reconstruct them inside blood vessel walls,e.g., Anacetrapib, Genetic variants that improve cholesterol levels are stimulating development of additional medications.
We can propose that atheroma build up in arterial blood vessel walls constitutes a maladaptive defense against aneurysm and risk of vessel rupture from hypertension.
Arguably, HMG-CoA reductase inhibitors, statin therapy is a second example of a medication that helps protect vascular elasticity, both by its lipid effects and its anti-inflammatory effects.
The best-selling statin is atorvastatin, marketed as Lipitor (manufactured by Pfizer) and Torvast. By 2003, atorvastatin became the best-selling pharmaceutical in history,[4] with Pfizer reporting sales of US$12.4 billion in 2008.[5] As of 2010, a number of statinsare on the market: atorvastatin (Lipitor and Torvast), fluvastatin (Lescol), lovastatin (Mevacor, Altocor, Altoprev), pitavastatin(Livalo, Pitava), pravastatin (Pravachol, Selektine, Lipostat), rosuvastatin (Crestor) and simvastatin (Zocor, Lipex).[6] Several combination preparations of a statin and another agent, such as ezetimibe/simvastatin, are also available.
Compensatory Effects in the Physiology of Circulation
Before declaring vessel elasticity a new and highly desirable treatment target, consider that it is not firmly established that hardening of arteries (loss of elasticity) is entirely maladaptive.
In parallel with any focus on increasing vascular elasticity or compliance, each of the issues discussed, below merits scrutiny and investigation.
Cardiac Circulation Dynamics
Endothelium morphology, rheological properties of intra vasculature fluid dynamics and blood viscosity provided explanation for shear stress of vessels under arterial pressure
While among other reasons for Hypertension increasing prevalence with aging, arterial stiffening is one.
Yet, stiffer vessels are more efficient at transmitting pressure to distal targets. With aging, muscle mass diminishes markedly and the contribution to circulation from skeletal muscle tissue compressions combined with competent venous valves fades.
Aging and Myocardial Diminished Contractility and Ejection Fraction
With aging heart contractility diminishes. These issues can cause under perfusion of tissues, inadequate nutrient blood delivery (ischemia), lactic acidosis, tissue dysfunction and multi-organ failure. Hardened arteries may compensate. Thus, pharmacotherapy to increase Arterial Elasticity may be counterindicated for patients with mild to progressive CHF.
Diminished contractility will increase the amount of energy needed to maintain circulation. It will change efficiency dramatically – consider the difference between periodically pushing someone sitting on a swing at the resonance frequency if the pendulum versus significantly off resonance.
Increased Arterial Elasticity – Potential Risk to Myocardium
The hypothesis that we should focus on cellular therapies to increase vascular compliance may decrease the circulation efficiency and result in worsening of cardiac right ventricular morphology and development of Dilated cardiomyopathy and hypertrophic cardiomyopathy (muscle thickening and diastolic failure), an undesirable outcome resulting from an attempt to treat the hypertension.
4. Vascular Compliance – The Potential of Noval Therapies
Novel Mechanism for Disease Etiology for the Cardiac Phenotype: Modulation of Nuclear and Cytoskeletal Actin Polymerization.
Lamin A/C and emerin regulate MKL1–SRF activity by modulating actin dynamics
Cornell University, Weill Institute for Cell and Molecular Biology/Department of Biomedical Engineering, Ithaca, New York 14853, USA
Chin Yee Ho &
Jan Lammerding
Brigham and Women’s Hospital/Harvard Medical School, Department of Medicine, Boston 02115, Massachusetts, USA
Chin Yee Ho,
Diana E. Jaalouk &
Jan Lammerding
Institute of Biotechnology, University of Helsinki, 00014 Helsinki, Finland
Maria K. Vartiainen
Present address: American University of Beirut, Department of Biology, Beirut 1107 2020, Lebanon.
Diana E. Jaalouk
Contributions
C.Y.H., D.E.J. and J.L. conceived and designed the overall project, with valuable help from M.K.V. C.Y.H. and D.E.J. performed the experiments. C.Y.H., D.E.J. and J.L. analysed data. C.Y.H. and J.L. wrote the paper.
Laminopathies, caused by mutations in the LMNA gene encoding the nuclear envelope proteins lamins A and C, represent a diverse group of diseases that include Emery–Dreifuss muscular dystrophy (EDMD), dilated cardiomyopathy (DCM), limb-girdle muscular dystrophy, and Hutchison–Gilford progeria syndrome1. Most LMNA mutations affect skeletal and cardiac muscle by mechanisms that remain incompletely understood. Loss of structural function and altered interaction of mutant lamins with (tissue-specific) transcription factors have been proposed to explain the tissue-specific phenotypes1. Here we report in mice that lamin-A/C-deficient (Lmna−/−) and LmnaN195K/N195K mutant cells have impaired nuclear translocation and downstream signalling of the mechanosensitive transcription factor megakaryoblastic leukaemia 1 (MKL1), a myocardin family member that is pivotal in cardiac development and function2. Altered nucleo-cytoplasmic shuttling of MKL1 was caused by altered actin dynamics in Lmna−/− and LmnaN195K/N195K mutant cells. Ectopic expression of the nuclear envelope protein emerin, which is mislocalized in Lmnamutant cells and also linked to EDMD and DCM, restored MKL1 nuclear translocation and rescued actin dynamics in mutant cells. These findings present a novel mechanism that could provide insight into the disease aetiology for the cardiac phenotype in many laminopathies, whereby lamin A/C and emerin regulate gene expression through modulation of nuclear and cytoskeletal actin polymerization.
5. Stabilizing BP Variability is the next Big Target in Hypertension Management
Hypertension caused by Arterial Stiffening is Ineffectively Treated by Diuretics and Vasodilatation Antihypertensives
Barcelona, Spain – An aging population grappling with rising rates of hypertension and other cardiometabolic risk factors should prompt an overhaul of how hypertension is diagnosed and monitored and should spur development of drugs with entirely new mechanisms of action, one expert says. Speaking here at the 2013 International Conference on Prehypertension and Cardiometabolic Syndrome, meeting cochair Dr Reuven Zimlichman (Tel Aviv University, Israel) argued that the definitions of hypertension, as well as the risk-factor tables used to guide treatment, are no longer appropriate for a growing number of patients.
Most antihypertensives today work by producing vasodilation or decreasing blood volume and so are ineffective treatments in ISH patients. In the future, he predicts, “we will have to start looking for a totally different medication that will aim to improve or at least to stabilize arterial elasticity: medication that might affect factors that determine the stiffness of the arteries, like collagen, like fibroblasts. Those are not the aim of any group of antihypertensive medications today.”
