There are growing concerns about an unfortunate but often-unavoidable scenario in modern medicine. Although the latest generation of drugs has improved patient survival for a vast array of diseases, the prolongation of life is often accompanied by a sharp increase in the probability of adverse effects of medication. Treatment of one disease can provoke or complicate another.
Clinicians, of course, focus on the more urgent and life-threatening condition. However, the choice is neither always straightforward or easy.  In certain cases, there are both short-term complications and long-term consequences.
One major area of attention in recent years is cardio-oncology (or onco-cardiology). This concerns the development of heart problems in patients treated for cancer. In cancer survivors, years or even decades could elapse after chemotherapy or radiation, before the emergence and detection of problems.

Origins in anthracycline side effects
The origins of ‘cardio-oncology’ date back to the late 1960s/early 1970s, when the use of anthracycline anti-cancer medication began to be associated with cardiac dysfunction – a major side effect.
Anthracyclines like doxorubicin are commonly used in the treatment of solid tumours (e.g. breast cancer, osteosarcoma) and hematologic malignancies (acute lymphoblastic leukemia, Hodgkin- and non-Hodgkin lymphoma etc.)
A variety of studies beginning from the late 1990s through to the late-2000s found the risk of congestive heart failure (CHF) with high cumulative dose of anthracyclines ranging from 3-5% with 400 mg/m2, 7-26% at 550 mg/m2, and 18-48% at 700 mg/m2. Since then, better management of total anthracycline dose has seen CHF reduced significantly.
However, given two demographic factors (growing incidence and survival rates of cancer patients in a high-risk ageing population), the number of patients with cardiac complications remains elevated and is likely to grow further in the coming years.

Cardio-toxicity near-universal for anti-cancer drugs
Though breakthroughs in cancer research have led to therapies selectively targeting malignant cells, many new treatments too continue to cause problems with the heart. In reality, virtually all anti-cancer agents are associated with a significant degree of cardio-toxicity These range from direct cytotoxic effects and cardiac systolic dysfunction, to ischemia, arrhythmias, pericarditis and repolarization abnormalities.
The tyrosine kinase inhibitor, Trastuzumab, for example, also affects cardiac function. Indeed, the HER2/ErbB2 protein in certain breast cancer cells targeted by trastuzumab plays a major role in the myocardium, and it was the occurrence of severe cardiac side effects with trastuzumab which led to the recent revival of serious interest in cardio-oncology.

Other challenges are also seen with newer cardiac agents such as imatinib and bevacizumab. The first contributes to cardiac decompensation by altering preload through fluid retention, while the latter achieves the same effect by alteration afterload through hypertension. Ifosfamide is associated with arrhythmias, while 5-cisoplatin and the anti-metabolite 5-fluourouracil cause cerebrovascular disease.

Type I and II cardio-toxicity
Since 2005, physicians have been using a classification model to define and distinguish between two types of cardio-toxicity.
Type I results in the direct and irreversible damage to the cardiomyocyte, principally in a dose-dependent manner. Anthracyclines are a good example of Type I cardio-toxicity.
Conversely, Type II cardio-toxicity entails cardiac dysfunction with less prominent structural injury or irreversible cell damage. Crucially, it does not exhibit dose dependency, is usually transient and carries a better prognosis. Trastuzumab is associated with Type II cardio-toxicity .

No rest for the heart
Overall, the heart is especially vulnerable to cancer treatments. Cardiac cells are incapable of division or regeneration. They lack sufficient ability to heal if damaged, especially if active – an especially poignant issue since the heart in a living person never rests totally/stops beating. Cardiac cells are also highly sensitive to stress. Disruptions can impact the heart in a negative fashion and do so significantly. Such stress and disruption can be caused by medications, not least against cancer.

An understanding of onco-cardiology will therefore be critical for effective, long-term care of cancer patients, and there is growing recognition that cardiologists should be involved or consulted when cancer drugs are given to patients. 
There already are some promising results due to such involvement. Cardio-toxic effects of chemotherapy seem to be decreased by the concurrent use of angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers, or beta-blockers. Anti-platelet or anticoagulation therapy offer improvements in outlook for cancer patients with a potential hyper-coagulable status, associated with chemotherapy.

Cardiac risks of radiation therapy
Medication is however not the only problem.
Radiation therapy too is associated with all-inclusive involvement of the heart (myocardium, pericardium, valves and coronary arteries) and leads to accelerated atherosclerosis in the great vessels and fibrotic changes to the valves, pericardium and myocardium. However, reduction in left ventricular ejection fraction (LVEF) and development of congestive heart failure (CHF) is considered to be one of the most serious problems and has consequently drawn maximum attention. Confounding the problem is one of lead-lag. For most patients, such effects can appear only after a decade or more following radiotherapy.

