Hi. I’m David Kerr, professor of cancer medicine from the University of Oxford.
As you know, I’ve believed for some time that ploidy (the number of sets of chromosomes in a cell) measurements have been largely overlooked in terms of the relative importance of prognostic markers for the whole range of different cancer types. One of my friends and colleagues, Prof Håvard Danielsen, from the University of Oslo, has established what I consider one of the best assays in the world for measuring ploidy and DNA content in tumors, and characterizing it from paraffin-embedded tissue. ‘It’s a very available system.
New Data on an Overlooked Biomarker
To this end, a really interesting study was recently reported in Science by Teresa Davoli and colleagues, who looked at ploidy across a whole range of tumor types and tried to relate ploidy measurements to the hallmarks of cancer. A ploidy is also known as somatic copy number alterations (SCNAs), and [the authors] refined the definition of ploidy a little, into [SCNAs] that were predominantly focal or [SCNAs] that mainly correlated with whole-arm ploidy, or changes in DNA content in that way.
This was a fascinating study, in which they found that ploidy was indeed associated with prognosis, but also with signatures associated with proliferation, increased expression of the gene’s enzymes involved in control of proliferation and cell cycle—this was mainly for the focal SCNAs. The larger, long-arm, and chromosomal ploidy tended to be associated with reduced expression of immune signature and immune infiltration.
This is an important first step in showing that ploidy does correlate with drivers or hallmarks of cancer. There are some subtle differences that lead you toward increased proliferation or increased immune invasion, both of which work in terms of establishing the cancer.
The researchers then retrospectively analyzed ploidy levels in melanoma tumor specimens saved from two large trials using immune checkpoint inhibitors. What they showed was that aneuploid tumors (eg, elevated levels of SCNA) were indeed more resistant to immune blockade.
It’s a really fascinating new potential use of ploidy, which has been around for decades and has been much overlooked. Not only is it a prognostic marker and therefore gives us important information about the biological behavior of our patients’ tumors, but it may also be a predictive factor in that aneuploid tumors may be relatively resistant to immune checkpoint blockade.
[Because this study was conducted] retrospectively, there’s much work yet to be done. [However, it offers] a really interesting insight for a marker, which I think could be delivered relatively easily in a sophisticated way in every pathology lab in the world. It surprises me that we don’t measure ploidy more. [It is] another interesting insight—some beautiful basic science uncovering the subtle differences in ploidy, how it links to the different hallmarks of cancer, and how it may aid us in selecting patients who may benefit less from immune checkpoint inhibitors.
Thank you for listening. It will be really keen for you to have a look at the Science paper and post any comments that you may care to talk about. This is an unfinished story but one that must be followed up prospectively.
For all book lovers please visit my friend’s website.
There are a large number of biomarkers with potential utility for early cancer detection from blood samples
Few biomarkers have been studied sufficiently with clinical validation to allow their use in combination for screening in the general population.
We used an iterative mapping review of 20,000 references, retrieving 3,990 relevant papers, and identified 788 markers in blood of potential use
Screening for cancer can save lives, but it is difficult to justify individual screening programmes for many cancer types. However, cancers of different types share many attributes, and markers of cancer biology found in the blood. We surveyed the literature to identify known biomarkers using a new mapping approach. With nearly 20,000 papers on the subject, we retrieved 3990 papers, and identified 788 markers in blood of potential use. Most have not been studied enough to justify their use in clinical practice. This evidence based approach should help us to develop a blood-based cancer screening test in the general population.
The Early Cancer Detection Consortium is developing a blood-test to screen the general population for early identification of cancer, and has therefore conducted a systematic mapping review to identify blood-based biomarkers that could be used for early identification of cancer.
A mapping review with a systematic approach was performed to identify biomarkers and establish their state of development. Comprehensive searches of electronic databases Medline, Embase, CINAHL, the Cochrane library and Biosis were conducted in May 2014 to obtain relevant literature on blood-based biomarkers for cancer detection in humans. Screening of retrieved titles and abstracts was performed using an iterative sifting process known as “data mining”. All blood based biomarkers, their relevant properties and characteristics, and their corresponding references were entered into an inclusive database for further scrutiny by the Consortium, and subsequent selection of biomarkers for rapid review. This systematic review is registered with PROSPERO (no. CRD42014010827).