Zimlichman believes existing databases could be used to develop algorithms that take this progression of disease into account, in order to better guide hypertension management. He also points out that new ambulatory blood-pressure-monitoring devices also measure arterial elasticity. “Unquestionably, these will improve our ability to diagnose both the status of the arteries and the changes of the arteries with time as a result of our treatment. So if we treat the patient and we see no improvement in arterial elasticity, or the patient is worse, something is wrong, something is not working—either the patient is not taking the medication, or our choice of medication is not appropriate, or the dose is insufficient, etc.”
Oslo, Norway – New research that is only just starting to be digested by the hypertension community indicates that visit-to-visit variability in blood-pressure readings will likely become another way of looking for “at-risk” hypertensive patients and in fact is likely to be more reliable as an indicator of cardiovascular risk than the currently used mean BP.
Discussing the importance of this issue for guidelines and clinical practice, Dr Tony Heagerty (University of Manchester, UK) told the recent EuropeanSocietyofHypertension (ESH) EuropeanMeetingon Hypertension2010: “We are poking around in the dark, offering treatment blankly across a large community, and probably treating a lot of people who don’t need to be treated, while not necessarily treating the highest-risk patients. We should stop being reassured by ‘occasional’ normal BPs. The whole game now is, can we improve the identification of our ‘at-risk’ individuals?”
Heagerty was speaking at a special plenary session on late-breaking research discussing BP variability as a risk factor. This issue has emerged following new analyses reported at the ACC meeting and published in a number of papers in the Lancet and Lancet Neurology earlier this year, which showed that variability in blood pressure is a much stronger determinant of both stroke and coronary disease outcome than average blood pressure.
Three years later, 2/1/2013, Zimlichman also argued that definitions of essential and secondary hypertension have changed very little over the past few decades and have typically only been tweaked up or down related to other CV risk factors. Diastolic hypertension has been the primary goal of treatment, and treatment goals have not adequately taken patient age into account (in whom arterial stiffening plays a larger role), and they have typically relied too heavily on threshold cutoffs, rather than the “linear progression” of risk factors and their impact on organ damage.
(Submitted on 3 May 2013 (v1), last revised 6 May 2013 (this version, v2))
Hypertension is one of the most common age-related chronic diseases and by predisposing individuals for heart failure, stroke and kidney disease, it is a major source of morbidity and mortality. Its etiology remains enigmatic despite intense research efforts over many decades. By use of empirically well-constrained computer models describing the coupled function of the baroreceptor reflex and mechanics of the circulatory system, we demonstrate quantitatively that arterial stiffening seems sufficient to explain age-related emergence of hypertension. Specifically, the empirically observed chronic changes in pulse pressure with age, and the impaired capacity of hypertensive individuals to regulate short-term changes in blood pressure, arise as emergent properties of the integrated system. Results are consistent with available experimental data from chemical and surgical manipulation of the cardio-vascular system. In contrast to widely held opinions, the results suggest that primary hypertension can be attributed to a mechanogenic etiology without challenging current conceptions of renal and sympathetic nervous system function. The results support the view that a major target for treating chronic hypertension in the elderly is the reestablishment of a proper baroreflex response.
Klas H. Pettersen1, Scott M. Bugenhagen2, Javaid Nauman3, Daniel A. Beard2 & Stig W. Omholt3
1Department of Mathematical and Technological Sciences, Norwegian University of Life Science, Norway
2Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
3NTNU Norwegian University of Science and Technology, Department of Circulation and Medical Imaging, Cardiac Exercise Research Group, Trondheim, Norway
Correspondence should be addressed to: KHP (klas.pettersen@gmail.com)
Blood Pressure Single-Nucleotide Polymorphisms and Coronary Artery Sisease (page 995)
Blood pressure (BP) is considered a major cardiovascular risk factor that is influenced by multiple genetic and environmental factors. However, the precise genetic underpinning influencing interindividual BP variation is not well characterized; and it is unclear whether BP-associated genetic variants also predispose to clinically apparent cardiovascular disease. Such an association of BP-related variants with cardiovascular disease would strengthen the concept of BP as a causal risk factor for cardiovascular disease. In this issue of Hypertension, analyses within the Coronary ARtery DIsease Genome-Wide Replication And Meta-Analysis consortium indicate that common genetic variants associated with BP in the population, indeed, contribute to the susceptibility for coronary artery disease (CAD). Lieb et al tested 30 single-nucleotide polymorphisms—that based on prior studies were known to affect BP—for their association with CAD. In total, data from 22 233 CAD cases and 64 762 controls were analyzed. The vast majority (88%) of BP-related single-nucleotide polymorphisms were also shown to increase the risk of CAD (as defined by an odds ratio for CAD >1; Figure). On average, each of the multiple BP-raising alleles was associated with a 3% (95% confidence interval, 1.8%–4.3%) risk increase for CAD.
Masked Hypertension in Diabetes Mellitus (page 964)
The first important finding in the IDACO study of masked hypertension (MH) in the population with diabetes mellitus and non–diabetes mellitus was that antihypertensive treatment converted some sustained hypertensives into sustained normotensives; this resulted in an increased cardiovascular disease risk in the treated versus untreated normotensive comparator group (Figure). Not surprisingly, normalization of blood pressure (BP) with treatment did not eliminate the lifetime cardiovascular disease burden associated with prior elevated BP nor did it correct other cardiometabolic risk factors that clustered with the hypertensive state.
The second important IDACO finding was that treatment increased the prevalence of MH by decreasing conventional BP versus daytime ambulatory BP (ABP) by a ratio of ≈3 to 2. The clinical implication of increased prevalence of MH with therapy in the population of both diabetes mellitus and non–diabetes mellitus was that these subjects did not receive sufficient antihypertensive therapy to convert MH into normalized ABP (ie, treated, normalized ABP being the gold standard for minimizing cardiovascular disease risk). Indeed, there is a transformation-continuum from sustained hypertension to MH and finally to sustained normotension with increasing antihypertensive therapy. These IDACO findings strongly suggest that many physicians mistakenly have their primary focus on normalizing in-office rather than out-of-office home BP and/or 24-hour ABP values and this results in an increased prevalence of MH. However, what constitutes optimal normalized ABP will remain empirical until established in randomized controlled trials.