New approaches
Once again, new cardio-oncological approaches are seeking to improve longer-term outcomes by reducing the dose of radiation to the heart in cancer patients. Included here are techniques such as intensity-modulated radiation therapy, proton beam therapy, breath-hold techniques and prone positioning, as well as 3-D treatment planning with dose-volume histograms to precisely calculate both heart volume and dose.
The so-called normal tissue complication probability (NTCP) model takes account of the dose and the volume of normal tissues subject to radiation exposure and can be used to make a correlation between a given dose and the risk of cardiac mortality, over a period of 15 years.

Cardiac disease as a therapeutic barrier to cancer
Given the growing connection between today’s cancer survivor and tomorrow’s heart disease patient, many hospitals have begun to dedicate multidisciplinary programmes focused on cardio-oncology. Their aim is to proactively, and sometimes aggressively, balance benefits of cancer treatments against the risks of adverse cardiovascular effects. Though the immediate goal is to improve outcomes for cancer patients with cardiac challenges, eventually, cardio-oncology seeks to eliminate cardiac disease as a barrier to effective cancer therapy.
Some cardio-oncology programmes emphasize the need to consider cardiovascular health in the shortest possible interval of time after a cancer diagnosis. The objective is to not just manage complications as they arise, but assessing and mitigate cardiovascular risks, in both acute and chronic terms, to optimize long-term outcomes.
On their part, cardiologists are expected to stay abreast of all current and emerging cancer therapies – in terms of their cardio-toxic effects. This will allow them to recommend concurrent heart-protective interventions and establish a tailored approach to cardiac therapies for cancer patients.

Detecting cardio-toxicity with echocardiography
There are currently several approaches for the detection of cardio-toxicity and cardiac function. The most commonly used is 2-dimensional echocardiography (2-D echo), to identify anthracycline-induced cardiomyopathy based on left ventricular ejection fraction (LVEF) parameters. One recent study at the European Institute of Oncology in Milan, on a mainly breast cancer population treated with anthracyclines, used standard 2-D echo for prospective and close monitoring of LVEF over the first 12 months after completion of chemotherapy. The technique provided early detection of almost all cases of cardio-toxicity (98%), and prompt treatment led to normalization of cardiac function in most cases (82%).  In other words, LVEF at the end of chemotherapy was an independent predictor of further development of cardio-toxicity.
However, only 11% of patients made complete recovery (with LVEF at least equal to the value before initiation of chemotherapy initiation). The researchers concluded that approaches to prevent development of left ventricular dysfunction (LVD) appear more effective than therapy interventions aimed at countering existing damage which can be progressive and irreversible in many cases.
Indeed, some research suggests that diastolic dysfunction precedes LVEF reduction in patients with chemotherapy-induced cardio-toxicity. However, to date, no diastolic parameters have been proven to definitively predict cardio-toxicity, and the role of diastolic dysfunction in cardio-toxicity screening remains controversial.

Strain-echocardiography
Newer technology promising improved accuracy in calculating LVEF is strain-echocardiography, which measures myocardial deformation. One common metric, peak systolic longitudinal strain rate, is increasingly accepted as a tool to identify most early-stage variation in myocardial deformation during anticancer therapy.
However, long-term data on large populations confirming the clinical significance of this is not yet available. There are also several other limitations such as the need for offline, time-consuming, analysis and variability between echo machines and software packages.

Biomarkers
There is fast-growing enthusiasm about the use of biochemical markers, in particular cardiac troponins, for early real-time identification and monitoring of antitumour drug-induced cardio-toxicity Cardiac troponins are proteins within the myocardium, released within hours of damage to the myocyte. Studies show troponins detect cardio-toxicity at a preclinical phase, long before any reduction in LVEF in patients who have been treated with anticancer drugs.
Such an approach would annul the variability reported with imaging between ultrasound observations. However, there is still more research needed to determine the precise timing of biomarker measurement.
The most promising (and potentially useful) research priorities are allocated to prediction of the severity of future LVD, given that peak troponin value after chemotherapy closely correlates to LVEF reduction. Some researchers also seek to stratify cardiac risk after chemotherapy, in order to personalize the post-chemotherapy process, excluding patients who are not at risk from prolonged monitoring

Almost precisely a decade ago, the US National Institutes of Health remarked that point-of-care (POC) testing might offer a paradigm shift towards predictive and pre-emptive medicine.
Recent advances in areas such as genetics testing, biosensors and microfluidics continue to enthuse proponents of such scenarios.
However, several challenges still need to be addressed, along the way.