The searches retrieved 19,724 records after duplicate removal. The data mining approach retrieved 3990 records (i.e. 20% of the original 19,724), which were considered for inclusion. A list of 814 potential blood-based biomarkers was generated from included studies. Clinical experts scrutinised the list to identify miss-classified and duplicate markers, also volunteering the names of biomarkers that may have been missed: no new markers were identified as a result. This resulted in a final list of 788 biomarkers.
This study is the first to systematically and comprehensively map blood biomarkers for early detection of cancer. Use of this rapid systematic mapping approach found a broad range of relevant biomarkers allowing an evidence-based approach to identification of promising biomarkers for development of a blood-based cancer screening test in the general population.
Scientists have discovered a unique protein that gives away the presence of inactive HIV in the body.
Sniffing out these hidden caches of the virus is something researchers have been trying to do for decades. Now that we have a lead, the finding could speed up research on a cure.
Thanks to modern antiretroviral therapies, for many people, HIV is not the death sentence it once was. But we still don’t have a reliable way of permanently flushing it out of someone’s system.
Drugs can keep the virus in check, but unfortunately HIV has a major weapon – it stows away in secret reservoirs in the immune system. There it lies dormant until conditions are more suitable to re-emerge.
That’s why people infected with HIV have to spend a lifetime on expensive drugs, because the virus can take only weeks to come back from its latent state if drug treatment is stopped.
Those nasty secret reservoirs HIV creates are located in long-lived immune cells known as resting T cells. Because the virus hijacks these cells and integrates its genetic material into the DNA of the patient, it makes reservoir T cells extremely hard to track down.
Now a team of French scientists has managed to achieve this important milestone in HIV research by discovering a biomarker that exists only on the surface of T cells that harbour the latent virus.
“Since 1996, the dream has been to kill these nasty cells in hiding, but we had no way to do it because we had no way to recognise them,” says virologist Monsef Benkirane from University of Montpellier in France.
This is huge. Having CD32a as a biomarker for HIV reservoirs means scientists have a better chance to track them down in a patient’s blood. This paves the way for more research into the mechanisms that allow HIV to create such reservoirs in the first place.
Armed with such knowledge, scientists could then find ways to actually get rid of these HIV nests for good.
The team first detected the protein in a lab-made model of HIV infection, before moving on to test it as a biomarker in actual blood samples from 12 people who live with HIV and are receiving treatment.
They separated T cells with CD32a from other T cells in the blood samples, and found that the cells with this particular protein indeed had latent HIV harboured inside them.
Unfortunately, it’s not a smoking gun in every case, since the protein was found only on about half of all latently infected T cells.
Douglas Richman from University of California San Diego, who wasn’t involved in the research, writes that “the eradication of latent HIV would require a much greater reduction in the number of latently infected cells in the body.”
But it’s an extremely encouraging first step in the long search for a marker that could help us track down the nasty virus once it goes into hiding.
Tony Fauci, director of the US National Institute of Allergies and Infectious Disease, told Nature that a good next step would be to replicate the findings in more blood samples from a larger variety of patients who have the virus.
It’s still way too soon to say that we’re on the path to an actual HIV cure, but the news is super-exciting to researchers who have been hammering away at this problem for decades.
“I really hope this is correct,” says Fauci. “The fact that this work has been done by such competent investigators, and the data looks good, makes me optimistic.”
In a world where HIV continues to be a major health issue, this discovery indeed gives cause for optimism.
About 36.7 million people around the world live with HIV, but only 17 million have access to antiretroviral therapy, according to data from the US CDC.
The scientists have already filed a patent for the diagnostic and therapeutic use of the new biomarker.
What are some of the most troubling numbers in mental health? Six to 10 — the number of years it can take to properly diagnose a mental health condition. Dr. Elizabeth Osuch, a Researcher at Lawson Health Research Institute and a Psychiatrist at London Health Sciences Centre and the Department of Psychiatry at Western University, is helping to end misdiagnosis by looking for a ‘biomarker’ in the brain that will help diagnose and treat two commonly misdiagnosed disorders.
Major Depressive Disorder (MDD), otherwise known as Unipolar Disorder, and Bipolar Disorder (BD) are two common disorders. Currently, diagnosis is made by patient observation and verbal history. Mistakes are not uncommon, and patients can find themselves going from doctor to doctor receiving improper diagnoses and prescribed medications to little effect.
Dr. Osuch looked to identify a ‘biomarker’ in the brain which could help optimize the diagnostic process. She examined youth who were diagnosed with either MDD or BD (15 patients in each group) and imaged their brains with an MRI to see if there was a region of the brain which corresponded with the bipolarity index (BI). The BI is a diagnostic tool which encompasses varying degrees of bipolar disorder, identifying symptoms and behavior in order to place a patient on the spectrum.
