BSc(Chem)USA,BSc(Biol)USA,GCP Cert(London), PGCertTMed(Edinburgh), PGDipTMed(Edinburgh), MScTMed(Edinburgh),M/D Prof (London), cDSc(London),PGCertFMed(Glasgow),MRSC(Cambridge).
President and Chief Medical Editor of the Official Journal of Hellenic and International Society of Molecular and Genomic Medicine and Research.
President of the International association of Personalised Perioperative Medicine and Laser,Robotic and Genomic NANOSURGERY.

Introduction

Approximately 15-20% of breast Ca consists of triple-negative phenotype/basal-like Ca (BL/Triple(-)BCa) due to a lack of expression in ER,PR and HER-2 oncogene making it an extremely heterogeneous group of cancers that are very aggressive and have been associated with a very poor prognosis.
These tumors are characterized by an enhanced relapse pattern,and potent chemo/radioresistance due to breast CD44+ CD24- cancer stem cells (BCSCs) which are associated with cell-invasion and metastasis of breast Ca because CD44 is a receptor for hyaluronic acid that interacts with other ligands such as osteopontin which activates PI3K/AKT,HIF-1a and MMP2-9 [1],collagen that activates N-cadherin and c-JunNH(2)-terminal kinase (JNK) [2],and MMP 2,9 and 13 which dissolves bone matrix promoting osteolytic bone metastasis by complementing the activity of MMP-9,MT1-MMP and other invasive and metastatic enzymes [3]. This tumor has the tendency to metastasize to the liver,lung,bones and brain due to a mechanism which is mediated by the cell surface transmembrane glycoprotein,CD44.

More than 85% of breast cancer patients with BRCA1 mutations are triple negative tumors which are characterized by an enhanced risk of recurrence. Also,this risk is greater for cancer patients who are initially diagnosed before age forty because their tumours are much more aggressive than the tumours of older patients.Furthermore,African American breast cancer patients are at higher risk for tumour recurrence or relapse.
The reason that all the therapeutic approaches in advanced basal-like/triple(-) breast Ca such as chemotherapy,hormone-therapy,radiation,biological-therapy  and even surgery lead to cancer recurrence or relapse and metastasis is due to a small subset of cells within the tumor,the cancer stem cells (CSCs) which cause potent chemoresistance and radioresistance due to upregulated genes which activate proteins that act as drug-efflux pumps such as MDR1(ABCB1), ABCB5, MRP1(ABCC1),BCRP(ABCG2) etc [4],upregulated antiapoptotic genes, activated detoxifying or repair enzymes,and genes influencing dormancy, vascular-niche, hypoxic-stability,enhanced levels of radical scavengers, and redistribution in the cell-cycle [5] leading to self-renewal, differentiation and regeneration [6].
Breast cancer stem cells which represent only 1-2% of the total tumour cell population generate extremely heterogeneous tumour cell types because they arise from cells that possess properties of adult stem cells which self-renew rapidly and differentiate into multiple cell types which are characterized by an activated Notch signaling pathway [7].

     
Generally, conventional anticancer treatments such as chemotherapy,hormonal-therapy and even  biological-therapy cannot replace surgery which aims to remove all the cancerous tissue by using the most direct approach including lumpectomy or lump-removal, total or simple-mastectomy,modified radical-mastectomy,radical-mastectomy and some newer mastectomy procedures such as skin-sparing mastectomy, subcutaneous-mastectomy and nipple-sparing mastectomy.However,there is no difference in numbers of life-threatening metastases caused by cancer stem cells (CSCs) between lumpectomy and mastectomy with subsequent no difference in life-expectancy between these two surgical procedures.More than thirty percent of breast Ca patients that had lumpectomy required additional breast surgery or re-excision. Even with complete mastectomy,there still remains the risk of breast cancer recurrence and metastasis because this surgical procedure removes approximately 98% of the breast tissue leaving in the remaining area of 2% many breast cancer stem cells (BCSCs). 

Unfortunately even with adjuvant treatment recurrence occurs which is a cancer that returns in or near the original location.This tumour which is a derivative of breast cancer stem cells is much more aggressive,invasive,chemo/radioresistant and metastatic than the original one.These cancer stem cells are too small to be detected during treatment because MRI and CT-scans may detect tumour lesions above 1 cm while PET-scan may detect via metabolic activity facilitated by FDG absorption tumours which are larger than 0.50 cm.Thus,these cells continue to multiply growing to tumours large enough to be detected months or years after adjuvant treatment has been administered to these breast cancer patients. Subsequently,20% of breast cancer survivors have recurrences with metastatic lesions within 3-5 years after treatment.

It is a scientific fact that breast cancer stem cells which may remain in the tumour site even when surgical margins are clear can survive after postsurgical adjuvant chemotherapy and ionizing-radiation which is delivered to the chest wall after a mastectomy for reducing the risk of recurrence in breast cancer patients with tumors of 5 cm in size or larger,or with more than four positive lymph nodes.

These surviving breast cancer stem cells which are protected from DNA damage by specifically resistant to induction of apoptosis or type I PCD mechanisms become more mutant and malignant,fast spreading and resistant to chemo/radiotherapy  than the original tumour cells causing relapse of the disease which is associated with rise of new tumours and metastases leading to an extremely dismal prognosis [8]. 

Thus,the design of a novel therapeutic approach targeted towards breast cancer stem cells (BCSCs) is desperately needed for the complete eradication of tumour growth postsurgically with adjuvant treatment.This scenario seems like a science fiction with the present therapeutic capabilities resembling a field with numerous weeds of which no matter how many the whacker cuts,they come back much stronger because the roots, which in our case are the breast cancer stems cells (BCSCs),remain unharmed .
Thus,we need to identify breast cancer stem cells and target them with nanodelivery systems for their eradication sparing normal cells.This may give an answer to a life or death question

.
For this reason,we can use a theranostic approach against chemo/radioresistant breast cancer stem cells (BCSCs) combining noninvasive targeted nanoimaging with laser-nanosurgery based on nanophotothermolysis or near infrared plasmonic photothermal therapy (PPTT) under a personalized cancer medicine or personalized oncology approach based on pharmacogenomics and molecular targeting combined with nanomedicine and specifically nanooncology,as follows:

I] TARGETED NANOIMAGING: 
Immunotargeted near-infrared (NIR) contrast agents ,such as non-toxic pegylated gold-nanoparticles with covalently conjugated anti-CD44 antibodies or FAbs may be used for tumour imaging where breast cancer stem cells (BCSCs) via binding to their molecular receptors can be visualized using optical modalities for the measurement of light scattered by the gold-nanoparticles including phase sensitive optical coherence tomography (PSOCT)[9] ,and photoacoustic-tomography (PAT) which integrates high ultrasound resolution with the high optical contrast due to strong surface plasmon resonance[10]. 
In addition to an enhanced scattering signal and tunable longitudinal plasmon absorption,the gold-nanoparticles can provide optical contrast via absorption or luminescence.Furthermore,targeted nanogold particles may improve contrast with structural imaging modalities,such as MRI and CT-scans.Also,these contrast agents may be targeted to biomarkers under a molecular imaging approach for the production of information on the metabolic activity of breast cancer stem cells (BCSCs) using PET-scans with FDG.

II] IMMUNOTARGETED RADIATION THERAPY ENHANCEMENT (IRTE):
These immunotargeted pegylated gold nanoparticles can be used as X-ray contrast agents and radiosensitizers because they release in cancer stem cells and adjacent tumour cells energies including short range and low energy electrons, photoelectrons or characteristic X-ray,Auger electrons and a radiation dose enhancement due to enhanced photoelectric photon absorption by high-Z materials at kilovoltage photon energies.
Thus,since high-Z materials absorb ionizing-radiation (IR) more than tissue,there is production of highly localized heating which at a microscale causes burns in breast cancer stem cells (BCSCs) which generates reactive oxygen species (ROS), mitochondrial toxicity,release of cytokine,necrosis and apoptosis or type I programmed cell death (PCD).

III] POSTSURGICAL ADJUVANT NANOSURGERY VIA PHOTOABLATION FOR TARGETED PHOTOTHERMAL CANCER  THERAPY CAUSING NANOPHOTOTHERMOLYTIC  CANCER STEM CELL DEATH VIA PULSED NIR LASER:
Nanosurgery with NIR laser-pulses exerts adjuvant ablation of basal-like/triple(-) breast Ca stem-cells (BCSCs) by selective nano-photothermolysis mediated by pegylated-antiCD44 plasmonic gold-nanobombs.This non-invasive approach may be targeted to a specific molecular signature of  breast cancer stem cells (BCSCs) which have the potentiality to exert resistance to conventional anticancer treatments leading to metastasis.

Our immunotargeted NIR pegylated nanogold particles which are covalently conjugated to anti-CD44 Abs are used for highly specific molecular targeting of breast cancer stem cells (BCSCs).Our aim is to design a novel postsurgical adjuvant treatment facilitated by plasmonic laser nanosurgery (PLN) which will be targeted towards breast cancer stem cells (BCSCs) for the complete eradication of basal-like/triple(-) tumour growth.After preparing the plasmonic pegylated gold immunonanoparticles which are conjugated covalently with anti-CD44 Abs for selective molecular targeting of breast cancer stem cells (BCSCs),we administer them IV postsurgically for reaching the remaining BCSCs which overexpress CD44, circumventing with their stealth effect biological milieu interactions such as opsonin adsorption and subsequent reticuloendothelial system (RES) elimination, via the enhanced-permeability and retention (EPR) effect where bioconjugated nanoparticles passively accumulate at remaining   postsurgical tumour sites,which are characterized by leaky and immature vasculature that have wide fenestrations than normal mature blood vessels.

The nanoparticle size is 40-50 nm which is optimal for cellular entry of nanogold that has 600 times more absorption in cancer cells than normal cells.The particle size of nanogold-antiCD44 conjugate which is 40-50 nm is small enough to pass via the blood vessels of the remaining postsurgical tumor with fenestrae of 100 nm in diameter,and large enough to pass via the blood vessels of health organs which have fenestrae of no more than 5 nm in diameter[11].  

The anti-CD44 antibodies which are conjugated onto nanogolds target and bind specifically onto the cell surface transmembrane glycoprotein CD44 which is a hyaluronan receptor of breast cancer stem cells (BCSCs) activating cytoskeleton proteins such as microtubules (MTs) and actins which induce endocytotic internalization of nanoparticles that are transported into the cytoplasm of BCSCs by early and late endosomes.

Then,we irradiate with short NIR laser pulse of wavelength 1064 nm at 40 mJ/cm2 which is far below the safety standard for use of medical lasers for healthy cells and tissue which is 100 mJ/cm2.The short laser pulses exerted selective nanophotothermolysis only to the BCSCs which had nanogold particles intracellularly that caused necrotic and apoptotic or type I programmed cell death after there was thermal expansion of the gold nanoparticles which are characterized by a high plasmon resonance (SPR) absorption efficiency generating photoacoustic waves.The laser energy induced inside the BCSCs temperatures which have reached up to 950 C exerting hyperthermic effects which due to the short exposure will prevent extensive high temporative dissipation circumventing healthy cells.

BCSCs are very vulnerable to hyperthermia due to their rapid metabolic rates disrupting the signaling metabolic pathways,inducing acidosis and apoptosis due to the release of immunostimulants,such as heat-shock proteins [12].Also,the increases in temperature denaturate cytoskeletal and nuclear proteins inhibiting their synthesis by impending RNA and DNA polymerization.Furthermore, hyperthermia exerts cell membrane damage causing blebbing . Generally,thermal protein denaturation is caused in all intracellular proteins that are adjacent to the gold nanoparticles.The hyperthermic effects might damage the vasculative supply of the tumour cells,and cause disruption of homeostasis leading to microthrombosis.

Another mechanism consists of bubble formation around the gold-nanoparticles due to the explosive liquid evaporation (ELE) which is accompanied by acoustic and shock waves.This causes melting of the gold-nanoparticles which enhances tremendously their radius leading to their evaporation that forms small particles and gold vapor bubbles.