Quicker, better and cheaper
POC testing, which simply means diagnostic tests are done near the patient rather than a clinical laboratory, provides diagnostic information to physicians and/or patients in near-real time. Samples do not need to be transported, or results collected.  Short turnaround times are accompanied by high sensitivity and a sample-to-answer format, as well as reduced costs to the health service.

Push-and-pull
Unlike many other medical innovations, the push of POC technology has been accompanied by a pull from users. Patients find POCs convenient and empowering. Many POCs allow them to monitor their health and medical status at home. Alongside the growing availability of medical information on the Internet, and other enabling technologies such as telemedicine, POCs also mark the coming of age of personalized medicine.

Classifying POC tests
POC tests can be broken down in terms of size/disposability and complexity. At one end are small handheld tests, above all for glucose, and lateral flow strips which determine cardiac markers and infectious pathogens, or confirm pregnancy. 
In recent decades, strip technology has been coupled to meter-type readers, typified by the now-widely used glucose meter.  Due to their compact nature, such POC tests are often specialized and limited in overall functionality. However, some can be quite sophisticated. New POC tests for early detection of rheumatoid arthritis, for example, require only a single drop of whole blood, urine or saliva, and can be performed and interpreted by a general physician within minutes.
On the other side of the equation are laboratory instruments, which have been steadily reduced in size and complexity. Recent launches include small immunology or hematology analysers. These POC tests provide higher calibration sensitivity and quality control and are used for more complex diagnostic procedures. Such devices have been accompanied by increasing levels of automation, which translates into increased speed. However, it also leads sometimes to challenges in training users.

Technology drivers
Three key technologies driving the POC market currently consist of genetic tests, biosensors and microfluidics. Combinations of biosensors and microfluidics have recently been developing at an especially dramatic pace.

Genetic testing
Traditionally, genetic testing involved DNA analysis to detect genotypes of interest, either for clinical purposes or related to an inheritable disease. However, results took days or weeks, limiting the applicability of genetic testing in a POC setting.

Emergence of molecular genetics
In recent years, molecular genetics has emerged as one of the most exciting frontiers for POC testing.  It detects DNA and RNA-level abnormalities that provoke and fuel most diseases. As a result, it offers precise diagnosis, determines the susceptibility of a patient to a specific disease and assesses his or her response to therapy. Molecular diagnostics can also establish a patient’s prognosis over time far more scientifically than what is often no more than a physician’s informed guess. 
One of the first POC gene tests was US biotech firm Cepheid’s GeneXpert, developed to detect the chromosome translocation associated with chronic myeloid leukemia. The small benchtop device provided results in less than two hours, with minimal manual labour involved.
Several companies have been developing tests to analyse genetic polymorphisms which influence the effectiveness of drugs. For instance, Spartan from Canada has developed a one-hour test to analyse CYP2C19, the cytochrome P450 enzyme that activates the antiplatelet inhibitor clopidigrel. Different alleles of the CYP2C19 gene can impair the enzyme’s ability to metabolize the drug, leading to major adverse reactions. Others are developing quick turnaround tests (below 20 minutes), for instance, to detect polymorphisms associated with warfarin response, in order to guide dosage.
These developments focus on analysing very specific targets, with clinical decisions based on a handful of expected results. POC testing in such contexts evidently saves time and permits faster patient care.

Gene sequencing: challenges and breakthroughs
The case is different when the POC effort involves sequencing a gene or a whole genome. This is largely because the interpretation of (otherwise-quick) results are still time consuming and need trained experts.
In spite of this, some innovators are confident about the opportunity for handhelds in genomic sequencing. MinION is a 90 gm handheld device, and is seen by its developer Oxford Nanopore as a first step to ‘anything, anywhere’ sequencing. MinION, which has been used in UK hospitals and in West Africa during the Ebola outbreak, performs nanopore-based sequencing within just a few hours.
There is much more, however, that remains to be smoothed out. MinION shows a high error rate compared to existing next generation sequencing (NGS) platforms and it is impractical for use with larger genomes.
As these kinds of POC genomic technologies continue to develop, other enabling innovations are also likely to make an impact. For example, some researchers have harnessed mobile phone technology for gene variation analysis and DNA sequencing. Its implications in a POC setting would clearly be massive.

Biosensors
As mentioned above, another technology driving POC diagnostics consists of biosensors.
Biosensors are biological materials, closely associated with a transducer to detect the presence of specific compounds.
A biosensor system consists of a biospecific capture entity to detect the target molecule, a chemical interface to control the system function and a transducer for signal detection and measurement. Transducers can be electrochemical, optical, thermometric, magnetic or piezoelectric. Their aim is to produce an electronic signal proportional to an analyte or a group of analytes.
The biospecific capture entity (typically whole cells, enzymes, DNA/RNA strands, antibodies, antigens) is chosen according to the target analyte, while the chemical interface ensures the biospecific capture entity molecule is immobilized upon the relevant transducer. 

