Mircea CINTEZA

... and this is cancer. Equally for patients and for their doctors.
For patients, because having cancer is still considered a sentence to death. In these very years, too many announcements in the media make known publicly that this or that great personality, despite best medical treatment, finally dies because he/she lost the battle with cancer.
For doctors, because each new year they learn about newer and newer weapons in the fight against cancer: genomics, epigenomics, proteomics, metabolomics, chromatin, theranostics... But they end up being defeated so many times. It still happens in 2017.
Why still? It is said that „cancer is the disease of the genome”, while (1) human genome was deployed in the first year of the millenium, and (2) curiously (or not?), the Nobel Prize has not been attributed to this discovery yet.
Each tumour has its own set of genetic changes. To complicate things, some tumours have different genetic alterations in their different anathomopathological regions. And these alterations may even change during the evolution of the tumour. So, it is hard to imagine how these changes could be used as a therapeutic target. However, some projects – such as the Cancer Genomic Atlas (TGCA) of the National Institutes of Health (USA) – try to put together everything we discover in this field.
But the host has his/her own genetic characteristics, which make him/her establish a special relationship with cancer. First, there are several genetic features that predipose to cancer, but they account for a few cancers. Globally, it is considered that only 10-15% of all cancers are of hereditary origin (1); the rest are due to environmental or behavioural factors (diet, exercise, lifestyle in general). Interaction between such adverse factors – which are present in a lower or higher amount around the host and the host genetically drived predisposition to such an aggression – is so complex, that it is hard to be strictly defined.
However... The cancer process is initiated by mutations in genes, but later on it is developed by proteins and enzyme-mediated signal transduction (1). This is the task of another huge project of the International Epigenome Consortium (IHEC), that develops reference maps of human epigenome for different cellular states. The epigenome is constituted by the chemical compounds which surround the DNA and modify genome activity without changing its basic structure. The complex of macromolecules consisting of DNA + proteins + RNA is called chromatin and constitues another complex field of research. The main functions of chromatin are to package DNA into a compact stage, reinforced for mitosis, to prevent DNA damage, and to control replication. The Human Epigenomic Atlas tries to identify modifications in this process. For instance, a bad function of the previously described sequences is accomplished when there is a hypo-methylation of the DNA. Another point described in such an atlas is the aspect of RNA sequence and especially the small noncoding RNA (miRNA), which in special conditions may lead, however, to cancer development. Another database developed in this field is NIH Roadmap Epigenomics.
The next „regional” science in the field is called metabolomics; it studies all the metabolites in the cell – which are generally small molecules with an essential contribution to the understanding of a cell functional state. They are studied, for instance, by mass spectrometry or nuclear magnetic resonance spectometry, which deployed to date hundreds of thousands of chemical entities (1).
The last huge field of research in cancer, and not only in cancer, is the specific response to therapy – pharmacogenomics. This means the ability of the tumour and/or the host to respond to a therapy in respect to their gene composition. Because it implies different genetic compositions, this is a very complex issue. In the field of some cancer pharmacogenomics, today we may affirm that a specific cancer therapy does not work. For instance, in breast cancer, the presence of poor metabolizers on the CYP2D6 cytochrome means not to cure with tamoxifen (1). Or in colon cancer, the KRAS mutation announces the lack of response to cetuximab or panitumumab (3). Of course, it would be much better to have an atlas to show which marker announces a 100% response to a specific cancer therapy. But this is still a dream. To resume, genetics, epigenetics, metabolomic and pharmacogenomics may give important information about the inherrited predisposition to a special cancer, to the predisposition of a poor defence against the aggression of environmental factors, to bad habits of lifestyle regarding cancer and to the ability to respond or not to respond to a specific cancer therapy. A dramatic example in the field was Angelina Jolie’s decision to surgically remove her ovaries and breasts because of a poor genetic heritage predisposing to cancer.
The complexity of data presented so far makes the daily life of an oncologist very hard. That’s why a new synthetic science, called theranostics, develops. Using nanotechnology, it brings a single group of information for diagnostic and target therapy.
We may understand why this devastating amount of knowledge finally penetrated in the field of politics. In 2015, president Obama had an important talk dedicated to Precision Medicine (meaning „personalized medicine”) – as the medicine of the future and maybe of the present. He presented the American Government’s decision to provide substantial funds for this field. Attracting funds, research and briliant minds to cancer personalized medicine is the only way of bringing us today the medicine of tomorrow.