The next observed nonlinear mechanisms consisted of optical-breakdown with subsequent formation of plasma cavity,and generation of strong shock waves which cause explosion of the nanoparticles that act as nanobombs leading to their fragmentation and exerting extensive cellular damage via disintegration of organelles,and nuclear fragmentation which causes an apoptotic bystander killing effect.

Thus,the laser nanosurgery may lead to apoptosis of BCSCs via coagulation,and disruption which is caused by nanophotothermolysis that is associated with thermochemical transformation of vital cellular proteins,and explosive vaporization in the intracellular regions which are located near the gold nanobombs generating shock waves which are associated with supersonic expansion of dense vapor intracellularly which produces optical-plasma,and strong sound waves leading to photothermal apoptotic cell death (PACD) caused by oxidative stress and depolarization of the membranes of mitochondria which activate apoptotic caspases leading to fragmentation of the DNA.

This nanophotothermolysis of DNA caused by the thermal explosion of gold nanobombs due to possible Coulomb explosion via ionization of multiphotons and thermal explosion through electron photon excitation relaxation (EPER) eradicated the targeted BCSCs sparing the healthy adjacent breast cells.
Thus,we have the medical potentiality with targeted molecular imaging to identify the BCSCs after surgery,and subsequently as adjuvant eradicating treatment with nanosurgical laser ablation facilitated by a flexible optical fiber to selectively target the remaining BCSCs which cause metastasis under a personalized cancer medicine approach based on pharmacogenomics,and mediated by nanomedicine leading to their apoptotic cell death with a bystander killing effect by nanophotothermolysis without harming the adjacent healthy breast cells under a Trojan horse nanodelivery system which facilitates a “bow and arrow” theranostic approach circumventing the “one size fits all” approach.                          


REFERENCES:    
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8]Goymer P,Nature Reviews Cancer 2008;8:246-247.
9]Jain S et al,The British Journal of Radiology 2012;85:101-113.
10]Zhang Q et al,Nanotechnology 2009;20(39):395102.
11] Sandhu KK et al,Bioconjugate Chem. 2002;13:3-6.
12]Li G et al,Int J Hyperthermia 1995;1:459-488.

 Associate Professor in Plastic Surgery, Medical School, Aristotle University of Thessaloniki

Introduction

Plastic Surgery is the medical specialty that deals with reconstruction of tissue defects and restoration of deformities and functional impairment, concerning the skin, myo-osseous and neurovascular structures, located over the face and neck, the torso, the breast, the upper and lower extremities and the genitalia. [1] Etiologies of those deformities include trauma, chronic diseases, cancer, congenital anomalies or tissue degeneration. Plastic surgeons use various therapeutic approaches and surgical techniques focusing on the restoration of function, form and aesthetic appearance of the involved areas, and also the prevention of post-traumatic and post-operative complications. Although cosmetic surgery is perhaps the most popular part of the specialty, it covers only a limited area of the whole spectrum of plastic surgery fields and subjects, namely reconstructive surgery, microsurgery, hand surgery, oncological surgery of the skin and soft tissues, treatment of burns and traumas, tissue replanation, tissue engineering, etc. [2]

Reconstructive techniques: the use of flaps

The use of autologous grafts and flaps is the work-horse in reconstructive surgical methodology; the term «flap» describes a tissue unit, which is harvested surgically from its original place (donor site) but left attached to it by its vascular pedicle which assures blood supply to the flap; after being elevated, the flap is transposed to another area (recipient site) in order to restore an impaired form or function. Flaps are classified according to their consistency (skin flaps, muscle flaps, bone flaps, etc), the type of their transposition to the defect (rotation, advancement flaps), their vascular pattern (random, axial flaps) and their proximity to the recipient site (local flaps, regional flaps, distant flaps). [3]

The so-called «free flaps» are a special group of flaps which are dissected and detached completely from their donor area and transferred to a recipient site, which is usually located at a distant area of the body. In order to assure the free flap’s viability, it is mandatory to idenify and prepare its nutrient vessels (artery and vein) before its transfer to the recipient site, and anastomose them to other vessels, located near the defect which will be reconstructed by the flap. This re-vascularisation procedure of the free flap is performed using magnification of the surgical field with the aid of an operating microscope and microsurgical techniques. 

Free flaps are being used by plastic surgeons the last four decades; common indications for a free flap transfer include extended or composite tissue losses following high-energy injuries or major cancerological excisions over the face, the breast and the extremities.

Soft tissue reconstruction of open fractures of the lower limb

One of the most frequent indications for using flaps, either regional pedicled or distant free flaps, is the presence of post-traumatic soft tissue defects over the distal areas of the lower limb, following open fractures of the leg. According to Gustilo, open tibia fractures are classified to three types (I, II and III), the third one including the most severe and complex injuries with associated soft tissue losses, exposed bones and periosteal stripping (Gustilo IIIB) and major artery injuries requiring vascular repair (Gustilo IIIC). [4,5] Other indications for using free flaps over the leg are chronic bone infections (osteomyelitis) and congenital dysplasias (tibial pseudarthrosis).

The first step in managing complex injuries of the lower extremity, after bone stabilization and vascular repair, is to prepare the wound properly; in all cases, the role of meticulous surgical debridement, excision of all devitalised soft tissues and eradication of infection -before flap reconstruction- has already been well established. [6] Then, the characteristics of the defect (size and location, exposed underlying structures, associated injuries) should be carefully evaluated and parameters related to the patient (age, profession, general condition, other co-morbidities) should also be considered. Before coverage of the defect, the plastic surgeon should prioritize the reconstruction, based on patient needs and most critical functional deficits, and also consider the tissues that are injured or missing, and those that are available to use for reconstruction. Thus, the whole reconstructive procedure may now be planned: selection of the best indicated flap, donor area, recipient vessels, and/or need of vein grafts. [7,8] According to the principles of Godina, final coverage of an open lower extremity fracture should be performed as soon as possible [9,10] and followed by the appropriate rehabilitation of the extremity.

In the recent decades, the use of free flaps in covering severe open tibia fractures has changed the prognosis of those complex injuries and increased the number of salvaged limbs. [6] Published data shows that ~60% of limb-salvaged patients return to their previous work even with a several-years’ delay [11]; although the whole reconstructive process may last long and patients may frequently need many re-operations, the vast majority of them is satisfied with the result and happy to have their legs instead of being amputated. However, discussion and detailed information of the patient about these demanding reconstructive procedures is of utmost importance, because secondary amputation in severe open fractures of the lower limb may be required. [12]

Conclusion

Management of third-degree open fractures of the lower limb still consists a challenge for the reconstructive surgeon; a combined initial therapeutic approach by both orthopaedic and plastic surgeons is fundamental for a successful treatment, as it improves prognosis and quality of life of patients. [13,14] Besides, a mutlidisciplinary management and close collaboration of all specialties involved in those trauma cases (general surgeon, orthopaedic surgeon, vascular surgeon, plastic surgeon, infectiologist, intensivist, physiotherapist) may shorten the hospitalisation length and decrease the total cost needed for completing these most demanding surgical treatments. [15,16] 

In conclusion, it is absolutely necessary for all Trauma Centers and Emergency Hospitals to have well-trained and experienced Plastic Reconstructive Surgeons as members of their surgical teams; a plastic surgeon may significantly contribute to an optimal planning of the reconstruction, minimize complications, reduce hospitalisation and facilitate rehabilitation of the patients.

REFERENCES

[1]. http://en.wikipedia.org/wiki/Plastic_surgery

[2]. http://www.surgeons.org/media/293570/MED_2011-1019_Plastic_Surgery_a_misunderstood_specialty.pdf

[3]. Thornton JF, Gosman AA. Skin grafts and skin substitutes and principles of flaps. In Kenkel JM (ed) Selected Readings in Plastic Surgery, vol 10(1), Southwestern, University of Texas, Dallas, 2004.

[4]. Gustilo RB, Mendoza RM, Williams DN. Problems in the management of type III (severe) open fractures: A new classification of type III open fractures.  J Trauma. 24 (8): 742-746, 1984.

[5]. Gustilo RB, Gruninger RP, Davis T. Classification of type III (severe) open fractures relative to treatment and results. Orthopedics. 10(12): 1781-1788, 1987.

[6]. Yaremchuk MJ. Acute management of severe soft-tissue damage accompanying open fractures of the lower extremity. Clin Plast Surg. 13(4): 621-632, 1986.

[7]. Vlastou C, Earle AS, Jordan R. Vein grafts in reconstructive microsurgery of the lower extremity. Microsurgery. 13(5): 234-235, 1992.

[8]. Demiri EC, Hatzokos H, Dionyssiou D et al. Single stage arteriovenous short saphenous loops in microsurgical reconstruction of the lower extremity. Arch Orthop Trauma Surg. 129(4): 521-524, 2009.

[9]. Godina M. Early microsurgical reconstruction of complex trauma of extremities. Plast Reconstr Surg. 78(3): 285-292, 1986.

[10]. Arnez ZM. Immediate reconstruction of the lower extremity - an update. Clin Plast Surg. 18(3): 449-457, 1991.

[11]. Khouri RK, Shaw WW. Reconstruction of the lower extremity with microvascular free flaps: a 10-year experience with 304 consecutive cases. J Trauma. 29(8) 1086-1094, 1989.

[12]. Fochtmann A, Mittlböck M, Binder H et al. Potential prognostic factors predicting secondary amputation in third-degree open lower limb fractures. J Trauma Acute Care Surg. 76(4): 1076-1081, 2014.

[13]. Yaremchuk MJ, Gan BS. Soft tissue management of open tibia fractures. Acta Orthop Belg. 62 (suppl 1): 188-192, 1996.

[14]. Tomaino M, Bowen V. Reconstructive surgery for lower limb salvage. Can J Surg. 38(3) : 221-228, 1995.

[15]. Townley WA, Nguyen DQ, Rooker JC et al. Management of open tibial fractures - a regional experience. Ann R Coll Surg Engl. 92(8): 693-696, 2010.

[16]. Sen A, Xiao Y, Lee SA, Hu P et al. Daily multidisciplinary discharge rounds in a trauma center: a little time, well spent. J Trauma. 66(3): 880-887, 2009.

Dr Gerasimos Chatzidamianos Ph.D. (Cantab), MPhil. (Cantab), BSc (Hons)

Spectrum Centre for Mental Health Research

Division of Health Research, Faculty of Health and Medicine

Lancaster University, Lancaster, U.K.,

Schizophrenia is known to occur in prelingually profoundly Deaf individuals with probably the same frequency as in the hearing population. However, the impact of Deafness on the clinical features of schizophrenia is an under-researched area. The current thesis aims to provide the first comprehensive analysis of the ways schizophrenia manifests itself in Deaf adults, with particular reference to language disorders.

Two studies were performed. Study 1 empirically tested a clinical observation that motor dexterity for sign was preserved despite there being impairment in motor skill for purposes other than language in schizophrenia. 15 profoundly Deaf sign-using schizophrenic patients and 28 matched profoundly Deaf healthy volunteers were given specially devised measures for motor skill in linguistic and non-linguistic tasks. The study supported the hypothesis that there is a dissociation between relatively preserved motor skill for sign language and impaired motor skill for non-linguistic gestural tasks. This study also produced an incidental observation: the Deaf schizophrenic patients appeared to make frequent errors in handshape, which in the context of the study implied abnormality in production of a particular linguistic element of sign language, classifiers.

The aim in Study 2 was to further examine Study 1’s finding of abnormality in the production of handshapes in classifier construction, specifically to replicate it under controlled conditions and establish whether it is more pronounced than in other aspects of language. The performance of a second group of 14 profoundly Deaf signing schizophrenic patients and 35 Deaf healthy volunteers was recorded based on a battery of measures testing classifier and noun comprehension and production. This confirmed Study 1’s finding of errors in classifier production in Deaf schizophrenic patients and provided qualified support for the hypothesis that the impairment was more marked for production than comprehension, and more marked for classifiers than for nouns.