Elevated blood pressure (BP) is a strong, independent, and modifiable risk factor for stroke and heart disease. BP is a heritable trait, and genome-wide association studies have identified several genetic loci that are associated with systolic BP, diastolic BP, or both. Although the variants have modest effects on BP, typically 0.5 to 1.0 mm Hg, their presence may act over the entire life course and, therefore, lead to substantial increase in risk of cardiovascular disease (CVD). However, the independent impact of these variants on CVD risk has not been established in a prospective setting. Havulinna et al genotyped 32 common single-nucleotide polymorphisms in several Finnish cohorts, with up to 32 669 individuals after exclusion of prevalent CVD cases. The median follow-up was 9.8 years, during which 2295 incident CVD events occurred. Genetic risk scores were created for systolic BP and diastolic BP by multiplying the risk allele count of each single-nucleotide polymorphism by the effect size estimated in published genome-wide association studies on BP traits. The GRSs were strongly associated with baseline systolic BP, diastolic BP, and hypertension (all P<10–62). Hazard ratios for incident CVD increased roughly linearly by quintile of systolic BP or diastolic BP GRS (Figure). GRSs remained significant predictors of CVD risk after adjustment for traditional risk factors, even including BP and use of antihypertensive medication. These findings are consistent with a lifelong effect of these variants on BP and CVD risk.
1Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, Australia
2Biostatistics Unit, Group Health Research Institute, Seattle, Washington, USA
3Obesity and Population Health Unit, Baker IDI Heart and Diabetes Institute, Melbourne, Australia
Correspondence toDr Susan M Shortreed, Biostatistics Unit, Group Health Research Institute, 1730 Minor Avenue, Suite 1600, Seattle, WA 98101, USA; shortreed.s@ghc.org
Published Online First 8 March 2013
Abstract
Objective In the majority of studies, the effect of physical activity (PA) on cardiovascular disease (CVD) and mortality is estimated at a single time point. The impact of long-term PA is likely to differ. Our study objective was to estimate the effect of long-term adult-life PA compared with long-term inactivity on the risk of incident CVD, all-cause mortality and CVD-attributable mortality.
Design Observational cohort study.
Setting Framingham, MA, USA.
Patients 4729 Framingham Heart Study participants who were alive and CVD-free in 1956.
Exposures PA was measured at three visits over 30 years along with a variety of risk factors for CVD. Cumulative PA was defined as long-term active versus long-term inactive.
Main outcome measures Incident CVD, all-cause mortality and CVD-attributable mortality.
Results During 40 years of follow-up there were 2594 cases of incident CVD, 1313 CVD-attributable deaths and 3521 deaths. Compared with long-term physical inactivity, the rate ratio of long-term PA was 0.95 (95% CI 0.84 to 1.07) for CVD, 0.81 (0.71 to 0.93) for all-cause mortality and 0.83 (0.72 to 0.97) for CVD-attributable mortality. Assessment of effect modification by sex suggests greater protective effect of long-term PA on CVD incidence (p value for interaction=0.004) in men (0.79 (0.66 to 0.93)) than in women (1.15 (0.97 to 1.37)).
Conclusions
Cumulative long-term PA has a protective effect on incidence of all-cause and CVD-attributable mortality compared with long-term physical inactivity.
In men, but not women, long-term PA also appears to have a protective effect on incidence of CVD.
Summary – PENDING
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Other related articles were published on this Open Access Online Scientific Journal including the following:
Pearlman, JD and A. Lev-Ari 5/24/2013 Imaging Biomarker for Arterial Stiffness: Pathways in Pharmacotherapy for Hypertension and Hypercholesterolemia Management
Lev-Ari, A. 5/17/2013 Synthetic Biology: On Advanced Genome Interpretation for Gene Variants and Pathways: What is the Genetic Base of Atherosclerosis and Loss of Arterial Elasticity with Aging
Bernstein, HL and A. Lev-Ari 5/15/2013 Diagnosis of Cardiovascular Disease, Treatment and Prevention: Current & Predicted Cost of Care and the Promise of Individualized Medicine Using Clinical Decision Support Systems
Pearlman, JD and A. Lev-Ari 5/7/2013 On Devices and On Algorithms: Arrhythmia after Cardiac Surgery Prediction and ECG Prediction of Paroxysmal Atrial Fibrillation Onset
Abstract: 2209 Introduction and Objectives One of the biggest problems in the diagnosis of prostate cancer (PCa), which distinguishes it from many other solid tumors, is the difficulty of tumor imaging by means of standard visualization techniques. A transrectal ultrasound (TRUS) biopsy is mostly performed on the basis of risen PSA and is often blind – tissue specimens are taken from standard zones. Biopsy under MRI control is technically and logistically complicated and expensive, while TRUS can`t always differentiate the suspicious areas. A TRUS-based innovative technique, “Histoscanningâ€� is used in our centre for PCa identification and targeted biopsy.
Methods Prior to template biopsy we have performed Histoscanning to 31 patients, with previous one to six negative TRUS biopsies and persistent clinical suspicion of PCa (elevated PSA, high-grade prostatic intraepithelial neoplasia (HPIN) in 4 cores or suspicious TRUS findings). Age range was 51 – 75, with PSA values 3,8 – 14,3 ng/ml. Prostate size range 22-67cc. Most of the patients (n-26) from this group received therapy with 5α-reductase inhibitors for 6 months or more. Depending on the gland size, 10-14 standardized cores were taken + 4 additional cores from the suspicious zones marked on Histoscanning report.
Results Histopathology identified PCa in 13 out of 31 patients , adenocarcinomas with Gleason score ranging 6-8. In 11 patients with no signs of PCa we found HPIN or low-grade PIN. Comparing histology reports with Histoscanning mapping, in 8 PCa cases we found high correlation of this method with histopathological study on the amount and location of tumor lesions and in 5 cases Histoscanning showed greater spread of lesions, with good correlation of the tumor location.
Conclusions Due to the effectiveness, ease of use and the short time required for data processing, Histoscanning is a promising method for more effective targeted biopsy of the prostate.
As a result of ongoing research, we aim to evaluate sensitivity and specificity of the method, fuse it with MRI, to create a 3D model for biopsy or surgery. In the future, this data could be used for decision making on the nerve-sparing prostatectomy and minimally invasive focal treatments such as cryoablation, high-intensity focused ultrasound, radiofrequency or laser ablation.
Date & Time: May 8, 2013 10:30 AM Session Title: Prostate Cancer: Detection & Screening (V) Sources of Funding: none
Personal note:
On the authors’ intention to fuse HistoScanning with MRI: The authors report a very compelling clinical benefit just from using HistoScanning for guiding their biopsies. HistoScanning itself results in a 3D mapping of the prostate and the suspicious locations inside.
3D mapping of the prostate by HistoScanning analysis following motorised TRUS. the colored locations represents tissue suspicious for being cancer.
Fusing ultrasound & MRI images is prone to image-registration errors (e.g. due to differences in the prostate’s shape-distortion by the probe) which are larger than the accuracy sought for when performing biopsy or nerve-sparing surgery. I recommend anyone who wishes to guide biopsies and treatment based on MRI and therefore is in need for good level of localized-MRI interpretation, to rely on dedicated MRI interpretation applications and not intra-modalities image fusion.