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Mircea CINTEZA

”…we are entering a new era of immune interventions for cancer” – Adrian Bot, senior researcher in cancer therapy, stated in 2011, when he was appointed in a key position of an important research team in the field.

And the results did not retard (1). The team in which Dr. Bot works has recently shown that such a therapy had outstanding results in the therapy of resistant diffuse large B cell lymphoma, a deadly Non-Hodgkin disease when not responding to last line of chemotherapy or relapsing in 1 year after autologous stem cell transplant. In recent presented series of 7 patients, 4 had complete response (57%) and 5 overall response (71%) (1). 3 of the patients are in a complete response status after a 12+ month survey. In the initial group of patients treated aggressively with classical methods, the rate of complete response is only 8% and the median survival is 6.6 month. Axicabtagene Ciloleucel is the name of the therapeutic agent by which the patient’s T cells are transformed to express an antigen receptor to the antigen CD19, which is a protein on the surface of B-cell lymphomas and leukemia (2). The research team uses it in ZUMA-1 Phase 2 Study in both diffuse large B-cell lymphoma, primary mediastinal B-cell lymphoma and transformed follicular lymphoma. The trial is ongoing with great promise.
The concept of using antibodies in cancer therapy is complex and developed in two main directions (3, 4). The first direction is to identify antigens on the cancer cells enough specific for that cancer tissue. The second direction is more complex: firstly, to understand why the immune system of the host is weaker than normal (sometimes the weakness is induced by the cancer cells themselves – by which mechanisms?) and se condly, to create antibodies against the specific cancer antigens or to reprogram the immune system of the host to recognize those antigens and to destroy their host – the cancer cell (3, 4)

The field of pathology where antibodies play already, or may play, a therapeutic role is much larger than cancer: inflammatory diseases, such as systemic lupus erythematosus, rheumatoid arthritis, eosinophilic asthma or even chronic obstructive pulmonary disease, and antiviral agents, antibodies against B virus hepatitis and even against HIV. Many therapies are developed and some are already used in clinical trials (5).

Another field in which antibodies are already approved for human use is the therapy of dyslipidemia. The PCSK9 inhibitors are antibodies that block the receptor of PCSK9, an enzyme which occupies the LDL-C receptor on the hepatocyte and other membranes. This decreases dramatically the uptake of the LDL-C from the blood and, in consequence, high levels of LDL-C will circulate, favoring the development of atherosclerotic plaques.

Blocking the PCSK9 by an antibody, LDL-C is removed from the circulation and its concentration is reduced in a significant degree, comparable with the amount reduced by statins (6).
Two antibodies which inhibit PCSK9 are already approved for clinical use in the USA and Europe: alirocumab and evolocumab. But a third one was that which accomplished the largest clinical trials: more than 26 000 patients in SPIRE-1 and SPIRE-2 studies with bococizumab. And: big surprise!! After such human and financial investment, the drug was retired from the market because… because inflammation developed at the site of injection. An immune reaction of the host against the foreign antibody provoked this reaction (7). However, the other 2 competitors, as well as others on the pipeline promise to be a family of therapies as important as the outstanding family of statins was several decades before.

We may say that this moment is as important for medicine as the moment of antibiotic discovery. And even more. The fact that antibodies may cure a much wider field of diseases than infections may contribute essentially to the therapy of the strongest enemy of medicine – cancer – and may also help diagnosis in fields where the disease is not yet recognized in time to begin therapy.

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Mircea CINTEZA

The cardiovascular (cv) risk consists of the equilibrium of a balance. One pan bears the aggression, the other the defense.

The up-to-date calculators of this risk, both European and American take today into consideration the aggression pan only (1,2). The Europeans include the family history in the assessment, without giving to this element a numeric weight. Some papers analyze family history and find arguments to include it in risk assessment, but mainly as an aggressive factor when present, rather than a protective factor when absent (3).