Taking the results of the analyses of both studies together, the present thesis suggests that motor abnormalities are present in Deaf schizophrenia in the face of relatively intact motor skill for language. Despite its motor intactness, however, certain aspects of sign language in Deaf schizophrenia seem to be disproportionately affected than others (e.g. nouns). This primarily applies to the production of handshape in classifier construction. Conversely, Deaf people with schizophrenia appear to produce lexicalised responses at a comparable rate with that of their Deaf healthy counterparts. These results suggest that schizophrenia affects language production in Deaf patients with schizophrenia in unique ways.

Clinical implications

Being an under-research area, understanding how differently schizophrenia manifests itself in the Deaf population is critical. Whilst the prevalence of schizophrenia in the Deaf is similar to that of the hearing population, Deaf people are over-represented in psychiatric services. The underlying reasons are complicated, but it becomes apparent that the varied expression of schizophrenia, coupled with the idiosyncratic language proficiency as found in Deaf people increases the level of difficulty in diagnosing the condition. This is particularly relevant in the case of Deaf people as most clinician are unfamiliar with Deafness, sign language and the implication of growing up in a hearing world without access to appropriate education, information or services.

The present results put forward the idea that clinicians should expect language production to be motorically fine. If severe motor symptoms present, clinicians should investigate possible extrapyramidal side effects from the medication or the potential comorbidity with other neurological disorders. Despite its motor intactness, however, sign language production appears disproportionately impaired when compared to sign comprehension. That means that Deaf people with schizophrenia are able to understand sign sufficiently, but fail to produce it to a relatively similar degree. This is not to say that their linguistic output is incomprehensible similar to dysphasia, for example. In effect, Deaf people with schizophrenia should have no problem understand their clinicians in sign language. The marked but subtle impairment in production (especially in classifier constructions), however, increases the challenges in identifying symptoms such as formal thought disorder (i.e. incoherence of speech/sign). Given that lexicalisation of sign appears intact, clinicians should be mindful of these challenges and adjust their signing accordingly.

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M. M. Karindas, M.D., Molecular Oncologist, President, - The World Academy of Medical Sciences -

Cancer cells are the result of the multi-step, multi-dimensional and multi-generational process of oncogenesis, but they are never the products of cellular transformation. When a stem cell divides, asymmetrically or symmetrically, it produces two new (new generation) cells, a differentiated daughter cell and a daughter which is a parent-identical stem-cell, or two identical daughter stem cells, respectively. In either case, the daughter cells, differentiated or parent-identical, have their own individuality and character. A daughter cell is not a transformed parent cell; it has its own cellular identity, genotype and phenotype although it carries its parent’s genotypical and phenotypical features. The term “Cellular Transformation” in today’s Medical Research Literature, which refers to neoplastic cellular changes, is unintentionally amiss, but scientifically delusive; it implies a solitary cellular reign that misleadingly suggests a “single cell” origin for oncogenesis.      

In any living multicellular organism, whose multicellular existence and functionality is totally based on intercellular subsistence, a multicellular act or happening is absolutely impossible to start with or from a solitary cell action. In multicellular organisms, in vivo, malignant neoplasms, including leukemias, which all are the products of highly organized cellular teamwork from the very beginning, never arise from single cells; they arise from groups of cells.

Key Words:  Oncogenesis, Evolution of oncogenesis, Malignant transformation, Multicellular origin of cancer, Cancer stem cell, Dormancy, Microenvironment, Metastasis

The Definition of Oncogenesis

The human cell is mankind's basic unit of life and a dynamically functional, highly-organized, self-governed component of human body. It is the condition of this excellent micro-unit of tissue that determines the state of the health of the host organ and body. Somatic cells live with the guidance of a "Cell Cycle" through which their status as well as their internal and external conditions, circumstances and contingencies are meticilously monitored and controlled. Holding the intracellular executive power and command, DNA governs the absolute soverignty of the cell and controls its internal and external behaviors, functions, committments, transactions and affairs. Meanwhile, performing specific and specialized functions and duties of their own in a highly harmonious cooperation, the main molecules of this tiny elementary compartment of human life, proteins, nucleic acids, carbohydrates and lipids work together to build its organic, structural and inherent parts, elements, features and characteristics. 

As their name suggests, cellular organisms are organized living establishments. While a unicellular living organism is neatly organized in itself, a multicellular one is highly organized not only in its tiny constituent unit, the cell, but also across its whole multi-component, multi-tissue, multi-organ and multi-system structure. Behind the powerful look and omnipotent nature of this immense organization of multicellularity, however, which is made of quite impregnable, infallible and structurally and functionally collaborative assemblies, there are highly detailed, delicately integrated cellular compositions that are sensitive to intracellular, intercellular and extracellular changes and vulnerable to any internal or external threat to the cell's strict inner order and to its harmonious relations with its siblings and cousins and other cells of the neighborhood, as well as its relationship with its extracellular matrix (ECM) and with the rest of the microenvironment. Set to function physiologically and strategically to preserve the organism's welfare and livelihood, being given life and duty to keep the cell's stably prosperous and providential state, these compositions work as dedicated enterprises run by faithful artisans and toilers. The most typical and spectacular example of this is the human body, a masterpiece of bioarchitecture and bioengineering. This flawless, model multicellular organism, the excellence of bio-formation we take for granted, however, encounters more problems than the planet's other species of living organisms do. Some of these problems are unfortunate and ruthless enough to have the organism rendered defenseless and cast a shadow over its undisputed infallibility. The human cell, where a dramatically destructive set of happenings, neoplasia, as the most vicious one of these problems, begins, is ironically also the place where its corporate burocracy and supreme command is stationed. Despite the fact that the DNA-governed cellular behavior is basically performed impeccably, the cell may any time happen to encounter certain unfavorable situations that may individually or jointly affect its perfect governance in various sectors and at various levels. The persistence of such situations and their effects usually bring about unpropitious consequences that seriously intimidate or threaten the divinity and harmony of the cell's regime and order. Then a sequence of cytological changes through a series of interacting and inter-effecting cellular and tissue processes follows across the microenvironment. Unless there is an interruption or stoppage, this culmination of happenings brings to the scene an unfortunate, ill-bred progression which will have then already begun to ensconce around; oncogenesis.


The Basis of Oncogenesis

In a living multicellular organism, nothing is purposeless or by chance; intracellularly or extracellularly, nothing usual or expected can happen without a purpose, and nothing unusual or abnormal can occur without a reason. 

In our bodies, we get more than 0.5 trillion of our cells replaced daily. At any given moment in a human body, which is made of around 75-100 Trillion cells, there are 5-6 Trillion actively dividing cells among which there are billions of them that are either ready to go through mutations, or going through mutations. And billions of others are already mutated and highly prone to further mutations that may emerge any moment which is the case more in adult human bodies than young ones and more dramatically in-effect in the aging ones. Mutations bring cells immediate alienation in the tissue and make them become singled-out solitarily or multiply in groups. Such cells, solitary or in groups, mostly become dormant or undergo apoptosis before they find time to organize themselves to multiply and thrive. Larger groups sometimes show the power and organizational intelligence to organize, but, they still have no guarantee for a foreseeable future for fortune. So, we, as humans, should be thankful that our body is not a product of ordinary engineering and does not allow in its domains any unauthorized inauspicious acts to go ahead as they please. And we also should be grateful that in such an immaculate construction, our lives are not left in a biomolecular destiny where the fate is determined by chances or freaks, and that is why, not all mutations or series of mutations lead their cell groups to the genesis of neoplasm. And any neoplastic occurence that makes it in no way means that it has been given the authorization to proceed and will not be left alone, at least not before facing all the consequences and countermoves.

A malignant process is essentially based on and a product of the ordinary cellular and tissue biology, and the impending malignant cells of this insidious phenomenon, the new kids on the block, are in fact as much body property as the regular cells around, and just like the regular cells, they belong to the tissue. Also, they are not, when they first emerge, meant to be the assailants or adversaries of the prime tissue or its loyal cells and elements; on the contrary, they, at least originally, are produced and allowed to act and function like the regular cells that they begin to supplant, and they are given rights, privileges and duties just like the ordinary cells of the territory. Although, at the beginning, it is a mutually-established cellular happening within the expected standards and reasonable limits of tissue physiology and homeostasis and is no less than explainable by the natural laws of human biology, the oncogenic event progresses amiss to become a unfavorable event and then an unwanted escapade.

Cellular proliferation by division, and differentiation processes are arranged, programmed and executed through an immense range of interconnecting intracellular, intercellular and extracellular signaling networks which are the livelihood of the elemental constituents of human infrastructure from the embriologic period to the end of lifetime. In this wholesome natural phenomenon of existence, an oncogenetic development emerges as an ultimately conflicting, confusing and disorganizing occurrence with dramatic imposition, and brings out bands of new cells, the neoplastic cells, which impudently crop up ultimately demanding full habitation which they do their best to make eventually unconditional. Seeing well that their fresh existence proves quite contingent upon arrival, they in no time go through some big efforts to achieve two painstaking tasks which they immediately realize they should fulfill for their survival: 1. Organizing a no-default governance for themselves, 2. Establishing some mutual communal relationship with the environment as trouble-free as possible aiming to make it at least indulgent and permissive if not interactive. Their main goal is to survive not to invade. Their demand for settlement receives in the first instance an instinctive embrace in the tissue's microenvironment as they are naturally far from being considered strangers at that stage. But, as they begin to show their oddity, which soon turns into some boldly-dramatized unconformity, the callow embrace they have already been given leaves its place to a state of gradual, reluctant tolerance which will be existing for a considerable period. But they settle in the way they find suitable for themselves anyway. Because of their dissociative disposition and behavior, the recognition of their full settlement and their integration to the territory soon becomes difficult to materialize as the prime tissue eventually sees dramatically increasing lack of structural and functional coordination with this no-longer-favorable horde of newcomers, and increasing necessity to cope with their burden with ever-increasing incompatibility and discordance. That eventually induces the prime tissue to consider a full mobilization of all its available means of preserving and defending its own livelihood and welfare while dealing with this disappointing and increasingly-burdening situation which soon proves to be a predicament going far beyond its expectation or readiness. Before long, the body's immune system also becomes aware of the situation and gives the prime tissue the hint that all the tissue-wide, bodily means of defense and order are to be mobilized apace to suppress the emerging disequilibrium which has been becoming more obvious to inevitably cope with. The whole matter here is nothing other than a base for clone-colony actions and movements through which the neoplastic cells’ efforts for survival change their mode to “invade to survive”, and then to “invade and destroy to survive”. From then on, the confrontation turns into a wholesome showdown between groups where a solitary cell, on either side, can never act, function or fight alone.


No grounds for solitary Cells

We are living in a body of multicellular organism, in which no single cell of any kind can initiate a normal or abnormal group act or function by its own. A solitary cellular act or behavior, should it even be practically possible, would have no value or meaning in its microenvironment, and no significance to the tissue and organism it belongs to, simply because it can not pursue any objective on its own, it would not achieve its aim, and it would not reach a goal. Its individual cellular performance  with acts, functions and activities are meaningful and countable only in its own cell group.

In a multicellular organism, under optimum circumstances, no cell can be looked upon or reckoned with in any way as solitary, and neither can it be apportioned as such. If a cell, in vivo, is in question singly, there has to be something unusual in it or with it, not necessarily around it; and that unusual thing is most frequently something wrong. The most pronounced example of this would be a mutated oncogenetic cell. If it is having a first mutation, it then possesses no significance or exclusivity and it is far from tolling any bells for a future oncogenetic happening. When its mutation amplifies and adds up generations later, it is not itself anymore, but it is the long gone ancient forefather of the new-generation cells which are the current holders of those highly potential accumulated mutations.  Let’s imagine, for a moment, a solitary cell of accumulated mutation in the middle of a tissue, Regardless of its phenotypical/genotypical status, privileges, functionality in normality or abnormality, this single cell, like any other, has recruitement and attraction capability and capacity of various levels. But "putting that ability in life", for an ultimately-mutated high-potential cell, has to begin essentially on its own block; without having the fellow cells of its Group convinced of its altruism, it stands no chance of going further, and can not survive either. Extremely tough, such an achieved grouping is the beginning of everything. From that point on, the "defined and established" group act shows off boldly, and soon becomes the prime tissue's enigma and the immune system's bad news. The heart of the matter here is really a matter of "equalizing" the conditions and "conforming" to the outcomes or consequences in inner subpopulation affairs.  The main goal of the subpopulation’s cells  is to keep and use all the means and instrumentation available for survival. There are here combinations of equalizing/conforming; desired or undesired outcomes; and handleable or dispatching consequences whose whole chain of fulfillment is totally favorably quite rare.