Key requirements
One key requirement in a biosensor is selective bio-recognition for a target analyte, and the ability to maintain this selectivity in the presence of interference from other compounds. The selectivity depends on the ability of a bio-receptor to bind to the analyte. Bio-receptors are developed from biological origins (e.g. antibodies) or patterned after biological systems (such as peptides, surface- and molecularly-imprinted polymers).
The second requirement in a biosensor is sensitivity. This depends on a wide range of factors, such as the properties of the sensor material, the geometry of the sensing surface and resolution of the measurement system. One of the most important factors in this context is surface chemistry, used to immobilize the bio-recognition element on the sensing surface.

BioMEMS
In the field of POC, there has for some time been considerable excitement about biomedical (or biological) microelectromechanical systems, known by their abbreviation BioMEMS.
BioMEMS are biosensors fabricated on a micro- or nano-scale, resulting in higher sensitivity, reduced detection time and increased reliability. Reagent volumes are also reduced due to the smaller size of BioMEMS, which increases their operational cost-effectiveness.
The miniaturization inherent to BioMEMS means greater portability, which is of course a cardinal requirement for POC applications.
Next-generation POC systems are expected to go beyond diagnostics to advance warning, by ‘learning’ about patients (including vital signs such as heart rate, oxygen saturation, changes in plasma profile etc.), and discovering problems in advance through the use of sophisticated algorithms. Such monitoring systems are likely to comprise different types of wearable or implantable biosensors, communicating via wireless or 4G links to their smartphones and onwards to a medical centre. Such systems would dramatically reduce response time and make testing available in environments where laboratory testing is simply not feasible.

Microfluidics: lab-on-a-chip
Microfluidics, also known as lab-on-a-chip, miniaturize and integrate most of the functional modules used in central laboratories into a single chip. The technology is seen as a high-potential driver of POC diagnostics, not least in developing countries.
There are three principal families of POC microfluidic tests – lateral flow devices, desktop or handheld platforms and (emerging) molecular diagnostic systems. The systems range from zero-instrumented POC devices for the detection of pathogens to fully-instrumented equipment such as NGS sequencing and droplet-based microfluidics.
Microfluidic applications have grown at a dizzying speed, due to the inherent advantages and promises of the technology. These include the ability to manipulate very small volumes of liquids and perform all analytical steps in an automated format – from sample pretreatment, through reaction and separation to detection. Assay volumes are therefore reduced dramatically, while sample processing and readout are accelerated. Other salient features of microfluidics consist of parallel processing of samples with greater precision control, and versatility in formats for different detection schemes. These of course translate to greater sensitivity.

Technology trends
Key technology trends in the field of microfluidics, which have a direct bearing on POC use, include growing miniaturization, higher efficiency chemical reagents, accelerated sampling times as well as larger throughputs in synthesis and screening. As with BioMEMS biosensors, the advantages of microfluidics also consist of low device production costs and disposability,
Some researchers are looking at the commodification of microfluidics – for example, mass production by using inexpensive materials such as paper, plastic and threads, coupled to cost-effective manufacturing processes.
Paper has drawn the highest degree of attention, given that it is lightweight, biocompatible with assays and ecologically friendly.  In terms of operation, paper microfluidics is seen as an innovative means to escape the limitations of external pumps and detection systems. Flow in paper is driven by simple capillary forces. Another major advantage of paper is its application in colorimetric tests for detection by the naked eye.  Given the proliferation of smartphones equipped with high-resolution cameras, some experts view paper microfluidics becoming the tool of choice for POC diagnostics in developing countries.

Biosensor-microfluidics combinations: developing at a ‘violent’ pace
Efforts to merge biosensors with microfluidics have also been demonstrated since the mid-2000s. Progress has been encouraging. Last year, a University of Copenhagen research team, led by biotechnologist Alexander Jönsson and visiting Canadian scientist Josiane Lafleur, noted that the “marriage of highly sensitive biosensor designs with the versatility in sample handling and fluidic manipulation” offered by microfluidics promises to “yield powerful tools for analytical and, in particular, diagnostic applications.” Their article, ‘Recent advances in lab-on-a-chip for biosensing applications’, was published in the February 2016 issue of the journal ‘Biosensors and Bioelectronics’, and noted that areas where microfluidics  and biosensors converged was “rapidly and almost violently developing.” Nevertheless, the authors also found there is still much more to be done, with the observation that “solutions where the full potentials are being exploited are still surprisingly rare.”