In addition, major benefits of using HistoScanning for managing prostate cancer patients are the accessibility; A urologist can perform himself, at any time he chooses and at any place, simplicity; it only requires routine TRUS, patient-friendly; it lasts less than a minute and does not require anesthesia and low-cost; it’s ultrasound! Mixing HistoScanning with MRI will certainly eliminate these.
This is the second article of a three part series recognizing the immense contribution of Elazer Edelman, MD, PhD, and his laboratory group at MIT to vascular biology, cardiovascular disease studies, and the bioengineering, development, and use of stenting technology for drug delivery, vascular repair, and limitation of vessel damage caused by stent placement.
The first article, published on this Open Access Online Scientific Journal
was concerned with vascular biology, and largely on both the impact of drug delivery design and placement on the endothelium of the vessel wall, and on the kinetics of drug delivery based on the location of stent placement versus intravascular injection as well as the metabolic events taking place in the arterial endothelium, intima, and muscularis.
This second article, is concerned with stents and drug delivery as it has evolved since the last decade of the 20th century based on biomaterials development and vascular biology principles to minimize inherent injury risk over this period.
The third. will be concerned with the lessons from biomaterials and stent mechanics going forward.
Heart care is in the midst of a transformation. Patients who once required heart surgery are treated with a stent, catheters for repair of valves, rhythm abnormalities, and a growing number of heart or vascular distrbances.
The catheters are threaded in through the femoral artery, and sometimes through the radial artery. The American College of Cardiology annual meeting highlights research on these devices. The procedure allows patients to leave the hospital after a day or two post-implant, but the initial cost of the novel devices is high. Not everyone qualifies for the treatment, and it will take a few years to compare the long term results with the benefits from surgery. But these procedures have allowed many patients treatment alternatives to surgery, and they offer an option for people who cannot be successfully managed by conservative medical therapy.
The effects of stent placement on vascular injury and the initiation of an inflammatory response
Leukocytes are recruited early and abundantly to experimentally injured vessels,
in direct proportion to cell proliferation and intimal growth.
Activated circulating leukocytes and Mac-1 (CD11 by CD18, aMb2) (monocytic) expression are
markers of restenosis risk in patients undergoing angioplasty.
Angioplastied vessels lack endothelium but have extensive fibrin(ogen) and platelet deposition. Consequently, Mac-1-dependent adhesion to fibrin(ogen) would be expected to
signal leukocyte recruitment and function, thereby
promote intimal growth
In this study
M1/70, an anti-CD11b blocking mAb, was administered to rabbits before, and every 48 hr for 3, 6, or 14 days after iliac artery balloon denudation.
M1/70 was bound to isolated rabbit monocytes.
The result was
Mac-1-mediated dose-dependent
inhibition of fibrinogen binding in vitro, thereby,
reducing by half leukocyte recruitment at 3, 6, and 14 days after injury.
Neointimal growth 14 days after injury was markedly attenuated by treatment with M1/70 –
intimal area after balloon injury, 0.12+0.09 mm2, compared with
0.32+0.08 mm2 in vehicle treated controls, P<0.01, and
intimal area after stent injury, 0.56+0.16 mm2, compared with
0.84+ 0.13 mm2 in vehicle-treated controls, P <0.05, and
0.90+0.15 mm2 in IgG-treated controls, P <0.02).
Mac-1 blockade reduces experimental neointimal thickening. These findings suggest that
leukocyte recruitment to and
infiltration of injured arteries
may be a valid target for preventing intimal hyperplasia. (1) Emerging data indicate that the inflammatory response after mechanical arterial injury
correlates with the severity of neointimal hyperplasia in animal models
and post angioplasty restenosis in humans.
The present study was designed to examine whether a nonspecific
stimulation of the innate immune system,
induced in close temporal proximity to the vascular injury,
would modulate the results of the procedure.
A LPS dose was chosen to be sufficient to induce systemic inflammation but not septic shock. Key markers of inflammation increased after LPS administration were:
serum interleukin-1 levels, and
monocytic stimulation (CD14 levels on monocytes)
Arterial macrophage infiltration at 7 days after injury was
1.7+1.2% of total cells in controls and
4.2+1.8% in LPS-treated rabbits (n=4, P<0.05).
The injured arteries 4 weeks after injury had significantly increased
luminal stenosis: 38+4.2% versus 23+2.6%, mean+SEM; n=8, P<0.05; and
neointima-to-media ratio: 1.26+0.21 versus 0.66+0.09, P<0.05 in LPS-treated animals compared with controls.
This effect was abolished by anti-CD14 Ab administration. Serum Il-1 levels and monocyte CD14 expression were significantly increased
in correlation with the severity of intimal hyperplasia.
LPS treatment increased neointimal area after stenting
from 0.57+0.07 to 0.77+0.1 mm2, and
stenosis from 9+1% to 13+1.7% (n=5, P<0.05).
Nonspecific systemic stimulation of the innate immune system
concurrently with arterial vascular injury
facilitates neointimal formation, and conditions associated with
increased inflammation may increase restenosis.(2)
The efficacy and toxicity of these local therapeutics depend upon
arterial drug deposition,
distribution, and
retention.
To examine how administered dose and drug release kinetics control arterial drug uptake, a model was created using principles of
computational fluid dynamics and
transient drug diffusion–convection.
The modeling predictions for drug elution were validated using
empiric data from stented porcine coronary arteries.
Inefficient, minimal arterial drug deposition was predicted when a bolus of drug was released and depleted within seconds.
Month-long stent-based drug release
efficiently delivered nearly continuous drug levels, but
the slow rate of drug presentation limited arterial drug uptake.
Uptake was only maximized when
the rates of drug release and absorption matched,
which occurred for hour-long drug release.
Of the two possible means for increasing the amount of drug on the stent,
modulation of drug concentration potently impacts
the magnitude of arterial drug deposition,
while changes in coating drug mass affect duration of release.
We demonstrate the importance of drug release kinetics and administered drug dose
in governing arterial drug uptake and suggest
novel drug delivery strategies for controlling spatio-temporal arterial drug distribution.(3)
Arterial drug concentrations determine local toxicity. Therefore, the emergent safety concerns surrounding drug-eluting stents mandate an investigation of the factors contributing to fluctuations in arterial drug uptake.
Drug-eluting stents were implanted into porcine coronary arteries, arterial drug uptake was followed and modeled using 2-dimensional computational drug transport.
Arterial drug uptake in vivo occurred faster than predicted by free drug diffusion, thus
an alternate, mechanism for rapid transport has been proposed involving carrier-mediated transport.
Though there was minimal variation in vivo in release kinetics from stent to stent,
arterial drug deposition varied by up to 114% two weeks after stent implantation.
extent of adherent mural thrombus fluctuated by 113% within 3 days.
The computational drug transport model predicted that focal and diffuse thrombi
elevate arterial drug deposition in proportion to the thrombus size
by reducing drug washout subsequently increasing local drug availability.