In a multicellular organism, any cellular act, action, reaction or function is planned, arranged, materialized and performed on the basis of a multicellular, communal constitution which sets strict rules and regulations that are administered stringently. Normal or abnormal, there is no one single cell in a multicellular organism, that has, genotypically or phenotypically, any exclusive singular status in terms of  livelihood or functionality, and therefore no cell of any kind, favorable or unfavorable, has any particular privilege or power to act or function solitarily. Being a main part of the duty performed by a highly organized commune cellular collaboration, good or bad cellular attitudes in the chaotic oncogenetic process are the joint product of cells’ indivudually contributed work and giving and has no input that directly comes from any single-cellular initiative.

Cancer cells are never the products of cellular transformation.

Cancer cells are not the transformation of the cells that preceed them. In or between multiple generational steps that take place between normal or abnormal new cells of any kind and their ancestors of generations, there is a series of successive offspring with progressive undifferentiation, but there is no cellular transformation. Referring to the last generational step of oncogenesis, some scientists describe the malignant transformation as a cellular transformation. In the multiple generational stages in oncogenesis, cancer can not be described as a cellular transformation.

If we must talk about a transformation in oncogenetic process, to avoid wrong interpretative trajectories in research work at large, that should be the malignant tissue transformation, not a malignant cellular transformation. Cells do not just become cancerous, and they do not transform into neoplastic cells; they get mutated and breed mutated cells. Malignant transformation is the territorial progression through which the properties of neoplasm are progressively acquired by each new generation of cells which, through that progression, never have any individual transformation. A cellular transformation, if it could be described, would be a cell’s transforming into a different genotype or phenotype or both, changing from one shape, nature and identity to another while remaining in its self. We see such a model of cell, in vivo, neither in a neoplastic tissue nor in a normal tissue. When a cell’s DNA has a change or damage, the cell gets mutated, not transformed. If that cell lives on to breed, generating its own daughter cells which produce newer lines of clones, it contributes, with genetic and epigenetic effects, to the ever-changing landscape of the microenvironment; such a change is biologically possible only in breeding, and breeding is not a cellular transformation but a dramatic input into a “malignant tissue transformation” which is the ever-present battlefield of the warring powers of oncogenesis. 

When a stem cell divides, asymmetrically or symmetrically, it produces two new (new generation) cells, a differentiated daughter cell and a daughter which is a parent-identical stem-cell, or two identical daughter stem cells, respectively. In either case, the daughter cells, differentiated or parent-identical, have their own individuality and character. A daughter cell is not a transformed parent cell; it has its own cellular identity, genotype and phenotype although it carries its parent’s genotypical and phenotypical features. The term “Cellular Transformation” in today’s Medical Research Literature, which refers to neoplastic cellular changes, is unintentionally amiss, but scientifically delusive; it implies a solitary cellular reign that misleadingly suggests a “single cell” origin for oncogenesis.

The overwhelming tissue transformation is the oncogenesis itself

In a neoplastic environment that is changing and evolving non-stop, a full-blown neoplastic tumor, makes the body, unless undealt with, go through an enormously progressive multi-range series of events while evolving a way and style of its own ultimately turning the whole process into its own escapade.

Cancer cells, the cells of abnormal new growth coming from several generations of parentage, are new-generation cells emerging in the neoplastic stage of oncogenesis as the ultimate offsprings of a long, differential linage of cells involved in a series of amplifying intracellular changes incited by various factors or elements and then in ensuing extracellular eventualities. Within this frame, we see the neoplastic transformation as an uncontrolled cellular proliferation with an increasing mutational complexity and a pathologic cellular growth that results from the accumulation of myriad genetic mutations that opens way to cascades of happenings that overpower positions, situations as well as points of balance and control via or at multitudes of junctures bringing scores of molecular and morphologic consequences at the expense of the organism. The heterogeneity of the cells of this metamorphosis, resulted by the cells’ mutational amplification and complexity, eventually helps the emerging colonies of natural selection outplay the nonpermissive microenvironment.

In relation to natural selection, a key mechanism of evolution [1],  as Merlo, Pepper and Graves [2-4] observe, the fundamentals of cancer has been validated as a complex, Darwinian, adaptive system.  We can further state that natural selection is the exact model of the evolutionary selection in oncogenesis. The all-the-way transformation of tissues along the trans-generational oncogenetic process follows the pattern that we see in natural transformation in species at large. Acting on the phenotype whose genetic basis gives a reproductive advantage to certain populations that specialize for particular niches, natural selection eventually results in generated new species. 

The main players, opponents and proponents, are the “Cell Groups”
While we describe tumors as abnormal tissue, we must not see them as alien structures, because they simply are not. They belong to the body as much as a normal tissues do and they come from exactly where normal tissues do. Their recapitulating the outgrowth and differentiation patterns of normal tissues is not a clever and insidious skill they create and perform, but an ability and power out of the proficiency they are inheritably granted.

The changing environment of a tissue riddled by a neoplastic activity, brings an enormous volume of plays and players to the scene. As this oncogenetic process is a clonal evolution from the start, only successively emerging various clones give rise to the progression in which, from the very beginning, an exclusively privileged status of power or function for a single cell is never possible. In the whole process, however, contrary to the current belief, there is no shared play between any of the contending powers. There are many different plays and a multitude of dedicated players in each of them. In the further stages of neoplastic progression there is “Play my game, or get out of my way!”, and a multi-way “Or else”. The illusory play-sharing look of the picture, quite away from the deep fact of the matter, immensely affects the wide external view of it extending its impact as distantly as carried-away research lines, and as remotely as new and novel oncotherapeutic steps which are yet to prove “resolving”.

Being realistically in the same niche as normal stem cells, the stem cells of malignant tumors, cancer stem cells (CSCs), have two tasks to do for their groups: keeping their groups as prosper and going as possible, and engaging in a strictly “no-compromise” neighborhood relationship with the prime tissue on a mutual but “everybody-their-own-way” basis. Their restless furtherance without a break is not totally a misuse of the the prime tissue’s profuse tolerance and hospitality, but a matter of their own strict task and agenda which they can not afford to neglect simply because they have to survive.

The clonal evolution of the Oncogenetic Process begins well before the tumorigenic cell groups’ entry into the introduction-turned-confrontation stage in the niche whose ever-changing life is lived and experienced by all that are in it.  The disruption of growth regulation, the main molecular consequence of the progressively continuing mutations, soon brings the next consequence along: the loss of the control of proliferation, differentiation and apoptosis. It becomes quite difficult for the microenvironment and its prime tissue to close eyes to that latest one of the turns which is also the most critical one. From that moment on the whole microenvironment turns into a battlefield for an all-out multi-power war in which, not only the opposing groups, but also allies, ultimately, declare war on one another.


Metastasis is not quite the end of the Oncogenetic Evolution
The epic journey of oncogenesis is an evolution that is not programmed to end with metastasis. Could a terminally ill human body with an aggressive metastatic tumor somehow be able to live on, the oncogenetic evolution would have continued with tertiary, quaternary and quinary tumors, and so forth. But hardly living their “secondary” stage of multi-generations, almost all tumors prematurely see the end of their evolvement, passing away along with the organisms they kill.  

A primary tumor’s genomic instability persists in metastasis not frequently [5] but always. The sequence of the growth advantage metastatic cells gain through accumulated mutations takes place with the same means and mechanisms as the ones we see with primary tumors. In the microenvironment of a metastatic tumor, with a few exceptions, most of the conditions of the neoplastic progression are identical with the ones seen in the primary tumor’s microenvironment, and in metastatic tumors, we see the same consequences of being a solitary cell exactly as the ones in primary tumors.

The selective pressures and conditions of the changing environment and immune system with warrants and sanctions ultimately define the fittest of the outcompeting cell groups.  As conventionally agreed upon, it is the survival of the strongest. But, contrary to another general opinion, it is not “every cell for itself”. Just like the primary tumor’s own environment, the territory of the metastatic neoplastic progression is a platform where metastatic cells’ destinies are determined as dormant state or tumor progression, or apoptosis. As one of the striking main features, the genetic heterogeneity of metastases reflects heterogeneity already existing within the primary tumor which  is a mixture of numerous subclones each of which has independently expanded to constitute a large number of their own cell groups [6].

While the tissue’s healthy cells together act as a microenvironmental control system to prevent the development and progression of emerging tumor cells [7], all the cells without exception get variably involved in the countless molecular and biomolecular transactions and alterations by which they all get their development, prosperity, maintenance and affluence effected one way or another. The responsibilities, obligations and liabilities carried out by the overseeing tissue governance are exactly the ones that are observed in the primary tumor’s microenvironment. Just like the way it happens in the primary tumor microenvironment, this domain can in no way allow any exception for any particular cell of any nature within the territory. So, just like the primary tumor’s microenvironment, the microenvironment of the metastatic tumor executes the same strict rules which no cell can overcome solitarily.

Through the evolutionary process of neoplastic tumors, the natural selection leans on phenotypic variability generated by the accumulation of genetic, genomic and epigenetic alterations [8]. The deriving productive aggressive phenotypes, however, take quite a time to take hold. With an average doubling time of 20-40 hours [9], newly produced cancer cells are basically not robust enough to live their younger days successfully in terms of survival, and most of them die before they can manage to carry out their own division, which is the reason it takes some time for any primary or metastatic tumor to fully establish itself as equipped to the hilt, and therefore, the pursuance of neoplastic formation both primarily and metastatically is a part of clonal evolution and a matter of clonal expansion and clonal selection, and ultimately a matter of clonal wars where solitary cells of commitment, ascendancy or eloquence have yet to conform to integrate or get doomed to destruction. Just by being singular, solitary cells lose the fight for survival as soon as the fact that they are limited in the long term to fully meet the conditions to fit in becomes apparent and gets discovered by the regime to which the solitariness, with favorable or unfavorable nature, nothing other than redundant presence within the multi-power, multi-pressure and multi-liability commune of integral significance and values which is in an ongoing state of conflict and clashes for differences to equalize and exchanges to compromise.

Cancer cells’ genotypical, phenotypical and biological heterogeneity, which collectively brings intraclonal and microenvironmental mechanization and mobility, is directly proportional to their ultimate individual and colonial invasiveness and metastatic ability both in primary tumors and metastases. In order to live with a guaranteed future in a metastatic niche, disseminated cancer cells should land there in clusters or in assembling groups, not necessarily at the same time, but within a certain short period of time. Just grouping, however, to have a decent settlers life, is not sufficient; in addition to the abilities they have, they should generate and acquire capabilities that are necessary to confront and overcome the new barriers of the unpermissive microenvironment while organizing themselves to form an aggressive colony. Their fate mainly depends on their own qualities and capabilities while in part, they are under the effects of microenvironment’s signaling system to which they principally do their best not to succumb.

If a metastatic cancer cell lands in a new location solitarily and remains so for 12-18 hours without having a chance to perform reproductive activity, it becomes dormant or undergoes apoptosis.                                                                                                                                                                                                                                                                                                                                                                                                                                           

If a solitary metastatic cell is the only tumor cell that has landed in a distant tissue site, whatever productive and aggressive capacity and capability it may have, it will be forced to dormancy or apoptosis. Should it be quick and smart enough to keep  the control and pressure mechanisms of  the microenvironment busy and therefore earn time to go into mitosis, which is its only goal anyway, its daughters, the ones which would be more difficult cells for the microenvironment’s governing power to suppress, would in fact be the problem the microenvironment is afraid of. That’s why, under normal circumstances, that would not be the case as the indisputable power of the microenvironment would not allow such a trivial settlement to become a threat.