Now come the news. A very serious study published in 2016 (4) developed a genetic cardiovascular risk score (GRS – Genomic Risk Score) based on more than 49 000 single nucleotide polymorphisms (SNP) found in 3 Finrisk cohorts (n=12 676) and in 2 of Framingham Heart Study cohorts (n=3406). These populations were followed for 10-20 years. The GRS improved the cv risk prediction based on traditional risk factors with high statistical significance and independent of these traditional risk factors.

The degree of methylation of the genes promoting lipid species is also considered important as a cv risk factor. The lower the methylation, the lower is the cv risk (5). In this direction, lipidomics analyses are also progressing. Data from a deep analysis in diabetic patients (6) clearly identified lipid species associated independently with a higher risk. The model was prospectively validated (6). Of course, this is an identification of new aggressive factors, but the lack of those species, or a lower methylation of genes promoting some lipid species seem to be a protective factor.
However, in these moment, the European Prevention Guidelines, after analyzing some of the progress, consider that all these findings should be confirmed and than validated with further studies. The European statement is clearly NO (citation: “The generalized use of DNAbased tests for CVD risk assessment is not recommended - III B”). The Americans do not present now in this field any statement in their guidelines.

Some questions are more important than others.

Which genetic tests, to whom to be applied and what is the cost? Of course, as usual, they should be mainly addressed to people in the grey zone and, maybe, to those at apparently low risk.

And another important question is what is the difference between populations regarding these genetic analyses.

I think that, however, the present empty pan of the balance – the genetic defense of an individual against cv aggression – will soon be filled.

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Mircea CINTEZA

Heart Team is, of course, a part of a medical team. In a definition of this term, a free online dictionary (Segen’s Medical Dictionary. © 2012 Farlex, Inc) says that the medical team approach recognizes that today it is impossible that one person is capable to realize all the diagnosis and therapy necessary for any illness.
The importance of Heart Team concept developed after two important achievements in the field of cardiovascular therapy: the Syntax Score, the transcatheter aortic valve implant (TAVI) and any other hybrid cardiac intervention. Of course, other complex therapeutic situations necessitate the contribution of a team, but those cited before are important landmarks.
The Syntax Score developed after the publishing of the Syntax Study by Serruys and all the Syntax Investigators in 2009 (1). It showed the conditions in which coronary artery by-pass surgery (CABG) is superior or not to the percutaneous coronary intervention (PCI) in revascularization in coronary artery disease. The developed Syntax Score was an anatomic score. Later on Nam and colab (2) developed a Syntax functional score based on the coronary flow reserve and Capodano and colab (cited by 3) developed a third more sophisticated score, a Syntax clinical score based on the presence of heart failure, renal failure and, of course, the age of the patient.
For sure, to apply such a complex Syntax Score in the revascularization process necesitates the collaboration of the cardiologist, the interventional cardiologist, the heart surgeon, the intensive care specialist, the anesthesiologist ... means a complex medical team.
The second example is the development of the TAVI procedure. Not any cardiologist can implant a transcatheter aortic valve (TAVI), but a cardiac interventionist. And more: some cardiac interventionists practice only implanting coronary stents and are not licensed to practice TAVI. So the branch in this tree is a forth degree branch: a physician – a cardiologist – a cardiac interventionist – a TAVI specialist.
But the patient who needs TAVI is commonly old, frail, with associated heart failure or coronary artery diseaese, with associated comorbidities. Who is the doctor who takes care and is responsible for the entire pathology of such a person? In a paper in 2013, Osnabrugger and colleagues showed that in Europe and the USA about 290 000 patients are candidates for TAVI, with new 27 000 patients coming every year (4). About 40% of them are initially considered candidates for surgery, but finally the risk of surgical intervention is considered too high. These figures are really impressive.
In the European and American Guidelines on Valvular Heart Disease (5,6) the decision of performing surgery or TAVI in such patients is directed sharp to the Heart Team and this is a Class I indication.
The examples in which collaboration between different sub-specialists in taking decisions in cardiology may continue with carotid revascularisation, grafts for aortic aneurysms, other percutaneous valvar interventions and the list becomes longer and longer. The problem extends to the so called silo-bound professional societies (7), where collaboration between specialities is compulsory and sometimes too complex. A good example is the JNC 8 guidelines on High Blood Pressure published in 2014 (8). The JNC 8 Committee includes 42 North American Professional Societies, such as cardiology, internal medicine, neurology, nephrology, geriatry, general practice etc. It took 11 years to complete this new guideline from the previous one (JNC 7 – 2003). The huge professional team was completed by a representative from the USA official body in the field – the Heart, Lung and Blood Institute (NHLBI) in Bethesda. The controversies between specialists were so sharp, that some of them retired officially from the team, because they did not aggree to sign the final version of the guideline. Even the representant from Bethesda retired. NHLBI declared that, from that moment on, the institute will not participate to any new American guideline ellaboration, it will only accept to be informed about the final results. All these show how difficult is to work in the complex reality of medicine of today, joining together so complex knowledge coming through the participation of so many specialists.
Coming back, who is the captain of different medical teams?
Let us remind that medical teams have very difficult tasks in different fields of clinical medicine. A good example is in the field of oncology, the so called Tumour Board. We may imagine the hard work in front of such a team.
But who is the captain of a Heart Team?
It depends. For the heart team ellaborating a guideline there is no single captain. The captain is the consensus of all the authors regarding every phrase of the guideline. If somebody is finally not convinced, he or she leaves the vessel, like in the JNC 8 case.
For the classical therapeutic team, the captain remains the main decided therapeut, be he/she surgeon, interventionist, cardiologist etc.
But we may have other sort of therapeutic decisions. Recently, I assisted to the discussion of choosing the best therapy for a very complex congenital disease in a newborn. A young doctor proposed a very risky but radical solution. An old member of the team argued in favour of a much more secure, but less radical procedure. Finally, the team decided in-between, for a procedure which was either enough radical and enough safe.
So... who is the Captain of a Heart Team?
The Captain is.... the internal medicine specialist! Does this guy live anymore?
I am afraid not.
So, the Captain is.... that guy of middle age, who puts together the intempestive solutions of the young and the too wise solutions of the old. And he or she ellaborates and applies the winning midway solution.