Variable peristrut thrombus can explain fluctuations in arterial drug uptake even in the face of a narrow range of drug release from the stent. The mural thrombus effects on arterial drug deposition may be circumvented by forcing slow rate limiting arterial transport, that cannot be further hindered by mural thrombus. (4)
1. A mAb to the b2-leukocyte integrin Mac-1 (CD11byCD18) Reduces Intimal Thickening after Angioplasty or Stent Implantation in Rabbits. C Rogers, ER Edelman, and DI Simon. PNAS Aug 1998; 95: 10134–10139.
2. Formation After Balloon and Stent Injury in Rabbits Systemic Inflammation Induced by Lipopolysaccharide increases Neointimal Formation After Balloon and Stent Injury in Rabbits. HD Danenberg, FGP Welt, M Walker, III, P Seifert, et al. Circulation 2002;105;2917-2922; http://dx.doi.org/10.1161/01.CIR.0000018168.15904.BB
3. Intravascular drug release kinetics dictate arterial drug deposition, retention, and distribution.
4. Thrombus causes fluctuations in arterial drug delivery from intravascular stents. B Balakrishnan, J Dooley, G Kopia, ER Edelman. J Control Release 2008. http://dx.doi.org/10.1016/j.jconrel.2008.07.027
Perivascular Graft Repair
Heparin remains the gold-standard inhibitor of the processes involved in the vascular response to injury. Though this compound has profound and wide-reaching effects on vascular cells, its clinical utility is unclear. It is clear that the mode of heparin delivery is critical to its potential and it may well be that
routine forms of administration are insufficient
to observe benefit given the heparin’s short half-life and complex pharmacokinetics.
When ingested orally, heparin is degraded to inactive oligomer fragments while systemic administration
is complicated by the need for continuous infusion
and the potential for uncontrolled hemorrhage.
Thus alternative heparin delivery systems have been proposed to maximize regional effects while limiting systemic toxicity. Yet, as heparin is such a potent antithrombotic compound and since existing local delivery systems lack the ability to
precisely regulate release kinetics,
even site-specific therapy is prone to bleeding.
Authors now describe the design and development of a novel biodegradable system for the perivascular delivery of heparin to the blood vessel wall with well-defined release kinetics.
This system consists of heparin-encapsulated
poly(DL lactide-co-glycolide) (pLGA) microspheres sequestered in an alginate gel.
Controlled release of heparin from this heterogeneous system is obtained for a period of 25 days.
The experimental variables affecting heparin release from these matrices were investigated by
gel permeation chromatography (GPC) and scanning electron microscopy (SEM)
to monitor the degradation process and correlated well with the release kinetics.
Heparin-releasing gels inhibited growth in tissue culture of
bovine vascular smooth muscle cells in a dose-dependent manner.
and also controlled vascular injury in denuding and
interposition vascular graft animal models of disease even when uncontrolled bleeding was evident with standard matrix-type release.
This system provided an effective means of examining
the effects of various compounds in
the control of smooth muscle cell proliferation in accelerated arteriopathies and also
shed light on the biologic nature of these processes.(1)
Soft tissue adhesives are employed to repair and seal many different organs that range in both
tissue surface chemistry and
mechanical effects during organ function.
This complexity motivates the development of tunable adhesive materials with
high resistance to uniaxial or multiaxial loads
dictated by a specific organ environment.
Co-polymeric hydrogels comprising
aminated star polyethylene glycol and
dextran aldehyde (PEG:dextran)
are materials exhibiting physico-chemical properties that can be modified
Here we report that resistance to failure
under specific loading conditions, as well as
tissue response at the adhesive material–tissue interface, can be modulated through regulation of
the number and density of adhesive aldehyde groups.
Author found that atomic force microscopy (AFM) can
characterize the material aldehyde density available for tissue interaction,
facilitating rapid, informed material choice.
Further, the correlation between AFM quantification of nanoscale unbinding forces
with macroscale measurements of adhesion strength
by uniaxial tension or multiaxial burst pressure allows the design of materials with specific cohesion and adhesion strengths.
However, failure strength alone does not predict optimal in vivo reactivity. The development of adhesive materials is significantly enabled when
experiments are integrated along length scales to consider
organ chemistry and mechanical loading states concurrently
with adhesive material properties and tissue response. (2)
Cell culture and animal data support the role of endothelial cells and endothelial-based compounds in regulating vascular repair after injury.
Authors describe a long-term study in pigs in which the biological and immunological
responses to endothelial cell implants were investigated 3 months after angioplasty,
approximately 2 months after the implants have degraded.
Confluent porcine or bovine endothelial cells grown in polymer matrices were implanted adjacent to 28 injured porcine carotid arteries.
Porcine and bovine endothelial cell implants significantly
reduced experimental restenosis compared to control by 56 and 31%, respectively.
Host humoral responses were investigated by detection of an increase in serum antibodies that bind to the bovine or porcine cell strains used for implantation.
A significant increase in titer of circulating antibodies to the bovine cells was observed
after 4 days in all animals implanted with xenogeneic cells.
Detected antibodies returned to presurgery levels after Day 40.
No significant increase in titer of antibodies to the porcine cells was observed during the experiment in animals implanted with porcine endothelial cells.
No implanted cells, Gelfoam, or focal inflammatory reaction could be detected
histologically at any of the implant sites at 90 days.
Suggesting that tissue engineered endothelial cell implants
may provide long term control of vascular repair after injury,
rather than simply delaying lesion formation and that
allogeneic implants are able to provide a greater benefit than xenogeneic implants. (3)
Vascular access complications are a major problem in hemodialysis patients. Native arteriovenous fistulae, historically the preferred mode of access, have a patency rate of only 60% at 1 year.
The most common mode of failure is due to progressive stenosis at the anastomotic site.
Authors have previously demonstrated that perivascular endothelial cell implants
inhibit intimal thickening following acute balloon injury in pigs, and now seek to determine if these
implants provide a similar benefit in the chronic and more complex injury model of arteriovenous anastomoses.
Side-to-side femoral artery-femoral vein anastomoses were created in 24 domestic swine.
toxicological,
biological and
immunological responses
were investigated 3 days and 1 and 2 months postoperatively to allogeneic endothelial cellimplants . The anastomoses were wrapped with polymer matrices containing
confluent porcine aortic endothelial cells (PAE; n = 14) or
control matrices without cells (n = 10).
PAE implants significantly reduced intimal hyperplasia at the anastomotic sites
compared to controls by 68% (p ! 0.05) at 2 months.
The beneficial effects of the PAE implants were not due to
differences in the rates of reendothelialization between the groups.
No significant immunological response to the allogeneic endothelial cells that impacted on efficacy was detected in any of the pigs.