If two or more solitary metastatic tumor cells land in a distant tissue site together at the same time or in succession and close enough to each other, they engage in communication using their exosomes. Unless they become dormant or undergo apoptosis, they quickly team up to flourish and multiply to create a micrometastasis. But reaching their goal is not easy if they are from different clones of a primary tumor, and their chance of achievement is the highest if most or all of them come from the same clone. Different-clone cells have a tough time equilizing their geno-phenotypical differences while at the same time they both make their best efforts individually to communicate with the watchful microenvironment to convince it to sanction and even cooperate. Their presence as newcomers with their swiftly emerging dynamism of both individualism and group-conflict immediately becomes difficult for the uncooperative microenvironment to deal with, and the required “host measures” emerge to eliminate them by forcing them to dormancy or apoptosis. The cells of a multi-clone group can get away only when they manage to equalize their differences via their communication which not only conflicts in itself, but also gets disrupted by the microenvironmental forces. Same-clone cells, on the other hand, whose running into each other is mathematically less likely than that of different-clone cells, would be more concurring to team up, more powerful to flourish and more convincing to get the microenvironment’s acquiescence. 

For the flourishing metastatic group cells, establishing micrometastasis is not a guarantee for a bright future as every new generation becomes more ineffectual than the preceding one. In a “Limited Survival of Early Micrometastases” study titled “Multistep Nature of Metastatic Inefficiency”, Luzzi and his colleagues [10] neatly demonstrated that metastatic inefficiency is principally determined by two distinct aspects of cell growth after extravasation: Failure of solitary cells to initiate growth and failure of early micrometastases to continue growth into macroscopic tumors.

Therapeutic intervention may well destroy cancer clones and erode their habitats, but it can also inadvertently provide a potent selective pressure for the expansion of resistant variants. This facet of the Darwinian character of oncogenesis is currently the primary impediment to the Universal oncotherapy on all fronts. 


Outlook

In oncogenesis, where an unreserved display of Darwin’s Evolution Theory is seen [1], what all we are able to see so far is only a tiny fraction of its happenings and changes reflected to the cancer cell's morphology. And therefore, what all we know today in this scarce provision of the cell's abundant resources and data in a partial display of its rich composition and orchestration, and in its external relations, is quite limited, because our comprehension of it is limited. Our confinement within this limitation, also in other certain fields of clinical and research medicine, render our interpretation of it linearly insufficient, and it often puts us in efficacy and hindrance which we most frustratedly experience in today’s Oncology where unavailing scientific beliefs and views archaically continue to feed analytical preoccupations. Whence there is a fundamental reason for us to open wider paths and avenues to "understanding and solving oncogenesis" with rational approaches and cataclysmic insights, and to embrace overall management of the oncologic disease with radical implements. In this regard, we must aim at opening a new, reformative, reconstituting era of Oncology not only in the fundementals and basics of universal cancer research and studies, but also in the practice and management of Oncology at clinical and molecular levels where new, better thought of and more effective strategies of oncotherapy are crucially needed.


Competing interests:  The author declares that he has no competing interests.

References:

1. Darwin C: On the Origin of Species by Means of Natural Selection, or the Preservation of Favoured Races in the Struggle for Life. John Murray 1859 London.

2. Merlo LM, Pepper JW, Reid BJ, Maley CC. Cancer as an evolutionary and ecological process. Nat Rev Cancer.2006;6:924–935

3. Pepper J, Scott Findlay C, Kassen R, Spencer S, Maley C. Cancer research meets evolutionary biology. Evolutionary Applications. 2009;2:62–70.

4. Graves M, Maley CC: Clonal evolution in cancer. Nature 2012, 481:306-313

5. Campbell PJ et al: The patterns and dynamics of genomic instability in metastatic pancreatic cancer. Nature 2010, 467:1109–1113

6. Yachida S et al: Distant metastasis occurs late during the genetic evolution of pancreatic cancer. Nature 2010, 467:1114–1117

7. Klein G: Toward a genetics of cancer resistance. PNAS 2009, 106:859-863.

8. Podlaha O, Riester M, De S, Michor F: Evolution of the cancer genome. Trends in Genetics 2012, 28(4):155-163

9. Malaise EP, Chavaudra N, Tubiana M: The relationship between growth rate, labelling index and histological type of human solid tumours. Eur J Cancer 1973, 9(4):305-12.

10. Luzzi KJ, MacDonald IC, schmidt EE,  Groom AC: Multistep Nature of Metastatic Inefficiency. Am J Pathol 1998, 153(3):865–873.

The advantages of Gamma Knife radiosurgery compared with other treatments for conditions in the brain, head and neck .

Michael Torrens MPhil ChM FRCS

Consultant Neurosurgeon

Director, Gamma Knife Department

Hygeia Hospital, Athens

Gamma Knife radiosurgery [1] is the ablation of a chosen target by a (usually) single large dose of focused photon radiation. The mechanical accuracy of this treatment is <0.3mm.

EQUALLY EFFECTIVE AS SURGERY: Total control by radiosurgery is achieved in over 92% of most benign conditions [2].

NON-INVASIVE: The ability to effectively treat these conditions with similar surgical precision and results through the intact skull eliminates many of the risks and discomfort of open surgery and general anesthesia. Gamma Knife radiosurgery requires no incisions, is performed under local anesthesia and is performed with minimal discomfort.

FEWER COMPLICATIONS: Radiosurgery has fewer complications and a better outcome than surgery [3] and is particularly useful in patients with co-existent illnesses where conventional surgery would pose an unacceptable risk. It also causes fewer cognitive changes than radiotherapy [4].

MORE COST EFFECTIVE: As a one-day outpatient procedure, the cost effectiveness of Gamma Knife treatment usually exceeds that of open surgery and radiotherapy [5,6].

CAN BE USED AFTER OTHER TREATMENTS FAIL: Recurrence after surgery, radiotherapy and drug treatment is not a contraindication to Gamma Knife treatment.

MORE ACCURATE: The mechanical accuracy is up to ten times more accurate than linear accelerator based radiosurgery [7,8].

PATIENT ACCEPTABILITY: The safety, simplicity and improved quality of life make Gamma knife treatment the preferred choice of informed patients. Hospitalization is only required in exceptional circumstances and most patients are able to return to their normal activities within 24 hours of the procedure.

For all these reasons the method is recommended after appropriate review by multidisciplinary teams (MDT) by entities such as the UK National Health service [9].

WHO CAN BENEFIT FROM THIS TREATMENT?

The technique, indications and results have been reviewed [10] but include:

Arteriovenous malformations

Benign brain tumors such as meningiomas, acoustic neuromas, pituitary adenomas and craniopharyngiomas

Brain metastases such as from melanoma or lung, breast, colon or kidney cancer

Head and neck tumors such as nasopharyngeal carcinomas and ocular melanomas

Primary or recurrent malignant brain tumors such as astrocytomas, oligodendrogliomas, glioblastoma multiforme and ependymomas

Trigeminal neuralgia

 CONTRAINDICATIONS

Lesions that are causing intracranial hypertension or serious symptoms of pressure on the brain.

Lesions larger than about 4cm diameter or volume 20cc.

Multiple lesions such as metastases if more than 10-15, depending on volume.

Lesions where the diagnosis is not well substantiated or other, better treatment exists.

EPIDEMIOLOGY

The incidence of primary intracranial tumours is 50 per million in the UK [11] and the incidence of secondary metastatic tumours is much higher at perhaps 450 per million [12]. AVM incidence is 10 per million and prevalence of trigeminal neuralgia 155 per million [13].

If Gamma Knife radiosurgery were to be appropriate for only 20% of such cases (and it is likely to be more frequently useful) then a machine would be necessary for every 5 million population, because each machine can treat 2-3 cases per working day.

BIBLIOGRAPHY

1. http://www.elekta.com/healthcare-professionals/products/elekta-neuroscience/gamma-knife-surgery.html?utm_source=gamma-knife&utm_medium=redirect&utm_campaign=redirects
2. Pellet W, Regis J, Roche PH, Delsanti C. Relative indications for radiosurgery and microsurgery for acoustic schwannoma. Adv Tech Stand Neurosurg. 2003;28:227-82.
3. Noudel R, Gomis P, Duntze J, Marnet D, Bazin A, Roche PH.   Hearing preservation and facial nerve function after microsurgery for intracanalicular vestibular schwannomas: comparison of middle fossa and retrosigmoid approaches. Acta Neurochir (Wien). 2009;151(8):935-44.
4. Chang EL, Wefel JS, Hess KR, Allen PK, Lang FF, Kornguth DG, Arbuckle RB, Swint JM, Shiu AS, Maor MH, Meyers CA. Neurocognition in patients with brain metastases treated with radiosurgery or radiosurgery plus whole-brain irradiation: a randomised controlled trial. Lancet Oncol. 2009;10(11):1037-44.
5. Rutigliano MJ,Lunsford LD, Kondziolka D, Strauss M, Khanna V, Green M. The Cost Effectiveness of Stereotactic Radiosurgery versus Surgical Resection in the Treatment of Solitary Metastatic Brain Tumors. Neurosurgery 1995; 37(3): 445–455
6. Lee WY, Cho DY, Lee HC, Chuang HC, Chen CC, Liu JL, Yang SN, Liang JA, Ho LH. Outcomes and cost-effectiveness of gamma knife radiosurgery and whole brain radiotherapy for multiple metastatic brain tumors. J Clin Neurosci. 2009;16(5):630-4.
7. Heck B, Jess-Hempen A, Kreiner HJ, Schöpgens H, Mack A. Accuracy and stability of positioning in radiosurgery: long-term results of the Gamma Knife system. Med Phys. 2007 Apr;34(4):1487-95.

Christos Lionis MD PhD FRC GP(Hon)

Professor of General Practice and Primary Care, Clinic of Social and Family Medicine, School of Medicine,

University of Crete, Greece

Prof. dr Miroslav Trajanović

Department for production, IT and management

Prof. dr Miroslav Trajanovic.

University of Nis

Faculty of Mechanical Engineering

Miroslav Trajanovic [Αυτή η διεύθυνση ηλεκτρονικού ταχυδρομείου προστατεύεται από τους αυτοματισμούς αποστολέων ανεπιθύμητων μηνυμάτων. Χρειάζεται να ενεργοποιήσετε τη JavaScript για να μπορέσετε να τη δείτε.]

Serbian EURAXESS portal

Faculty of Technical Sciences in Novi Sad, organized the 11th International Scientific Conference MMA 2012 under the motto ADVANCED PRODUCTION TECHNOLOGIES and entitled as: 11th INTERNATIONAL SCIENTIFIC CONFERENCE 
MMA 2012 - ADVANCED PRODUCTION TECHNOLOGIES

During the conference presented case studies, from part of project VIHOS Virtual human Osteoarticular system, it’s an application in preclinical and clinical practice funded by the Ministry of Education and Science of Republic of Serbia. We receive from Prof. Dr. Trajanovic M. the following case studies

1.   Estimation of Exposure Dose of Human Head During CT Scanning Procedure Using Monte Carlo Simulation

2.   Morphometric Analysis of the Hip Bone as the Basis for Reverse Engineering

3.   Finite Element Model of Human TIBIA and Preliminary Analysis

4.   Geometrical Models of Human Bones and Implants, and their Usage in Application for Preoperative Planning in Orthopedics

Iraklis Karampourniotis

Ms Eng. Rural & Surveying Engineer

Dr. Eng. Candidate

Rural & Surveying Engineering Dept.

Polytechnic Faculty

Aristotle University of Thessaloniki

Abstract

Geographic Information Systems (GIS) are software packages that can be used in a variety of applications with multifaceted results thus being able to cover a very large range of needs. Especially in medicine and health related applications in general, GIS can be used from the simplest visualization of an epidemic spread on a map of a region to the support of decisions through Decision Support Systems (DSS) and disease spread scenarios and how to minimize damages and losses.

Introduction

A wide definition of a Geographic Information System is that it is the combined hardware, software, tools and human resources used to record, manage, analyze and visualize any type of information with or without a spatial component.

Based on the above, a GIS application allows its users to introduce the recorded data into a database and visualize them on maps based on specifications developed by the group of people that will use these maps. Through the same application the user may search for information as it was recorded as well as extracted information based on calculations performed on the raw data while in parallel visualizing the results on a map. The information may or may not have a spatial component. In the case that it does have one then additional data can be extracted such as area being covered, perimeter, location of a specific characteristic etc.