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Mircea CINTEZA

ABSTRACT

In our days, arterial atherosclerosis which leads to atherothrombosis is the principal cause of death in many, if not in most countries. To fight against we have two categories of interventions: prevention and direct therapies. The direct therapies of today include some drugs, from which statins are the most important, interventional cardiology with stents and bypass surgery.
To analyse other therapies we have first to put some appropriate questions:
• Why internal mammary artery is atherosclerosis free?
• Why don’t we have success in angiogenesis?
• Why are we not capable to construct functional artificial arteries of medium and small size?
Let us begin with the first question. To continue, we have to put new “sub-questions”: Why medium size arteries are differently affected by atherosclerosis (ATS)? And some observations have to be added:
• Leg arteries make ATS often
– Because of gravity ! – it is said
• And forearm do not
– Because of the lack of gravity – it is said again
• But what about head arteries who are so atherosclerotic despite lack of gravity ?
• And why radial artery or mesenteric arteries are not as good as grafts like the mammary on al long term?

Let us try to find some answers from the internal mammary artery structure (1,2). Histologically, compared with other arteries, the mammary artery has:
– Fewer fenestrations of the endothelium
– Lower intercellular permeability
– Greater antithrombotic molecules
– Greater NO production

Is this relevant for the clinician? Maybe. But most of all: it may have therapeutic consequences. For the moment everything is played at basic science: ”Arterial territory-specific phosphorylated retinoblastoma protein species and CDK2 promote differences in the vascular smooth muscle cell response to mitogens” say Lange and coll (3). And Hiesinger and coll add: ... (these are) ... ”factors and mechanisms that convert SMCs to a phenotype that promotes plaque stabilization versus plaque destabilization” and are ”...new targets to potentially manipulate the phenotypic state of arterial SMCs for therapeutic purposes” (4). We shall live and see such examples of molecular manipulation coming to a therapeutic level. Let us continue with the second question: Why did we not succeed yet to use neovascularisation in severe cases of ischemia – be it coronary or not – where neither angioplasty nor bypass surgery cannot intervene beacause of the precariousness of the native vessels? And not only: neo-vessels could add flow in earlier stages of ischemia, not waiting for no-solution cases (but transplant, when appliable).