What she found was the activation of the putamen correlated positively with BD. This is the region of the brain that controls motor skills, and has a strong link to reinforcement and reward. This speaks directly to the symptoms of bipolar disorder. “The identification of the putamen in our positive correlation may indicate a potential trait marker for the symptoms of mania in bipolar disorder,” states Dr. Osuch.
In order to reach this conclusion, the study approached mental health research from a different angle. “The unique aspect of this research is that, instead of dividing the patients by psychiatric diagnoses of bipolar disorder and unipolar depression, we correlated their functional brain images with a measure of bipolarity which spans across a spectrum of diagnoses.” Dr. Osuch explains, “This approach can help to uncover a ‘biomarker’ for bipolarity, independent of the current mood symptoms or mood state of the patient.”
Moving forward Dr. Osuch will repeat the study with more patients, seeking to prove that the activation of the putamen is the start of a trend in large numbers of patients. The hope is that one day there could be a definitive biological marker which could help differentiate the two disorders, leading to a faster diagnosis and optimal care.
In using a co-relative approach, a novel method in the field, Dr. Osuch uncovered results in patients that extend beyond verbal history and observation. These results may go on to change the way mental health is diagnosed, and subsequently treated, worldwide.
We compared 12 biomarkers in plasma obtained a median of 16 days after therapy initiation from 10 patients with a complete response by day 28 after therapy initiation and in plasma obtained from 10 patients with progressive GVHD during therapy. The lead biomarker, suppression of tumorigenicity 2 (ST2), was measured at the beginning of treatment for GVHD in plasma from 381 patients and during the first month after transplantation in three independent sets totaling 673 patients to determine the association of this biomarker with treatment-resistant GVHD and 6-month mortality after treatment or transplantation.
Of the 12 markers, ST2 had the most significant association with resistance to GVHD therapy and subsequent death without relapse. As compared with patients with low ST2 values at therapy initiation, patients with high ST2 values were 2.3 times as likely to have treatment-resistant GVHD (95% confidence interval [CI], 1.5 to 3.6) and 3.7 times as likely to die within 6 months after therapy (95% CI, 2.3 to 5.9). Patients with low ST2 values had lower mortality without relapse than patients with high ST2 values, regardless of the GVHD grade (11% vs. 31% among patients with grade I or II GVHD and 14% vs. 67% among patients with grade III or IV GVHD, P<0.001 for both comparisons). Plasma ST2 values at day 14 after transplantation were associated with 6-month mortality without relapse, regardless of the intensity of the conditioning regimen.
ST2 levels measured at the initiation of therapy for GVHD and during the first month after transplantation improved risk stratification for treatment-resistant GVHD and death without relapse after transplantation.
Empirical treatment with antifungal drugs is often used in haematology patients at high risk of invasive aspergillosis. We compared a standard diagnostic strategy (culture and histology) with a rapid biomarker-based diagnostic strategy (aspergillus galactomannan and PCR) for directing the use of antifungal treatment in this group of patients.
In this open-label, parallel-group, randomised controlled trial, eligible patients were adults undergoing allogeneic stem-cell transplantation or chemotherapy for acute leukaemia, with no history of invasive fungal disease. Enrolled patients were randomly assigned (1:1) by a computer-generated schedule to follow either a standard diagnostic strategy (based on culture and histology) or a biomarker-based diagnostic strategy (aspergillus galactomannan and PCR) to direct treatment with antifungal drugs. Patients, were followed up for 26 weeks or until death. Masking of the use of different diagnostic tests was not possible for patients, treating physicians, or investigators. The primary endpoint was empirical treatment with antifungal drugs in the 26 weeks after enrolment (for the biomarker-based diagnostic strategy, a single postive galactomannan or PCR result was deemed insufficient to confirm invasive aspergillosis, so treatment in this context was classified as empirical). This outcome was assessed by an independent data review committee from which the study allocations were masked. Analyses were by intention to treat and included all enrolled patients. This study is registered withClinicalTrial.gov, number NCT00163722.
240 eligible patients were recruited from six Australian centres between Sept 30, 2005, and Nov 19, 2009. 122 were assigned the standard diagnostic strategy and 118 the biomarker-based diagnostic strategy. 39 patients (32%) in the standard diagnosis group and 18 (15%) in the biomarker diagnosis group received empirical antifungal treatment (difference 17%, 95% CI 4—26; p=0·002). The numbers of patients who had hepatotoxic and nephrotoxic effects did not differ significantly between the standard diagnosis and biomarker diagnosis groups (hepatotoxic effects: 21 [17%] vs 12 [10%], p=0·11; nephrotoxic effects: 52 [43%] vs 60 [51%], p=0·20).