A very interesting and yet simple example is taken from the website of healthmap.org which is being used as a world map for recording and reporting incidents relevant to health. The following image shows a map where incidents of the virus of the Western Nile where reported.

Figure 1. Western Nile Virus reported incidents[1]

Understanding the variety of subjects ranging from epidemiology to access to health facilities requires the understanding of the geography of these subjects and this can only be achieved through the use of Geographic Information Systems (Najafabadi, 2009).

GIS have a very wide range of applications in the field of health such as:

• Visualization, trend and correlation analysis of epidemiological data
• Epidemic expansion monitoring
• Scenario analysis for decision support
• Mapping and correlating health issues with geographic regions
• Use of satellite imagery to extrapolate data and correlate information on atmospheric conditions, temperature, soil conditions etc with medical data and conditions
• Health infrastructure management such as identifying the most prominent location to setup a new hospital
• Publication of health related data such as health infrastructure installation locations, epidemics etc.

All the above items are directly connected to quality in health as they can be crucial in maintaining a high level of awareness with regard to the variety of factors that can affect public and personal health.

GIS tools that can be used for health applications

Buffers: This is one of the most useful GIS tools specific to geographic analysis. It provides the user with the ability to create a zone / buffer around a specific subject / phenomenon. For example the user can create a buffer of specific radius around the location of a chemicals' factory and then combine the resulting buffer with a function that provides as a result the number of cancer patients in relation to the distance from the factory. The user may also opt to acquire the number of cancer patients inside the buffer zone. This way buffering can also be used to identify the rate with which the number of cancer patients increase or decrease in relation to the distance from the factory.

Spatial and Temporal Analysis: GIS provides a multitude of tools to analyze data on a spatial as well as on a temporal basis overlaying temporal information over spatial information. Spatial Analysis tools allow the user / researcher to visualize the data relevant to the subject he/she is working on by using isopleth or choropleth lines, contour lines, ranges and check the spatial correlation of the data (Balaji) as for example the area where a specific virus can be located. This way the user can identify not only the medical but also the spatial and geographic qualities of the research area that can lead to the specific virus appearing.

The use of temporal analysis allows the combination of spatial data with the parameter of time and thus the user can now monitor the spatial and temporal evolution of a phenomenon as well as make projections for the future of the evolution based on trend and correlation analysis.

For example, specific atmospheric conditions combined with specific geographical conditions of an area allows for a pathogen to thrive. Monitoring this pathogen on spatial and temporal level can allow the user to detect the parameters that affect the evolution of the pathogen and thus support the decision process on how to prevent this pathogen from spreading or even appearing again thus enhancing the level of the quality of health in that specific region.

Mapping and Visualization: The most basic ability and capacity of a GIS is the visualization of data in the form of maps. The user can visualize on the maps the relevant data using a variety of thematic mapping techniques.

A very important example is taken from Longley, Goodman, Maguire και Rhind who used a GIS application in order to monitor poliomyelitis in India while being able to track the virus and correlate it with specific geographic characteristics that allowed for the virus to appear. Using this data they were able to create a model and plan to support the effort of fighting the appearance of the virus instead of only trying to cure it (Longley, Goodchild, Maguire, & Rhind, 2005).

Network Analysis: GIS provide the ability to analyze information being provided in the form of a network. For example, the road network can be used to transfer a disease simply by moving diseased animals from one location to the other. Analyzing the network can provide information about the areas that the animals went through and in combination with all other relevant to the disease data such as environmental conditions, atmospheric conditions, geography etc a set of scenarios about the spread of the disease can be created along with the strategies to mitigate the risks and results.

Network analysis can also be used in order to identify areas that would benefit from the installation of a new hospital. Both Roovali & Kiivet and Jordan et al used versions of the same technique (travel time) to identify the covariance and correlation between the use of a hospital in relation to the distance from it and thus leading to a model for the creation of new hospitals (Roovali & Kiivet, 2006), (Jordan, Roderick, Martin, & Barnett, 2004) and thus supporting a higher level of quality in public health.

Statistical Analysis: Statistical Analysis can be used to calculate statistical data and statistical correlations between the data. For example, statistical analysis can be used to correlate the appearance of cancer incidents in relation to the distance from a nuclear power plant. It can also be used to calculate the number of victims that a hospital can care for after a large accident in relation to its distance from the location of the accident.

Querying: GIS provide the ability to create dynamic queries and combine data from a variety of data sources.

Interpolation and Data Extraction: Using modeling techniques "new" data can be created for areas where data does not exists using interpolation.

References

Balaji, L. GIS in Health. UNICEF, India Country Office, Monitoring & Evaluation Section.

Jordan, H., Roderick, P., Martin, D., & Barnett, S. (2004). Distance, rurality, and the need for care: access to health services in South West England. Int. J. Health Geograph .

Longley, P., Goodchild, M., Maguire, D., & Rhind, D. (2005). Geographic Information Systems and Science 2005. Wiley.

Najafabadi, A. T. (2009, October). Application of GIS in Health Sciences. Shiraz E Medical Journal , 10, σσ. 221-230.

Roovali, L., & Kiivet, R. (2006). Geographical variations in hospital use in Estonia. Health & Place , σσ. 195-202.

Pitilakis K.¹, Anastasiadis A.², Alexoudi M.³, ArgyroudisS.⁴

1. Professor, Aristotle University of Thessaloniki, Department of Civil Engineering, Αυτή η διεύθυνση ηλεκτρονικού ταχυδρομείου προστατεύεται από τους αυτοματισμούς αποστολέων ανεπιθύμητων μηνυμάτων. Χρειάζεται να ενεργοποιήσετε τη JavaScript για να μπορέσετε να τη δείτε..

2. Professor, Aristotle University of Thessaloniki, Department of Architecture, Αυτή η διεύθυνση ηλεκτρονικού ταχυδρομείου προστατεύεται από τους αυτοματισμούς αποστολέων ανεπιθύμητων μηνυμάτων. Χρειάζεται να ενεργοποιήσετε τη JavaScript για να μπορέσετε να τη δείτε..

3. Civil Engineer, MSc, Aristotle University of Thessaloniki, Department of Civil Engineering, Αυτή η διεύθυνση ηλεκτρονικού ταχυδρομείου προστατεύεται από τους αυτοματισμούς αποστολέων ανεπιθύμητων μηνυμάτων. Χρειάζεται να ενεργοποιήσετε τη JavaScript για να μπορέσετε να τη δείτε..

4. Civil Engineer, Aristotle University of Thessaloniki, Department of Civil Engineering, Αυτή η διεύθυνση ηλεκτρονικού ταχυδρομείου προστατεύεται από τους αυτοματισμούς αποστολέων ανεπιθύμητων μηνυμάτων. Χρειάζεται να ενεργοποιήσετε τη JavaScript για να μπορέσετε να τη δείτε..

Introduction

The "smart" organization of the health network through modern hospital units is of special importance as it represents the level of social welfare of a country. Modern hospital units are not only characterized by the infrastructure (buildings) or the installations inside them, but also by a multitude of parameters such as their "smart" location within the urban fabric, population criteria, proper architectural design of the individual buildings as well as the hospital complex, transportation means and by their independence of any lifelines (e.g. by possessing of alternative power sources). Efficient planning of the health care system is a multidimensional task, as it includes land-planning as well as organization and management of the system in regional and local level for normal, crisis and recovery periods.

Earthquakes constitute emergency situations with particularly harmful consequences on human life, living conditions, economic and cultural activities and the built environment. The Hellenic area is characterized by high seismicity and a significant frequency of catastrophic seismic events within large (e.g. Thessaloniki, 1978, Athens, 1999) and medium size (e.g. Kalamata, 1986, Aeghio, 1995, Kozani, 1995) urban environments and touristic (e.g. Lefkas, 2003) areas. Facing of such disastrous events requires an efficient operational plan that will be based on a multi-level approach, taking into account the distinctive features of the study area and of the other elements at seismic risk. The health care system and especially the hospital units play a primary role in successfully facing the direct effects of a catastrophic earthquake concerning the most valuable resource, human life. Thus, they constitute an essential factor in operational planning, while the minimization of damages in all the components of the system and the ensuring of its access and function conditions are of vital importance.

The damages that are usually recorded as a result of seismic events could be classified as:

-          Damage to the structural elements, meaning damage to the bearing system of the building 
           (e.g. columns, beams and slabs for reinforced concrete buildings).

-          Damage to the non-structural elements (e.g. internal walls or glass partitions).

-          Damage to the installations and lifelines (e.g. elevators, water networks, electric power networks).

Table 1 presents common types of damage in lifeline networks and non-structural elements of hospital units, as observed in earthquakes all over the world. Table 2 shows indicative cases of damage in four hospitals, as recorded after the 1997, Umbria-Marce (Italy) earthquake.

The damage observed after strong earthquakes in hospital complexes all over the world in combination with the importance of the medical care system, contributed to the activation of various state authorities/services and research groups. Indicative research studies are those of Masri et al. (2004), Lewis and Wang (2004), Kuwata and Takada (2003), Guevara and Alvarez (2000), Poland (1994) egarding the seismic risk assessment and management of hospitals. In Greece, no integrated study for the seismic risk of hospitals has been performed, however there are cases where the structural seismic fragility was examined (Stylianidis et al., 2003).

Methodology for the seismic risk analysis of hospitals

In the present study an integrated methodology is proposed (Figure 1) which is offered for the improvement of the existing hospitals’ management sufficiency in crisis period (earthquake), while it can also significantly contribute to the design and construction of new hospital facilities.

The basic steps of the proposed methodology are developed below:

1. Identification of the functions performed in each hospital or each building, in the case of a complexfacility, and inventory of the structural characteristics. All hospitals together should be treated as a global network.

2. Seismic hazard analysis - Selection of the seismic scenarios: The design of hospitals, like the design of standard buildings, is based on regulations (e.g. Greek Aseismic Code 2000) and special provisions that define the imposed seismic loads. However, the realistic seismic design, the vulnerability assessment of existing structures and the development of emergency plans, require a more advanced and specialized description of the expected seismic hazard. The seismic hazard is defined as the probability P of a certain ground motion parameter (acceleration, velocity, displacement) exceeding a specific value within a period of T years.

It can be performed deterministically (selection of seismic events that occurred in historical or modern years) or probabilistically. The analytical assessment of the seismic ground motion parameters is performed through specialized microzonation studies, taking into account the local soil conditions. In figure 2, together with the locations of the hospitals and clinics, the distribution of the expected peak ground accelerations for the central area of Thessaloniki is illustrated, as derived from the microzonation study of the city for a return period of 475years (Anastasiadis et al. 2002). The microzonation study is based on the results of the seismic hazard analysis and the probabilistic study of the greater area's seismicity (Alexoudi et al., 2002)

3. Definition of the elements and sub-elements that comprise the hospital and the relation between them through"logic diagrams". The basic elements of a hospital complex, mainly in a crisis period, are the operating theaters, radiology departments, laboratories, pharmacies, critical installations and lifelines that serve the needs of the complex hospital facilities and connect it with the urban fabric (e.g. water and waste water, electric power, communication networks). Moreover, internal installations (e.g. elevators) and medical equipment could be considered as sub-elements of the hospital. An indicative “logic diagram” (Figure 4) was produced by Nuti et al. (1999) for a hospital complex in Italy.

4. Definition of the “Fault Tree”. The “Fault tree” graphically defines the organization of the hospital, while its branches define all the possible ways in which a “top event” may occur. The failure of the hospital, which can be characterized as a “top event”, is based on serial or parallel connections between the elements or the sub-elements. If there is a serial connection, the failure of one element influences all the other elements or sub-elements that depend on it. Otherwise, a parallel connection provides several alternative routings that can improve the final response of the hospital complex. The failure of each element or sub-element is defined by fragility curves, which correlate the strong motion parameters with the probability of exceeding a specific damage state (minor, moderate, extensive, complete damage). Fragility curves can be defined analytically, statistically or by engineering judgment using the “logic diagrams” mentioned above. Finally, the site and case-specific fragilities can be obtained for the particular organization and structure of the hospital facilities, equipment and buildings. An example of a fragility curve for a complex hospital is illustrated in Figure 5.