There can be three main types of neo-vessel development:
– ANGIOGENESIS – formation of new capillaries
– ARTERIOGENESIS – development of the existing but nonfunctional collateral vessels
– VASCULOGENESIS - new vessel growth derived from progenitor/stem cells

The first two could be developed from the natural existing, but nonfunctional vessels in a person without earlier chronic ischemia (5). The third could be promoted through bio-engineering methods, which seem to develop towards a clinical level (6). Use of inflammation as a tool to promote vasculogenesis is promising (6,7). However, we have not to forget that vasculogenesis could also be dangerous, leading to neoformation tissues.

The third question – why are we not capable to construct artificial vessels of medium or small size (like artificial coronaries) is also in hard work for biological engineers. For the moment, simple Dacron or other current material used successfully for aorta and large arteries produces clots when having smaller diameters. The closest hope today seems to be from the stent grafts (8). Stent grafts do no permit new tissue development and restenosis inside. But at their proximity the restenosis is aggressive. They have other advantages and disadvantages (8). But the most promising perspective with stent grafts is that, before other artificial vessels, they will be „seeded” with endothelial cells to make a very friendly surface of an artificial vessel.

In one sentence – the three answers to the questions put before are already today in the hands of engineers and basic science researchers. We wait with impatience that these therapeutic tools will be transferred in the hands of clinicians.

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Mircea CINTEZA

In February 1816, Dr René-Théophile-Hyacinthe Laennec was looking, near Louvre in Paris, some children playing (1). One scratched with a needle at the end of a beam and another listened, with the ear put on the other end of the beam, the sounds produced by the first. Turning back to the Necker Hospital, where he worked, he took a piece of paper, twisted it and put it with one end on the chest of a cardiac women and leasened on the other end. The sounds of the heart were very clear, as well the respiratory sounds. Laennec built very quickly a tube of wood and communicated his invention on February 17, 1816, under the name of „sthetos scope”, from the greek word „sthetos” – means chest and „scope” – to see. He presumed that in this way he could „see” in directly into the chest. This was the birthday of the stethoscope (1).
In the next 2 months (!) Laennec described practically all the auscultatory semiology of the respiratory system, which is valid today as well. And 10 years later he died of tuberculosis, at the age of 45...
Now his invention is 200 years old. At this venerable age, he has to resist to many attacks coming from the descendants of his father, the doctors of this century (2-4). Their main argument is that the stethoscope does not give any information about the most important and dangereous cardiac structural and functional modifications. By contrast, the small ultrasound machines, as great as a tablet or less describe in detail the morphology and the function of the heart. Some introduced already training to use this examination even from the undergraduate period of medical learning (3,4). The cost of such machines is lower and lower and any medical office can afford today to have such an instrument.
The problem with these point of care ultrasound is that they can be useful for the general practice, allowing to recognize elementary abnormalities, but this instrument is totally operator dependent and there are at least three levels of competence in using ultrasound diagnosis. If you are trained for the first level – as some claim to do this for undergraduate training (3,4) – you may miss important diagnosis put only by the second level of competence and this could be disastrous in an emergency patient.
The most elegant advocate of the major role of physical examination and, thus, of the stethoscope is Valentin Fuster (5). In his paper he gave 6 examples of his clinical activity of the last only 48 hours (!) in which the ultrasound missed information given by the stethoscope. He put himself and to us a question (5): „Let me ask you a question: what if a physician comes upon a sick person in the street and has not received the proper training for a physical examination? Does she or he have to abandon that sick individual? We cannot teach our medical students to become reliant upon advanced technologies without which they become useless”.
Indeed, we cannot imagine a doctor who cannot do anything for his patient without a machine. Old, but eternal medicine says that the doctor should interact with his patient by inspection, palpation, percussion, auscultation, and olfaction (5) and, most of all, by much attention in the direct discussion with him or her. The stethoscope is an important simple instrument to examine the heart, the lungs, the vessels, the abdomen, to measure blood pressure. During all these moments the patient feels that he interacts with his/her doctor and trusts him or her. We know how enourmously important is to trust your doctor in the process of healing.
We should mix the new technology with classical medical skills and it is most important to practice both solidly in order to perform a solid medicine (6). Today you cannot imagine a doctor without knowledge to apply medical technology. But it is equally important to use it by the filter of clinical exam.
Let us finish with the words of the great master Valentin Fuster (5): at the age of 200 „the Stethoscope’s prognosis very much alive and very necessary.”

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