No apparent toxicity was observed in any of the animals treated with endothelial implants.
These data suggest that perivascular endothelial cell implants
are safe and reduce early intimal hyperplasia in a porcine model of arteriovenous anastomoses. (4)
1. Perivascular graft heparin delivery using biodegradable polymer wraps. ER Edelman, A Nathan,
3. Endothelial Implants Provide Long-Term Control of Vascular Repair in a Porcine Model of Arterial Injury. HM Nugent, ER Edelman. J Surg Res 2001; 99:228–234. http://dx.doi.org/10.1006/jsre.2001.6198
4. Perivascular Endothelial Implants Inhibit Intimal Hyperplasia in a Model of Arteriovenous Fistulae: A Safety and Efficacy Study in the Pig. HM Nugent, A Groothuis, P Seifert, et al. J Vasc Res 2002;39:524–533.
Endovascular stents reside in a dynamic flow environment and yet the impact of flow
on arterial drug deposition after stent-based delivery is only now emerging.
Authors employed computational fluid dynamic modeling tools to investigate
the influence of luminal flow patterns on arterial drug deposition and distribution.
Flow imposes recirculation zones distal and proximal to the stent strut that extend
the coverage of tissue absorption of eluted drug and
induce asymmetry in tissue drug distribution.
Our analysis now explains how the disparity in
sizes of the two recirculation zones and
the asymmetry in drug distribution are determined by a complex interplay of local flow and strut geometry.
When temporal periodicity was introduced as a model of
pulsatile flow,
the net luminal flow served as an index of flow-mediated spatiotemporal tissue drug uptake.
Dynamically changing luminal flow patterns are intrinsic to the coronary arterial tree. Coronary drug-eluting stents should be appropriately considered where
luminal flow,
strut design and
pulsatility
have direct effects on tissue drug uptake after local delivery.(1)
The efficacy of drug-eluting stents (DES) requires delivery of potent compounds directly to the underlying arterial tissue.
The commercially available DES drugs rapamycin and paclitaxel bind specifically to
their respective therapeutic targets, FKBP12 and polymerized microtubules,
while also associating in a more general manner with other tissue elements.
As it is binding that provides biological effect, the question arises as to whether other
locally released or systemically circulating drugs can
displace DES drugs from their tissue binding domains.
Specific and general binding sites for both drugs are distributed across the media and adventitia with higher specific binding associated with the binding site densities in the media.
The ability of rapamycin and paclitaxel to compete for specific protein binding and general tissue deposition
was assessed for both compounds simultaneously and
in the presence of other commonly administered cardiac drugs.
Drugs classically used to treat standard cardiovascular diseases, such as hypertension and hypercoaguability,
displace rapamycin and paclitaxel from general binding sites, possibly
decreasing tissue reserve capacity for locally delivered drugs.
Paclitaxel and rapamycin do not affect the other’s binding
to their biologically relevant specific protein targets, but
can displace each other from tissue at three log order molar excess,
decreasing arterial loads by greater than 50%.
Local competitive binding therefore should not limit the placement of rapamycin and paclitaxel eluting stents in close proximity.(2)
Stent thrombosis is a lethal complication of endovascular intervention. There is concern about the inherent risk associated with specific stent designs and drug-eluting coatings
Authored examined whether drug-eluting coatings are inherently thrombogenic and whether the response to these materials was determined to any degree
by stent design and
stent deployment with custom-built stents.
Drug/polymer coatings uniformly reduce rather than increase thrombogenicity relative to matched bare metal counterparts (0.65-fold; P 0.011).
Thick-strutted (162 m) stents were 1.5-fold more thrombogenic than otherwise
identical thin-strutted (81 m) devices in ex vivo flow loops (P< 0.001),
commensurate with 1.6-fold greater thrombus coverage
3 days after implantation in porcine coronary arteries (P 0.004).
When bare metal stents were deployed in
malapposed or overlapping configurations, thrombogenicity increased compared with apposed, length-matched controls (1.58-fold, P < 0.001; and 2.32-fold, P <0.001).
The thrombogenicity of polymer-coated stents with thin struts was
lowest in all configurations and remained insensitive to incomplete deployment.
Computational modeling– based
predictions of stent-induced flow derangements
correlated with spatial distribution of formed clots.
Drug/polymer coatings do not inherently increase acute stent clotting;
they reducethrombosis.
However, strut dimensions and positioning relative to the vessel wall
are critical factors in modulating stent thrombogenicity.
Optimal stent geometries and surfaces, as demonstrated with thin stent struts,
help reduce the potential for thrombosis
despite complex stent configurations and variability in deployment. (Circulation. 2011;123:1400-1409.) (3)
1. Luminal flow patterns dictate arterial drug deposition in stent-based delivery.
VB Kolachalama, AR Tzafriri, DY Arifin, ER Edelman. J Control Release 2009; 133:24–30.
Multiple studies have shown that diabetes mellitus (DM) can affect the
efficacy of revascularization therapies and subsequent clinical outcomes.
Selecting the appropriate myocardial revascularization strategy is critically important
in the setting of multivessel coronary disease.
Optimal medical therapy is an appropriate first-line strategy in patients with DM and mild symptoms. When medical therapy does not adequately control symptoms,
revascularization with either PCI or CABG may be used.
In patients with treated DM, moderate to severe symptoms and complex multivessel coronary disease,
coronary artery bypass graft surgery provides better survival,
fewer recurrent infarctions and
greater freedom from re-intervention.
Decisions regarding revascularization in patients with DM must take into account multiple factors and as such require a multidisciplinary team approach (‘heart team’). (1)
An incomplete understanding of the transport forces and local tissue structures
that modulate drug distribution has hampered
local pharmacotherapies in many organ systems.
These issues are especially relevant to arteries, where stent-based delivery allows fine control of locally directed drug release.
Local delivery produces tremendous drug concentration gradients
these are in part derived from transport forces,
differences in deposition from tissue to tissue
This suggests that tissue ultrastructure also plays an important role.
Authors measured the equilibrium drug uptake and the penetration and diffusivity of
dextrans (a model hydrophilic drug similar to heparin) and albumin
in orthogonal planes in arteries explanted from different vascular beds.
Authors found significant variations in drug distribution with
geometric orientation and
arterial connective tissue content.
Drug diffusivities parallel to the connective tissue sheaths were
one to two orders of magnitude greater than across these sheaths.
This diffusivity difference remained relatively constant for drugs up to 70 kDa
before decreasing for larger drugs.
Drugs also distributed better into elastic arteries, especially at lower molecular weights,
with almost 66% greater transfer into the thoracic aorta
than into the carotid artery.
Arterial drug transport is thus highly anisotropic and
dependent on arterial tissue content.