5. Calculation of urban vulnerability: Although a hospital is mainly influenced by the medical equipment and personnel, it interacts directly with the urban environment from which its patients come. Lifelines can act as a link between the hospital and the urban environment as they supply water, energy and communication (Figure 6). Moreover, the transportation system is essential for transporting patients and injured persons to the hospital facilities (Figure 7).

The response of the road network includes the estimation of potential damage to bridges, tunnels and roads and more generally the determination of road blockage as a result of building debris (Αrgyroudis, 2004). The definition of serviceability level of the transportation network is accomplished through the calculation of travel time for the transfer of injured people to the hospital. The optimization of time through the definition of more secure and faster routes appoints the extent of interaction between the urban environment and an effective hospital network. 

6. Estimation of hospital’s ‘global value’: The classification of the hospital’s importance is based on various criteria such as the provided services (e.g the type of clinics), operational (e.g number of beds, available personnel) and urban (distance from urban areas, location in urban environment). The hierarchy of importance plays an important role in emergency situations. The “urban system analysis” that classifies the importance of the elements at risk is carried out for three periods: a) Normal: It includes the phase before the catastrophic event. b) Crisis: it is the disaster period and the following few hours. c) Restoration: It starts immediately after the crisis and is related to the recovery progress of facilities and activities that were damaged or malfunctioned during crisis period.

The definition of hospital’s global value is directly connected to the urban organization of the city, the population and building density, the distribution of open spaces, land uses and with the framework of building provisions in general.

The hospitals are classified in to two categories, according to urban and building organization:

-  inside the urban agglomeration, placed in central areas of the city, with high densities and buildingcoefficients.

-     in areas with low structural density, inside the urban agglomeration, or outside, in the urban unit of the city.

7. Proposals for the mitigation of seismic risk through appropriate pre-earthquake interventions in the weak parts of the system together with the preparation of emergency plans and efficient restoration policies. For all of the above a full cooperation of Public Authorities and the Organisations managing the networks is needed.

Conclusions - Suggestions

The medical care system is undoubtedly of vital importance, especially in emergency situations (e.g. earthquakes). International experience reveals that this system could be quite vulnerable in earthquakes not only because of its structural vulnerability, but mainly as a result of the non-structural vulnerability of elements and sub-elements within hospital units. Moreover, the internal and external interactions between hospital networks and lifelines or transportation systems of the urban fabric, greatly influence the response of the system.

In this paper, the basic principles of an integrated methodology for the seismic risk assessment of the medical care system were presented, considering the various parameters that define the response not only of individual hospital units but of the global network as well. This kind of approach is deemed essential, as it proposes effective and technologically viable solutions for the ‘smart’ design, improvement and organization of hospitals.

An efficient management policy includes the following:

• Mitigation of the seismic risk through:

-          Seismic retrofitting of the bearing system of the buildings, in cases of high structural vulnerability and importance (global value).

-          Pre-earthquake reinforcement measures and anchorage of the critical hospital equipment.

-          ‘Intelligent’ building organization and architectural design of hospitals.

-          Functional sufficiency according to the basic regulations or codes such as fire safety, escape routes etc.

-          Application of safety measures against environmental pollution or technological accidents.

-          Efficient function of the transportation networks.

• Development of emergency plans with emphasis placed on:

-          Anticipation of outdoor open areas in order to temporarily house some of the hospital services if evacuation of the buildings is required after the earthquake.

-          Usage of new technologies (e.g. GIS, GPS) for the efficient transit of ambulance to the hospitals.

-          Definition of emergency routes and, possibly also emergency traffic lanes and helicopter landing locations for the transportation of injured persons.

-          Special well-organized areas for the reception of the public (first aid) inside the hospitals.

-          Measures against dysfunction/ malfunction of lifeline networks by predicting alternative routing, second supply tanks and mobile communication.

References

Alexoudi Μ. (2004) “Seismic risk management of lifelines in urban environments” PhD Thesis, Civil Engineer Department AUTh (in progress, Greek).

Alexoudi M., Hatzigogos Th. and Pitilakis K.(2002) “Earthquake-Hazard Assessment in Thessaloniki- Level I- Probabilistic & Deterministic Approach” in Proc. of International Conf. Earthquake Loss Estimation & Risk Reduction, ELE&RR Bucharest, Romania.

Anastasiadis A., Apessou M., Pitilakis K. (2002) “Earthquake- Hazard Assessment in Thessaloniki- Level II- Site Response Analyses” in Proc. of International Conf. Earthquake Loss Estimation & Risk Reduction, ELE&RR 2002, Bucharest, Romania.

Αrgyroudis S. (2004). “Seismic vulnerability assessment of transportation systems and infrastructure” PhD Thesis, Civil Engineer Department AUTh (in progress, Greek).

De Sortis A.., Di Pasquale G., Orsini G., Sano T, Biondi S., Nuti C., Vanzi L. (2000). “Hospitals behaviour during the September 1997 Earthquake in Umbria and Marche (Italy)”. Proceedings of 12^th World Conference on Earthquake Engineering

Guevara T. and Alvarez Y. (2000). “Functionality of the Architectural Program in the Remodeling of Existing Hospitals in Seismic Zones of Venezuela”. Procedings of 12^th World Conference on Earthquake Engineering, Auckland , New Zealand, January 30 - February 4.

Lewis J. and Wang M., (2004). “Seismic Risk Mitigation of Operational and Functional Components in Hospitals-The British Columbia Experience”. Proceedings of 13^th World Conference on Earthquake Engineering, Vancouver, B.C., Canada, August 1-6.

Masri S., Caffrey J., Myrtle R., Nigbor R., Agbabian M., Johnson E., Petak W., Shiozuka M., Tasbihgoo F., Tranquada R., Wellford L., (2004). “The FEMA-USC Hospital Project: Nonstructural Mitigation in Hospitals”. Proceedings of 13^th World Conference on Earthquake Engineering, Vancouver, B.C., Canada, August 1-6.

Nuti C., Vanzi I. and Ferrini M. (1999).  “Structural and non structural interventions for seismic retrofitting of existing hospitals. case studies of system approach for upgrading two hospitals in Tuscany”. Proceedings of the Workshop on Design and Retrofitting of Hospitals in Seismic Areas, Florence, October 21- 22.

Kuwata Y. and Takada S., (2003). “Seismic Risk Assessment and Upgrade Strategy of Hospital-Lifeline Performance”. Proceedings of the 6th U.S. Conference on Lifeline Earthquake Engineering, TCLEE, Long Beach, August 10-13.

Poland C., (1994). “Repair and Retrofit of Health Care Facilities”. Earthquake Spectra, Vol. 10, No. 1.

Stylianidis, Κ.Χ., Kappos, Α. Ι., Penelis G.G, Ignatakis, Χ.Ε, Karakostas Χ.Ζ. (2003) “Pre-earthquake assessment of hospital and Schools in Central Macedonia” 14^th National Reinforce Conference, Kos, Vol.C, pp. 539-550 (in greek).

Ιωάννης Φούζας

Επίκουρος Καθηγητής

Χειρουργική Κλινική Μεταμοσχεύσεων Α.Π.Θ.

Ιπποκράτειο ΓΝΘ

Η μεταμόσχευση είναι μία ιατρική πράξη κατά την οποία υγιή όργανα, ιστοί ή κύτταρα μεταφέρονται από ένα νεκρό ή ζωντανό δότη σε έναν χρονίως πάσχοντα άνθρωπο με σκοπό την αποκατάσταση της λειτουργίας των οργάνων του. Η μεταμόσχευση, η οποία αποτελεί μία από τις μεγαλύτερες κατακτήσεις της ιατρικής του 20ού αιώνα και έχει καθιερωθεί πλέον σήμερα ως μία θεραπευτική πρακτική, επιτρέπει την αποκατάσταση των λειτουργιών του σώματος που είχαν μέχρι εκείνη τη στιγμή χαθεί και σε μερικές περιπτώσεις είχαν μερικώς υποκατασταθεί με μία μηχανικού τύπου μέθοδο. Τα ποσοστά επιτυχίας των μεταμοσχεύσεων έχουν αυξηθεί σημαντικά τα τελευταία χρόνια, ενώ η εχει μειωθεί η θνητότητα και οι μετεγχειρητικές επιπλοκές.

Η μεταμόσχευση του ήπατος έχει αλλάξει τη φυσική ιστορία της βαριάς μη αναστρέψιμης οξείας ή χρονίας ηπατικής ανεπάρκειας από οποιαδήποτε αιτία. Πριν από τη μεταμόσχευση οι ασθενείς με προχωρημένη ηπατική ανεπάρκεια πέθαιναν μέσα σε μήνες ή λίγα χρόνια. Σήμερα, το 80-90% των  ασθενών που μεταμοσχεύονται επιβιώνει τον πρώτο χρόνο, ενώ η 5-ετής και η 10-ετής επιβίωση ανέρχονται στο 70 % και 65 %, με εξαιρετική ποιότητα ζωής. Η γενίκευση αυτής της θεραπευτικής τεχνικής περιορίζεται, όμως, από την έλλειψη μοσχευμάτων.

Η έλλειψη ηπατικών μοσχευμάτων αντιμετωπίζεται, μεταξύ άλλων και με την τμηματική μεταμόσχευση ήπατος, μία νέα χειρουργική τεχνική η οποία συνίσταται στην εκτομή τμημάτων του ήπατος από ζώντες ή πτωματικούς δότες και τη μεταμόσχευση τους στους λήπτες (παιδιά και ενήλικες). Bασίζεται στη λειτουργική ανατομική και την αναγεννητική ικανότητα του ήπατος, η οποία επιτρέπει τον διαχωρισμό του σε επιμέρους τμήματα, με αυτόνομη αγγείωση και παροχέτευση και επαρκή μάζα ηπατοκυττάρων γιά να καλύψουν τις μεταβολικές ανάγκες τόσο του δότη όσο και του λήπτη, ενώ ταυτόχρονα αναγεννώνται. 

H τμηματική μεταμόσχευση ήπατος προήλθε από μία σειρά εγχειρητικών επινοήσεων οι οποίες είχαν ως στόχο την αντιμετώπιση της δραματικής αύξησης των ληπτών ηπατικών μοσχευμάτων, σε σχέση με τους διαθέσιμους πτωματικούς δότες. Ειδικότερα, το αρχικό κίνητρο γιά την τροποποίηση της κλασικής τεχνικής της ορθοτοπικής μεταμόσχευσης ήπατος ήταν έλλειψη παιδιατρικών πτωματικών μοσχευμάτων, με αποτέλεσμα η θνητότητα στις λίστες αναμονής παιδιατρικών ασθενών να ξεπερνά το 25%, σε ορισμένα μεταμοσχευτικά κέντρα   Η προσπάθεια για την αντιμετώπιση αυτού του προβλήματος οδήγησε, αρχικά, στη μεταμόσχευση μειωμένου μεγέθους πτωματικών μοσχευμάτων ενηλίκων (reduced-size liver transplantation, RLTx, Bismuth, 1984),  ενώ στη συνέχεια αναπτύχθηκαν οι τεχνικές του ex vivo (Pichlmayr, 1988) και του in situ (Rogiers και Broelsch, 1995) διαχωρισμού των ηπατικών μοσχευμάτων (split liver transplantation, SLTx),   της μεταμόσχευσης τμήματος του ήπατος ζώντων ενηλίκων δοτών σε παιδιά (adult-to-pediatric living donor liver transplantation, pLDLTx, Strong 1990 και Broelsch 1991) και τελικά της μεταμόσχευσης τμήματος του ήπατος ζώντων ενηλίκων δοτών σε ενήλικες (adult to adult living donor liver transplantation, aLDLTx, Hashikura 1994)  .