Use of aspergillus galactomannan and PCR to direct treatment reduced use of empirical antifungal treatment. This approach is an effective strategy for the management of invasive aspergillosis in high-risk haematology patients.
Tobacco smoke constituent metabolites are established biomarkers of cigarette smoke exposure. ► This paper demonstrates that some of these metabolites are also biomarkers of cancer risk in male smokers from Shanghai. ► The biomarkers of cancer risk are total cotinine, total NNAL, PheT, and total NNN.
Metabolites of tobacco smoke constituents can be quantified in urine and other body fluids providing a realistic measure of carcinogen and toxicant dose in a smoker. Many previous studies have demonstrated that these metabolites – referred to as biomarkers in this paper – are related to tobacco smoke exposure. The studies reviewed here were designed to answer another question: are these substances also biomarkers of cancer risk? Using a prospective study design comparing biomarker levels in cancer cases and controls, all of whom were smokers, the results demonstrate that several of these biomarkers – total cotinine, total 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), r-1-,t-2,3,c-4-tetrahydroxy-1,2,3,4-tetrahydrophenanthrene (PheT), and total N′-nitrosonornicotine (NNN) – are biomarkers of cancer risk. Therefore, these biomarkers have the potential to become part of a cancer risk prediction algorithm for smokers.
Source: cancer letters
Traumatic brain injury (TBI), the third most common CNS pathology, plagues 5.3 million Americans with permanent TBI-related disabilities. To evaluate injury severity and prognosis, physicians rely on clinical variables. Here, the authors seek objective, biochemical markers reflecting molecular injury mechanisms specific to the CNS as more accurate measurements of injury severity and outcome. One such secondary injury mechanism, the innate immune response, is regulated by the inflammasome, a molecular platform that activates caspase-1 and interleukin-1β.
The authors investigated whether inflammasome components were present in the CSF of 23 patients with TBI and whether levels of inflammasome components correlate with outcome. The authors performed an immunoblot analysis of CSF samples from patients who suffered TBI and nontrauma controls and assessed the outcomes 5 months postinjury by using the Glasgow Outcome Scale. Data were analyzed using Mann-Whitney U-tests and linear regression analysis.
Patients with severe or moderate cranial trauma exhibited significantly higher CSF levels of the inflammasome proteins ASC, caspase-1, and NALP-1 than nontrauma controls (p < 0.0001, p = 0.0029, and p = 0.0202, respectively). Expression of each protein correlated significantly with the Glasgow Outcome Scale score at 5 months postinjury (p < 0.05). ASC, caspase-1, and NALP-1 were significantly higher in the CSF of patients with unfavorable outcomes, including death and severe disability (p < 0.0001).
NALP-1 inflammasome proteins are potential biomarkers to assess TBI severity, outcome, and the secondary injury mechanisms impeding recovery, serving as adjuncts to clinical predictors.
Source: Journal of Neurosurgery
Women who undergo screening halve their risk of dying from breast cancer, a new study from the University of Melbourne has found.
The study, published in Cancer Epidemiology, Biomarkers and Prevention is the largest of its kind in Australia and one of the largest in the world. It followed about 4,000 women in a study of the BreastScreen program in Western Australia.
The study focused on women aged 50-69 years, who are in the target age range for screening. It included 427 cases where women had died from breast cancer and 3,650 control women who were still alive when the other women died.
The research team compared screening attendance between the two groups and found screening was much lower among women who had died from breast cancer, a finding that is consistent with a similar study from South Australia and with numerous studies from around the world. Comparison with similar studies showed an average estimate of a 49 per cent reduced risk of dying.
Some other studies including studies from Australia claim that screening doesn’t reduce risk of dying from breast cancer. However, these studies do not compare outcomes for individual women.
“Sound research methods have been used in this study. I believe it is time to move on from the debate about whether screening reduces mortality and to instead direct research resources to help improve the program for women who choose to use it,” Dr Nickson said.
“It is important that Australian women have accurate information about the pros and cons of participating in BreastScreen. The findings of this study may help women decide whether to participate.”
“Early detection is the key to early treatment and the free BreastScreen program is the best health service available to detect breast cancers earlier in women aged 50-69 years.”
Source: Science Alert