The role of the local composition and geometric organization of arterial tissue
in influencing vascular pharmacokinetics
is likely to become a critical consideration for local vascular drug delivery (2)
Radiolabeled drug-eluting stents have been proposed
to potentially reduce restenosis in coronary arteries.
A P-32 labeled oligonucleotide (ODN) loaded on a polymer coated stent
is slowly released in the arterial wall to deliver a therapeutic dose to the target tissue.
A relatively low proportion of drugs is transferred to the arterial wall (< 2%– 5% typically). This raises questions about the degree to which radiolabeled drugs eluted from the stent
can contribute to the total radiation dose delivered to tissues.
A three-dimensional diffusion-convection transport model is used
to model the transport of a hydrophilic drug released
from the surface of a stent to the arterial media.
Large drug concentration gradients are observed
near the stent struts giving rise to a
non-uniform radiation activity distribution for the drug
in the tissues as a function of time.
A voxel-based kernel convolution method is used to calculate the radiation dose rate
resulting from this activity build-up in the arterial wall
based on the medical internal radiation dose formalism.
Measured residence time for the P-32 ODN in the arterial wall and
at the stent surface obtained from animal studies
are used to normalize the results in terms of absolute dose to tissue.
The results indicate radiation due to drug eluted from the stent
contributes only a small fraction of the total radiation delivered to the arterial wall,
the main contribution comes from the activity embedded in the stent coating.
For hydrophilic compounds with rapid transit times in arterial tissue and minimal binding interactions,
the activity build-up in the arterial wall contributes only a small fraction
to the total dose delivered by the P-32 ODN stent.
For these compounds, it is concluded that radiolabeled drug-eluting stent
would not improve the performance of radioactive stents in treating restenosis.
Also, variability in the efficacy of drug delivery devices
makes accurate dosimetry difficult and
the drug washout in the systemic circulatory system
may yield an unnecessary activity build-up and dose to healthy organs. (3)
The first compounds considered for stent-based delivery,
such as heparin have failed to stop restenosis clinically.
More recent compounds, such as paclitaxel, are of a different sort.
They are hydrophobic, and their effects after local release seem far more profound.
This dichotomy raises the question of whether drugs that have an effect when released from a stent do so because of
differences in biology or differences in physicochemical properties and targeting.
Authored applied continuum pharmacokinetics to examine the effects of
transport forces and device geometry on
the distribution of stent-delivered hydrophilic and hydrophobic drugs.
Stent-based delivery leads to large concentration gradients.
Drug concentrations range from nil to several times the
mean tissue concentration over a few micrometers.
Concentration variations were a function of the Peclet number (Pe),
the ratio of convective to diffusive forces.
Although hydrophobic drugs exhibit greater variability than hydrophilic drugs,
more negatively than hydrophobic drugs, and notably
affect local concentrations without changing mean concentrations.
Local concentrations and gradients are inextricably linked to biological effect. Therefore,
these results provide a potential explanation for the variable success of stent-based delivery.
Authors conclude that mere proximity of delivery devices to tissues
does not ensure adequate targeting,
because physiological transport forces cause
local concentrations to deviate significantly from mean concentrations. (4)
1. Role of CABG in the management of obstructive coronary arterial disease in patients with diabetes mellitus. D Aronson, ER Edelman. Curr Opin Pharmacol 2012, 12:134–141. Issue on Cardiovascular and renal. [Eds: JY Jeremy, K Zacharowski, N Shukla, S Wan]. http://dx.doi.org/10.1016/j.coph.2012.01.011
3. Dose model for stent-based delivery of a radioactive compound for the treatment of restenosis in coronary arteries. C Janickia, Chao-Wei Hwang, ER Edelman. Med Phys 2003; 30(10), 2622-7. http://dx.doi.org/10.1118/1.1607506
4. Physiological Transport Forces Govern Drug Distribution for Stent-Based Delivery. Chao-Wei Hwang, D Wu, ER Edelman. Circulation. 2001;104(5) :600-605; e14 – e9010. http://dx.doi.org/10.1161/hc3101.09221
Stent-Versus-Stent Equivalency Trials. Are Some Stents More Equal Than Others? Elazer R. Edelman, Campbell Rogers Circulation. 1999; 100(9): 896-898; e47 – e47. http://dx.doi.org/10.1161/01.CIR.100.9.896
New endovascular stent designs are displacing tried and-true devices for use in an ever-broader array of lesions. There is disagreement as to which device is most advantageous and whether design determines outcome. Preclinical research says that this should be the case. Clinical trials have failed to validate design dependence. Can the divergent results be reconciled? More than 50 different stent configurations are available. The processes of industrial development and federal regulatory evaluation support the importance of design.
Stents are made from
a spectrum of materials
a range of manufacturing techniques, and have
variable surfaces,
dimensions,
surface coverage, and
strut configurations.
The number of parameters involved may doom the number of subsets to approach the number of designs. Moreover, each device seems to have a unique optimal mode of placement. Differences have been reported in
flexibility,
tracking ability,
expansion,
radiovisibility,
side-branch access, and
resistance to compression and recoil for different devices.
Regulatory approval includes standards for safety:
toxicity,
biocompatibility,
structural and material analysis, and
fatigue testing
It has been suggested that
hoop strength,
surface cracking,
uniformity of expansion, and
other features become standardized as well.
Four different direct comparisons of first-generation Palmaz-Schatz slotted-tube stents and
second-generation stents have been made. In several studies there were no significant differences
in restenosis at follow-up, including
minimal luminal diameter (MLD),
percent diameter stenosis,
late loss, or
binary restenosis rate.
In the fourth study, restenosis was far greater for the Gianturco-Roubin II (GR-II) stent (Cook) than
the Palmaz-Schatz stent (Cordis-Johnson & Johnson).
The data for all stents bunch across trials: with the exception of the GR-II stent,
variability between the test stent groups was no greater than
the variability between the Palmaz-Schatz stent groups in the different trials.
Three distinct possibilities exist to explain the absence of clinical evidence that different designs behave differently:
(1) no differences in clinical outcomes exist between devices;
(2) differences exist but are so slight as to be clinically meaningless; and
(3) differences exist that may be clinically meaningful, but trials performed to date were not designed to detect them.
Schematic representation of device performance plotting outcome against indication indicates that
complication rates rise as lesion complexity increases.
When 2 devices are clinically different, their curves are displaced, and when they are indistinguishable, their curves overlap.
Clinical trials that restrict the test population to lesions low on the complexity scale
ensure safety for all patients but are not the ideal venues in which to detect differences between devices.
Thus, although stents 1 and 2 may have different clinical outcomes, in a restricted-criteria equivalency trial with low complexity, they appear identical. It is only when the test device performs worse than the standard, that differences can be appreciated.
In contrast, an open registry will not only show when a test stent is worse than the standard stent but also when it is better.