Η μεταμόσχευση από συγγενείς δότες έχει αναδειχθεί σε σημαντικό παράγοντα αύξησης του αριθμού των ηπατικών μοσχευμάτων και έχει διενεργηθεί σε περισσότερα από 14000 παιδιά και ενήλικες, από το 1989 μέχρι το 2007  .  Τα πλεονεκτήματα της LDLTx, σε σχέση με την μεταμόσχευση από πτωματικό δότη, είναι ότι μπορεί να προγραμματισθεί πριν η κατάσταση του λήπτη επιδεινωθεί σε μη αναστρέψιμο σημείο, να επιλεγεί ο καλύτερος δυνατός δότης, με μόσχευμα με πολύ μικρό χρόνο ψυχρής ισχαιμίας, ενώ προσφέρει και την δυνατότητα επέκτασης των κριτηρίων επιλογής των ληπτών  και τελικά μειώνει   τη θνητότητα σε σχέση με την παραμονή στη λίστα αναμονής  .  Από την άλλη πλευρά, η επέμβαση παρουσιάζει δυνητική νοσηρότητα και θνητότητα 200% (100% για τον δότη και για τον λήπτη) και πρέπει να αποφασίζεται και να διενεργείται με πολλή προσοχή, από εξειδικευμένα κέντρα.

Τα κριτήρια επιλογής διαφέρουν στις διάφορες χώρες του κόσμου, ανάλογα με τις νομικές και πολιτιστικές ιδιαιτερότητες.  Η ηλικία του δότη, στις περισσότερες χώρες, είναι μεταξύ 18 και 60 ετών. Οι μεγαλύτεροι σε ηλικία δότες παρουσιάζουν αυξημένο κίνδυνο για αδιάγνωστα προβλήματα υγείας. Επιπλέον, πιστεύεται ότι η ηλικία επηρεάζει την αναγεννητική ικανότητα του ήπατος, με συνέπειες τόσο στον δότη όσο και στον λήπτη  . Η  ομάδα αίματος του δότη πρέπει να είναι ταυτόσημη ή συμβατή με εκείνη του λήπτη.  Σε ειδικές περιπτώσεις μπορεί να διενεργηθεί μη συμβατή μεταμόσχευση, όπως σε βρέφη μικρότερα του ενός έτους που δεν έχουν αναπτύξει ακόμη αντισώματα έναντι των ομάδων αίματος ή σε επείγουσες περιπτώσεις στις οποίες δεν υπάρχει συμβατό πτωματικό μόσχευμα Πρόσφατα, έχουν δημοσιευθεί μικρές σειρές με επιτυχείς μη συμβατές μεταμοσχεύσεις μετά από έντονη ειδική προετοιμασία απευαισθητοποίησης  .

Ο προεγχειρητικός έλεγχος γίνεται με συγεκριμένο πρωτόκολο και αποσκοπεί τόσο στην αποφυγή επιπλοκών από τον δότη, όσο και στην εξασφάλιση του καταλληλότερου μοσχεύματος για τον λήπτη. Ο έλεγχος γίνεται κατά στάδια, από τις λιγότερο προς τις περισσότερο επεμβατικές εξετάσεις, αλλά ταυτόχρονα πρέπει να αποκλείει τους ακατάλληλους δότες όσο το δυνατόν νωρίτερα  (Πίνακας 1) ²¹.

Ο προεγχειρητικός απεικονιστικός έλεγχος αποσκοπεί στην εκτίμηση της επάρκειας του όγκου του ηπατικού παρεγχύματος, στη διαλεύκανση της ανατομικής των αγγείων του ήπατος  και των χοληφόρων και στον σχεδιασμό της επεμβάσεως.

Η προεγχειρητική εκτίμηση της επάρκειας του όγκου του ηπατικού παρεγχύματος, τόσο για τον δότη όσο και για τον λήπτη,  διενεργείται με βάση με δύο μεθόδους : α. το επί τοις εκατό ποσοστό που αποτελεί ο όγκος του μοσχεύματος σε σχέση με τον κατ' εκτίμηση φυσιολογικό όγκο ήπατος του λήπτη (standard liver volume, SLV), με βάση σωματομετρικές εξισώσεις ^24-27 και β. το επί τοις εκατό ποσοστό που αποτελεί το βάρος του μοσχεύματος σε σχέση με το βάρος του σώματος του λήπτη (Graft Weight/Recipient Body Weight Ratio, GW/RBW) ²⁸.

Οι τύποι των ηπατικών μοσχευμάτων που χρησιμοποιούνται στις μεταμοσχεύσεις απο ζώντα δότη είναι: 1. Tο δεξιό ήπαρ (τμήματα V-VIII, ~ 800-1000 ml, για ενήλικα βάρους £ 80 Kgr), 2. Tο αριστερό ήπαρ (τμήματα II-IV), με ή χωρίς το τμήμα I, ~ 400 ml για ενήλικα βάρους £ 60 Kgr), 3. O αριστερός λοβός ή αριστερό έξω πλάγιο τμήμα (τμήματα II και III, ~250 ml, για ένα παιδί), 4. O δεξιός λοβός ή δεξιό εκτεταμένο μόσχευμα (τμήματα I, IV, V-VIII, ~ 1100 ml, για ενήλικα βάρους ³ 80 Kgr) και 5. O δεξιός οπίσθιος τομέας (τμήματα VI και VII, ) Το αριστερό έξω πλάγιο τμήμα  μπορεί να διαχωρισθεί περαιτέρω και να χρησιμοποιηθεί μόνο το τμήμα ΙΙΙ για μεταμόσχευση σε μικρά βρέφη και νεογνά^33-35.

Eικόνα 1. Διαφορές μεταξύ της αμερικανικής και της ευρωπαϊκής βιβλιογραφίας ως προς την ονοματολογία των τμηματικών ηπατικών μοσχευμάτων. Oι διαφορές αυτές οφείλονται στο ότι δεν έχει υπάρξει ομοφωνία ως προς την λειτουργική ανατομική διαίρεση του ήπατος. H σημαντικότερη διαφορά μεταξύ των δύο ταξινομήσεων αφορά το κριτήριο για την διαίρεση του ήπατος. Oι Αμερικανοί Healey και  Schroy, καθώς και οι Goldsmith και Woodburne,^{36, 37} χρησιμοποίησαν τους κλάδους του χοληφόρου δένδρου ως οδηγό για την διαίρεση του ήπατος, ενώ οι Γάλλοι Couinaud και Bismuth ^{2, 3, 37} χρησιμοποίησαν τις διακλαδώσεις της πυλαίας φλέβας.

Η πολύπλοκη ανατομική των αγγείων του ήπατος, καθώς και το υψηλό ποσοστό παραλλαγών καθιστά αναγκαία την ακριβή προεγχειρητική απεικόνιση. Στα αρχικά στάδια, οι ζώντες δότες υποβάλλονταν σε επεμβατικές μεθόδους, όπως η αγγειογραφία της αορτής και της ηπατικής αρτηρίας, με όλους τους σχετικούς κινδύνους και επιπλοκές ³⁸. Σήμερα, προτιμώνται λιγότερο επεμβατικές, αλλά το ίδιο αξιόπιστες μέθοδοι όπως η αρτηριογραφία με αξονικό τομογράφο πολλαπλών ανιχνευτών (Multi-detector computer tomography, MDCT) ή μαγνητική αρτηριογραφία ^{30, 40}. Τα δεδομένα των συνδυασμένων απεικονιστικών τεχνικών μπορούν να κατεργασθούν με ειδικό λογισμικό και να παρουσιασθούν σε τρισδιάστατη μορφή για τον σχεδιασμό της ηπατεκτομής (MeVis Liver-Analyzer and Liver-Viewer, Bremen, Germany). Επιπλέον, η κατεργασία των ανωτέρω δεδομένων με το λογισμικό HepaVision (MeVis, Bremen, Germany) επιτρέπει: α. την τρισδιάστατη λειτουργική απεικόνιση της αγγειακής ανατομικής του ήπατος και των περιοχών που αιματώνονται ή παροχετεύονται από κλάδους της ηπατικής αρτηριας, της πυλαίας φλέβας και των ηπατικών φλεβών, β. την τρισδιάστατη απεικόνιση του χοληφόρου δένδρου, γ. ογκομετρία των τμημάτων του ήπατος, δ. σχεδιασμό του επιπέδου διατομής του ήπατος και εκτίμηση του κινδύνου  (risk analysis) φλεβικής συμφορήσεως, ανάλογα με την κατανομή των ηπατικών φλεβών (hepatic vein dominance) ^44-47.

Εικόνα 2. Τρισδιάστατη απεικόνιση των αγγείων και των χοληφόρων του ήπατος και σχεδιασμός της ηπατεκτομής σε ζώντα δότη με το λογισμικό HepaVision -  MeVis ^43-47.

Όταν ο δότης φθάσει μέχρι το χειρουργείο μετατρέπεται σε ασθενή και απαιτεί από την χειρουργική ομάδα απόλυτη αφιέρωση στην αποφυγή επιπλοκών και στην εξασφάλιση του καλύτερου δυνατού αποτελέσματος για τον λήπτη ⁴⁸. H τεχνική της ηπατεκτομής σε ζώντες δότες έχει καθοριστική σημασία για την βιωσιμότητα και την αναγεννητική ικανότητα τόσο του ηπατικού κολοβώματος στο δότη, όσο και του μοσχεύματος . Για να επιτευχθεί αυτό πρέπει να εξασφαλισθεί η ακεραιότητα της παροχής αρτηριακού και πυλαίου αίματος και της παροχέτευσης τόσο του φλεβικού αίματος όσο και της χολής.

Η τελική επιλογή του είδους και της έκτασης της ηπατεκτομής γίνεται διεγχειρητικά με βάση τις ανάγκες του λήπτη για ηπατικό παρέγχυμα, τα ανατομικά ευρήματα, το διεγχειρητικό υπερηχογράφημα, την προηγούμενη απεικόνιση των χοληφόρων και την διεγχειρητική χολαγγειογραφία.

Η ασφάλεια του δότη είναι πρωταρχικός στόχος κατά τη LDLTx. Καθώς η εφαρμογή της LDLTx προχώρησε από τους ενήλικες στα παιδιά και από το αριστερό στο δεξιό ηπατικό μόσχευμα, το δίλημα μεταξύ της επιτυχίας στον λήπτη και της ασφάλειας του δότη ήλθε στο προσκήνιο. Το ποσοστό επιπλοκών του δότη είναι περίπου 20%, αλλά φθάνει μέχρι το 67% σε μία ανασκόπηση  . Το εύρος αυτό πιστεύεται ότι θα μειωθεί με την εφαρμογή ενός ενοποιημένου συστήματος αναφοράς των μετεγχειρητικών επιπλοκών  . Επιπλέον, ποικίλλει και η βαρύτητα των αναφερομένων επιπλοκών. Η πλειονότητα των επιπλοκών αφορά την διαπύηση του τραύματος και ακολουθεί ο μετεγχειρητικός ειλεός και η διαφυγή από τα χοληφόρα, η οποία μειώνεται καθώς αυξάνεται η εμπειρία του μεταμοσχευτικού κέντρου  .

Ο θάνατος του δότη είναι δραματική επιπλοκή της LDLTx και μέχρι τον Ιούνιο του 2007 έχουν ανακοινωθεί επίσημα 12 περιπτώσεις από τα μεταμοσχευτικά κέντρα  . Επιπλέον, υπάρχουν έμμεσες ανεπιβεβαίωτες αναφορές και για 21 ακόμη θανάτους ζώντων δοτών  . Οκτώ θάνατοι δοτών έχουν αναφερθεί στην Ευρώπη, 8 στις ΗΠΑ, 10 στην Ασία και 2 στην Νότια Αφρική  . Η θνητότητα εκτιμάται ότι είναι 0.1-0.3% στις 14000 ηπατεκτομές σε ζώντες δότες που έχουν γίνει μέχρι τον Ιούνιο του 2007 και ανέρχεται στο 0.5% στους δότες δεξιού ήπατος   Με άλλα λόγια, για να επιτευχθεί πενταετής επιβίωση 80% στους λήπτες απαιτείται η ζωή ενός δότη για να σωθούν 160 λήπτες  .

Πέρα όμως από τις αμιγείς ιατρικές παραμέτρους  άλλοι δύο τύποι παραγόντων  πρέπει να λαμβάνονται και αυτοί υπ’ όψιν, ο παράγων  κόστους /ωφελείας  καθώς και παράγοντες απτόμενοι της βιοηθικής.

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