Equivalency Trials
Stent-versus-stent trials are equivalency trials, designed to show that a test device performs “as well as” a standard, currently acceptable device. This is a valid regulatory threshold but
not the means to evaluate the full potential of a device.
Equivalency trials must by definition commence with a patient population for whom the standard device is safe. Trials with currently approved devices as the standard necessitate that
patient entry and lesion selection be determined by
limitations of the standard, not the device.
to observe a difference in such a trial
the test device performs worse
For the test device to perform better, both the test and the standard must be challenged.
This was not the case for the trials in which
the average reference vessel size was 3.0+0.05 mm and
American College of Cardiology type B2 and C lesions accounted for only ~65% of lesions.
These lesions are those for which the Palmaz-Schatz stent is approved and technically suited, but
they represent only a minority of those lesions now receiving stents
Complexity, Equivalence, and Better
In truth, it may be most appropriate to think about parameters of device success and safety as a continuum, describing a correlation between events such as
thrombosis or restenosis and
a continuous measure of indication,
vessel dimension, or lesion complexity (Figure).
A given device may be represented by a characteristic response over a range of indications.
When there is a lateral offset to the curves,
differences in potential performance are anticipated.
Curves might even cross, rather than run parallel, indicating that devices might be matched
to lesions and indications. Open trials would consider the entire range of the curves.
equivalency trials are limited to a small region of the curve.
The first-generation stents were a major innovation in interventional cardiology, and their place in medical history and biotechnology is unassailable.
Demonstration that new stents are better than old will require that evaluations be
performed in lesions for which current devices have marginal or limited application.
Complex or acutely unstable lesions, small arteries, and diseased bypass grafts are
the next great challenges of interventional cardiology.
Perhaps in these settings, future stent trials will provide firm evidence that
the manner in which blood vessels are manipulated dictates biological sequelae.
Proof that stent design can alter clinical outcomes may then unleash the potential
to change the way in which we consider design, approval, and use of new devices.
REFERENCES
Menichelli, M. (2006). Sirolimus Stent vs. Bare Stent in Acute Myocardial Infarction Trial. Presented at The European Paris Course on Revascularization (EuroPCR), May 16-19, 2006, Paris, France Paris, France.http://www.medscape.com/viewprogram/5505?rss
Pfisterer, P.E. (2006). Basel Stent Cost-effectiveness Trial-Late Thrombotic events (BASKET LATE) Trial. Presented at American College of Cardiology 55th Annual Scientific Session, March 11 – 14, 2006, Atlanta, Georgia.http://www.medscape.com/viewprogram/5185
Rogers, C. Edelman E.R. (2006). Pushing drug-eluting stents into uncharted territory, Simpler then you think – more complex than you imagine. Circulation,113, 2262-2265.
Shirota, T., Yasui, H., Shimokawa, H. & Matsuda, T. (2003). Fabrication of endothelial progenitor cell (EPC)-seeded intravascular stent devices and in vitro endothelialization on hybrid vascular tissue. Biomaterials 24(13), 2295–2302.
Simonton, C. (2006). The STENT Registry: A real-world look at Sirolimus- and Pacitaxel-Eluting Stents. Cath Lab Digest, 14 (1), 1-10.
Turco, M. (2006). TAXUS ATLAS Trial – 9-Month results: Evaluation of TAXUS Liberte vs. TAXUS Express. Presented at The European Paris Course on Revascularization (EuroPCR), May 16-19, 2006, Paris, France Paris, France.http://www.medscape.com/viewprogram/5505?rss
Hypertriglyceridemia concurrent Hyperlipidemia: Vertical Density Gradient Ultracentrifugation a Better Test to Prevent Undertreatment of High-Risk Cardiac Patients
Fight against Atherosclerotic Cardiovascular Disease: A Biologics not a Small Molecule – Recombinant Human lecithin-cholesterol acyltransferase (rhLCAT) attracted AstraZeneca to acquire AlphaCore
High-Density Lipoprotein (HDL): An Independent Predictor of Endothelial Function & Atherosclerosis, A Modulator, An Agonist, A Biomarker for Cardiovascular Risk
Peroxisome proliferator-activated receptor (PPAR-gamma) Receptors Activation: PPARγ transrepression for Angiogenesis in Cardiovascular Disease and PPARγ transactivation for Treatment of Diabetes
Clinical Trials Results for Endothelin System: Pathophysiological role in Chronic Heart Failure, Acute Coronary Syndromes and MI – Marker of Disease Severity or Genetic Determination?
Inhibition of ET-1, ETA and ETA-ETB, Induction of NO production, stimulation of eNOS and Treatment Regime with PPAR-gamma agonists (TZD): cEPCs Endogenous Augmentation for Cardiovascular Risk Reduction – A Bibliography
Positioning a Therapeutic Concept for Endogenous Augmentation of cEPCs — Therapeutic Indications for Macrovascular Disease: Coronary, Cerebrovascular and Peripheral
Cardiovascular Outcomes: Function of circulating Endothelial Progenitor Cells (cEPCs): Exploring Pharmaco-therapy targeted at Endogenous Augmentation of cEPCs
Vascular Medicine and Biology: CLASSIFICATION OF FAST ACTING THERAPY FOR PATIENTS AT HIGH RISK FOR MACROVASCULAR EVENTS Macrovascular Disease – Therapeutic Potential of cEPCs
Cardiac Surgery Theatre in China vs. in the US: Cardiac Repair Procedures, Medical Devices in Use, Technology in Hospitals, Surgeons’ Training and Cardiac Disease Severity”
Dilated Cardiomyopathy: Decisions on implantable cardioverter-defibrillators (ICDs) using left ventricular ejection fraction (LVEF) and Midwall Fibrosis: Decisions on Replacement using late gadolinium enhancement cardiovascular MR (LGE-CMR)
Competition in the Ecosystem of Medical Devices in Cardiac and Vascular Repair: Heart Valves, Stents, Catheterization Tools and Kits for Open Heart and Minimally Invasive Surgery (MIS)
Global Supplier Strategy for Market Penetration & Partnership Options (Niche Suppliers vs. National Leaders) in the Massachusetts Cardiology & Vascular Surgery Tools and Devices Market for Cardiac Operating Rooms and Angioplasty Suites
Diagram showing the location of vascular smooth muscle cells (Photo credit: Wikipedia)
English: simplified diagram of the human Arterial system in anterior view. Français : Diagramme simplifié du système artériel humain en vue antérieure (en anglais). (Photo credit: Wikipedia)
, where t is time, s is a complex parameter, and A is a complex scalar. Complex values simply mean two dimensional, e.g., magnitude (as in resistance) plus phase shift (to account for reactive components).
where V and I are the complex scalars in the voltage and current respectively and Z is the complex impedance.
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